NANOPARTICLES

Abrahamson, J. and J. Dinniss (2000). "Ball lightning caused by oxidation of nanoparticle networks from normal lightning strikes on soil." Nature 403(6769): 519-21. Observations of ball lightning have been reported for centuries, but the origin of this phenomenon remains an enigma. The 'average' ball lightning appears as a sphere with a diameter of 300 mm, a lifetime of about 10 s, and a luminosity similar to a 100-W lamp. It floats freely in the air, and ends either in an explosion, or by simply fading from view. It almost invariably occurs during stormy weather. Several energy sources have been proposed to explain the light, but none of these models has succeeded in explaining all of the observed characteristics. Here we report a model that potentially accounts for all of those properties, and which has some experimental support. When normal lightning strikes soil, chemical energy is stored in nanoparticles of Si, SiO or SiC, which are ejected into the air as a filamentary network. As the particles are slowly oxidized in air, the stored energy is released as heat and light. We investigated this basic process by exposing soil samples to a lightning-like discharge, which produced chain aggregates of nanoparticles: these particles oxidize at a rate appropriate for explaining the lifetime of ball lightning. Acosta-Avalos, D., E. Wajnberg, et al. (1999). "Isolation of magnetic nanoparticles from pachycondyla marginata ants." Journal of Experimental Biology 202(Pt 19)(2): 2687-92. We report on the presence of magnetic iron oxides in the migratory ant Pachycondyla marginata. Magnetic particles were extracted from different parts of the ant (head, thorax and abdomen) using magnetic precipitation methods. Electron spectroscopic images for iron and oxygen were obtained from the extracted particles, and, by using the corresponding electron micrographs, histograms of size distribution were constructed. Selected area diffraction patterns were also obtained from the particles, and analysis of these showed the presence of a mixture of different iron oxides, including the magnetic oxides, magnetite and maghemite. The size distribution of the particles in the abdomen is different from that in the thorax and the head. In accordance with the hypothesis of magnetic orientation based on the presence of magnetic material within the body, two regions of the ant, the head and the abdomen, could be implicated in the detection of the geomagnetic field. Adachi, N., A. Maruyama, et al. (1994). "Cellular distribution of polymer particles bearing various densities of carbohydrate ligands." Journal of Biomaterials Science Polymer Edition 6(5): 463-79. The density effect of carbohydrate-ligands on nanometer-order particles (nanoparticles) upon cellular binding and internalization was investigated. Poly(vinylbenzyl-beta-D-lactonamide) (PVLA), a beta-galactose-carrying styrene homopolymer, was employed as a model ligand for the asialoglycoprotein receptors on hepatocytes. In order to control the surface ligand densities on the particles, PVLA was mixed with poly(vinylbenzyl-D-gluconamide) (PVGA), a PVLA analog without beta-galactose, and their mixtures were used as surface coatings. The particles with low ligand densities associated more with hepatocytes than high ligand density particles. The surface density of the ligand considerably influenced the cellular distribution. Most of the particles bearing high densities of ligands were found inside the cells, whereas particles with low ligand densities were found on the plasma membrane surface of the hepatocytes. These results were indicative of high densities of ligands on the surface requiring hepatocytes to internalize the particles promptly by receptor-mediated endocytosis, while low densities of ligands on the surface was not sufficient to internalize, but allowed particles to bind on the cell surface. These findings enabled us to regulate cellular distributions of particles by controlling ligand density on the surface. Ago, H., T. Komatsu, et al. (2000). "Dispersion of metal nanoparticles for aligned carbon nanotube arrays." Applied Physics Letters 77(1): 79-81. We report that Co metal nanoparticles (an average diameter of 4 nm) chemically synthesized by a reverse micelle method catalyzes the growth of multiwall carbon nanotubes (MWNTs) aligned perpendicular to a substrate. The surface of the nanoparticles is covered with surfactants so that the nanoparticles can be dispersed in organic solvent. The dispersion of the nanoparticles was cast directly onto a plane Si substrate for thermal pyrolysis of acetylene. We have found that the pretreatment of the metal nanoparticles with hydrogen sulfide before the pyrolysis straightens the MWNTs, suggesting sulfurization of the nanoparticle catalyst plays an important role in regular growth of the MWNTs. The dispersion of the nanoparticles offers a conventional and processible approach to synthesize large area aligned MWNT arrays. (21 References). Agostiano, A., M. Catalano, et al. (2000). "Synthesis and structural characterisation of CdS nanoparticles prepared in a four-components "water-in-oil" microemulsion." Micron 31(3): 253-8. Nanostructured semiconductor particles are currently under intense investigation because of their enhanced photoreactivity and photocatalytic properties due to the quantum-size effect and the dependence of the photophysical and photochemical properties on their size as it approaches the exciton diameter. This increasing interest has led to the development of several synthetic procedures to prepare and stabilise uniform crystallites. In this paper, we report a novel synthetic pathway to obtain cadmium sulphide (CdS) nanoparticles in a quaternary "water-in-oil" microemulsion formed by a cationic surfactant cetyltrimethylammonium bromide (CTAB),

pentanol, n-hexane and water. The synthesis of CdS in this system is achieved by mixing two microemulsions containing Cd(NO3)2 and Na2S, respectively. The nanocrystals have been characterised by using UV--visible spectroscopy and Transmission Electron Microscopy to investigate the influence of various parameters of the particles' formation and stability in solution. Capping of nanoparticles with suitable organic molecules has been performed in order to increase their stability and afford solubility in a wide range of solvents. Ahlin, P., J. Kristl, et al. (2000). "Influence of spin probe structure on its distribution in SLN dispersions." International Journal of Pharmaceutics 196(2): 241-244. Solid lipid nanoparticles (SLN) are drug carrier system composed of biodegradable substances, which are solid at room temperature. The physico-chemical properties and structure of the incorporated compounds can affect their partitioning in SLN dispersions. In this work the influence of lipophilicity and structure of different SP on its location in SLN were studied. By electron paramagnetic resonance (EPR) measurements it was found that lipophilic SP distribute between a solid glyceride core and a soft phospholipid layer, with the more polar part (piperidine ring or methylcarboxylic groups) oriented toward the water-lipid interface. The majority of SP is located in the phospholipid layer, but the portion in the solid lipid core increases with SP lipophilicity. The hydrophilic Tempol does not incorporate into SLN. Ahmadi, T. S., Z. L. Wang, et al. (1996). "Shape-controlled synthesis of colloidal platinum nanoparticles." Science 272(5270): 1924-6. The shapes and sizes of platinum nanoparticles were controlled by changes in the ratio of the concentration of the capping polymer material to the concentration of the platinum cations used in the reductive synthesis of colloidal particles in solution at room temperature. Tetrahedral, cubic, irregular-prismatic, icosahedral, and cubo-octahedral particle shapes were observed, whose distribution was dependent on the concentration ratio of the capping polymer material to the platinum cation. Controlling the shape of platinum nanoparticles is potentially important in the field of catalysis. Ahrahamson, J. and J. Dinniss (2000). "Ball lightning caused by oxidation of nanoparticle networks from normal lightning strikes an soil." Nature 403(6769): 519-21. Observations of ball lightning have been reported for centuries, but the origin of this phenomenon remains an enigma. The `average' ball lightning appears as a sphere with a diameter of 300 mm, a lifetime of about 10 s, and a luminosity similar to a 100-W lamp. It floats freely in the air, and ends either in an explosion, or by simply fading from view. It almost invariably occurs during stormy weather. Several energy sources have been proposed to explain the light, but none of these models has succeeded in explaining all of the observed characteristics. The authors report a model that potentially accounts for all of those properties, and which has some experimental support. When normal lightning strikes soil, chemical energy is stored in nanoparticles of Si, SiO or SiC, which are ejected into the air as a filamentary network. As the particles are slowly oxidized in air, the stored energy is released as heat and light. They investigated this basic process by exposing soil samples to a lightning-like discharge, which produced chain aggregates of nanoparticles: these particles oxidize at a rate appropriate for explaining the lifetime of ball lightning. (25 References). Akiyoshi, K., S. Kobayashi, et al. (1998). "Self-assembled hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs: complexation and stabilization of insulin." Journal of Controled Release 54(3): 313-20. Insulin (Ins) spontaneously and easily complexed with the hydrogel nanoparticle of hydrophobized cholesterolbearing pullulan (CHP) in water. The complexed nanoparticles (diameter 20-30 nm) thus obtained formed a very stable colloid. The thermal denaturation and subsequent aggregation of Ins were effectively suppressed upon complexation. The complexed Ins was significantly protected from enzymatic degradation. Spontaneous dissociation of Ins from the complex was barely observed, except in the presence of bovine serum albumin. The original physiological activity of complexed Ins was preserved in vivo after i.v. injection. Akiyoshi, K., Y. Sasaki, et al. (1999). "Molecular chaperone-like activity of hydrogel nanoparticles of hydrophobized pullulan: thermal stabilization with refolding of carbonic anhydrase B." Bioconjugate Chemistry 10(3): 321-4. We have been studying the formation of hydrogel nanoparticles by the self-aggregation of hydrophobized polysaccharide and the effective complexation between these nanoparticles as a host and various globular soluble proteins as a guest. This paper describes a new finding that refolding of the heat-denatured enzyme effectively occurs with the nanoparticles and beta-cyclodextrin according to a mechanism similar to that of a molecular chaperone. In particular, the irreversible aggregation of carbonic anhydrase B (CAB) upon heating was completely prevented by complexation between the heat-denatured enzyme and hydrogel nanoparticles formed by the self-aggregation of cholesteryl group-bearing pullulan (CHP). The complexed CAB was released by dissociation of the self-aggregate upon the addition of beta-cyclodextrin. The released CAB refolded to the native form, and almost 100% recovery of the activity was achieved. The thermal stability of CAB was drastically improved by capture of the unfolded form which was then released to undergo refolding.

Aliautdin, R. N., V. E. Petrov, et al. (1996). "[Transport of the hexapeptide dalargin across the hemato-encephalic barrier into the brain using polymer nanoparticles]." Eksp Klin Farmakol 59(3): 57-60. The drug targeting to the brain by polysorbate 80-coated nanoparticles was studied. The leu-enkephalin analog dalargin was used as a model drug for investigating the drug penetration through the blood-brain barrier. The nociceptive threshold was measured by the tail flick test. The intravenous injection of dalargin bound by sorption to poly(butylcyanoacrylate) nanoparticles subsequently coated with polysorbate 80 induced the analgesic effect in 5.0 and 7.5 mg/kg doses. The pretreatment with naloxone prevented this effect No other controls exhibited the analgesic activity, including the dalargin solution (10 mg/kg, i.v.), dalargin bound to nanoparticles not coated with polysorbate 80; and a simple mixture of dalargin, nanoparticles, and polysorbate 80 mixed directly before the intravenous injection. The luminescent and electron microscopy demonstrated the presence of separate nanoparticles in the capillary endothelium and cerebral neurons, as well as luminescent-labeled polymer in Purkinje's cells of the cerebellum. Aliautdin, R. N., V. E. Petrov, et al. (1998). "[The delivery of loperamide to the brain by using polybutyl cyanoacrylate nanoparticles]." Eksp Klin Farmakol 61(1): 17-20. The possibility of using polysorbate 80-coated nanoparticles for the delivery of the water insoluble opioid (lyonist loperamide across the blood-brain barrier was investigated. The analgesic effect after i.v. injection of the preparations was used as the indication of drug transport through this barrier. Intravenous injection of the particulate formulation resulted in a long and significant analgesic effect. A polysorbate 80 loperamide solution induced a much less pronounced and very short analgesia. Uncoated nanoparticles loaded with loperamide were unable to produce analgesia. Polysorbate 80-coated PBCA nanoparticles loaded with loperamide led to the transport of loperamide to the brain. Allemann, E., J. C. Leroux, et al. (1993). "In vitro extended-release properties of drug-loaded poly(DL-lactic acid) nanoparticles produced by a salting-out procedure." Pharmacetical Research 10(12): 1732-7. Savoxepine-loaded poly(DL-lactic acid) (PLA) nanoparticles were prepared using an emulsion technique involving a salting-out process which avoids surfactants and chlorinated solvents. After their formation, the nanoparticles were purified by cross-flow microfiltration and subsequently freeze-dried. The drug loading and the drug entrapment efficacy were improved by using savoxepine base rather than the methanesulfonate salt and by modifying the pH of the aqueous phase. A drug entrapment efficacy as high as 95% was obtained with a 9% drug loading. The overall yield of the procedure can rise up to 93%. In vitro release studies have demonstrated that by varying the mean size of the nanoparticles and their drug loading, the release of the drug from the nanoparticles can be modulated to last from several hours to more than 30 days, thus allowing the preparation of an injectable extended-release dosage form. Allemann, E., N. Brasseur, et al. (1995). "PEG-coated poly(lactic acid) nanoparticles for the delivery of hexadecafluoro zinc phthalocyanine to EMT-6 mouse mammary tumours." Journal of Pharmacy and Pharmacology 47(5): 382-7. Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in three vehicles: poly(D,L-lactic acid) (PLA) nanoparticles, polyethylene glycol (PEG)coated nanoparticles and a Cremophor EL (CRM) oil-water emulsion. Nanoparticles were prepared by the saltingout procedure. Biodistribution of the dye was assessed by fluorescence in EMT-6 mammary tumour bearing mice after intravenous injection of 1 mumol kg-1 ZnPcF16. Plain nanoparticles were rapidly retained by the reticuloendothelial system (RES) as reflected by the low area under the blood concentration-time curve (AUC0168, 57 micrograms h g-1). Little tumour uptake of the dye was observed with this formulation. In contrast, PEGcoated nanoparticles displayed a reduced RES uptake, leading to significantly higher blood levels over an extended period (t1/2 30 h; AUC 0-168 227 micrograms h g-1) and enhanced tumour uptake. At 48 h post injection, tumour to skin and tumour to muscle concentration ratios reached 3.5 and 10.8, respectively. Blood levels of ZnPcF16 after administration as a CRM emulsion decreased faster than with PEG-coated nanoparticles (t1/2 12 h), but since no early liver uptake was observed, the AUC0-168 and the tumour uptake were only slightly lower. However, with the CRM formulation, a late liver uptake was observed, reaching 51% of the injected dose after 7 days. Allemann, E., J. Rousseau, et al. (1996). "Photodynamic therapy of tumours with hexadecafluoro zinc phthalocynine formulated in PEG-coated poly(lactic acid) nanoparticles." International Journal of Cancer 66(6): 821-4. Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second-generation sensitizer for the photodynamic therapy (PDT) of cancer, was formulated in polyethylene-glycol-coated poly(lactic acid) nanoparticles (PEG-coated PLANP) and tested in EMT-6 tumour-bearing mice for its photodynamic activity. The tumour response was compared to that induced by the same dye formulated as a Cremophor EL (CRM) emulsion. Formulation in the biodegradable NP improved PDT response of the tumour while providing prolonged tumour sensitivity towards PDT. Allemann, E., P. Gravel, et al. (1997). "Kinetics of blood component adsorption on poly(D,L-lactic acid) nanoparticles:

evidence of complement C3 component involvement." Journal of Biomedical Materials Research 37(2): 229-34. After intravenous administration, nanoparticles suffer a major drawback in that they are rapidly and massively taken up by the cells of the mononuclear phagocyte system. The mechanisms involved in the opsonization, adhesion, and internalization of biodegradable nanoparticles by the mononuclear phagocyte system are still poorly understood. In this work, the kinetics of blood protein adsorption onto nanoparticles of poly(D,L-lactic acid) prepared by the salting-out technique was investigated. Nanoparticles of 312 nm were incubated for variable periods of time (5-60 min) in human serum and citrated plasma. After incubation, the particles were washed and the proteins detached from them, denatured, and analyzed by two-dimensional polyacrylamide gel electrophoresis. In plasma, the predominant protein was immunoglobulin G (IgG), and the amount adsorbed was not dependent on incubation time. Albumin amounts were high for short incubation periods but decreased as a function of time, whereas apolipoprotein E levels increased significantly as a function of the incubation period. Owing to the possible complement cascade inactivation by addition of citrate to plasma, the kinetics of adsorption was also evaluated in serum. In this medium, adsorption of complement C3 components onto the surface of the nanoparticles was clearly evidenced by spots of increasing intensity and area, reaching levels comparable to those of the omnipresent IgG. This result confirms the important role of complement components in the opsonization process of poly(D,L-lactic acid) particles. Allemann, E., J. Leroux, et al. (1998). "Polymeric nano- and microparticles for the oral delivery of peptides and peptidomimetics." Advanced Drug Delivery Reviews 34(2-3): 171-189. Due to recent advances, numerous bioactive peptides are now available in large quantities. Administering these substances by the oral route appears as a formidable challenge due to their insufficient stability in the gastrointestinal tract and their poor absorption pattern. Several approaches have been investigated to improve their oral bioavailability. Among them, the use of polymeric particulate delivery systems (microparticles and nanoparticles) represents a promising concept. Encapsulating or incorporating peptides in particles should at least protect these substances against degradation and, in some cases, also enhance their absorption. The aim of this paper is to review the principal studies where peptide-loaded particles were administered by the oral route. The preparation methods and in vitro trials are presented and in vivo results are discussed with emphasis placed on the peptide blood levels reached or on the biological effects observed. Whether or not intact particles can be taken up and translocated to the systemic circulation is not the aim of this review. Almeida, A. J. and H. O. Alpar (1996). "Nasal delivery of vaccines." Journal of Drug Targeting 3(6): 455-67. Only relatively recently the significance of inducing not only systemic immunity but also significant local immunity at susceptible mucosal surfaces has become appreciated. A new field of mucosal immunity has been established as information accumulates on mucosal-associated lymphoid tissue (MALT) and on its role in both local and systemic immune responses. This review describes the formation of vaccines to be delivered to one of MALT components, i.e. the nasal-associated lymphoid tissue (NALT), which bears some similarities with the Peyer's patches of the intestine. The association of antigens with adjuvants and particulate carriers such as microparticles, nanoparticles and liposomes is emphasised. Alonso, M. J., A. Sanchez, et al. (1990). "Joint effects of monomer and stabilizer concentrations on physico-chemical characteristics of poly(butyl 2-cyanoacrylate) nanoparticles." Journal of Microencapsulation 7(4): 517-26. A rotatable central composite design was applied to the formulation of poly(butyl 2-cyanoacrylate) nanoparticles with the aim of modifying some physico-chemical properties of these carriers in a controlled way. The joint effect of stabilizer concentration and monomer concentration on the mean particle size, on the electrophoretic mobility and on the polymer molecular weight has been investigated. The results demonstrate that the particle size is only dependent on the stabilizer concentration, nevertheless the electrophoretic mobility and the molecular weight distribution were affected simultaneously by the monomer and the stabilizer concentrations. Moreover, using the response surface diagrams it is possible to deduce the experimental conditions to design particles with the desired properties. Finally, the degradation rates for two different molecular weight formulations were compared, showing the relevance of this property. Alyautdin, R. N., V. E. Petrov, et al. (1997). "Delivery of loperamide across the blood-brain barrier with polysorbate 80coated polybutylcyanoacrylate nanoparticles." Pharmacetical Research 14(3): 325-8. PURPOSE: The possibility of using polysorbate 80-coated nanoparticles for the delivery of the water insoluble opioid agonist loperamide across the blood-brain barrier was investigated. The analgesic effect after i.v. injection of the preparations was used to indicate drug transport through this barrier. METHODS: Loperamide was incorporated into PBCA nanoparticles. Drug-containing nanoparticles were coated with polysorbate 80 and injected intravenously into mice. Analgesia was then measured by the tail-flick test. RESULTS: Intravenous injection of the particulate formulation resulted in a long and significant analgesic effect. A polysorbate 80 loperamide solution induced a much less pronounced and very short analgesia. Uncoated nanoparticles loaded with loperamide were unable to produce analgesia. CONCLUSIONS: Polysorbate 80-coated PBCA nanoparticles loaded with loperamide enabled the transport of loperamide to the brain.

Alyautdin, R. N., E. B. Tezikov, et al. (1998). "Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study." Journal of Microencapsulation 15(1): 67-74. The possibility of using polysorbate 80-coated polybutylcyanoacrylate nanoparticles to deliver low molecular polar hydrophilic drugs to the CNS has been studied. Tubocurarine (a quaternary ammonium salt) does not penetrate the normal intact blood-brain barrier. However, the injection of this drug directly into the cerebral ventricles of the brain provokes the development of epileptiform seizures as assessed by electroencephalogram (EEG). An in situ perfused rat brain technique was used as an experimental technique together with a simultaneous recording of the EEG. Nanoparticles were prepared by butylcyanoacrylate polymerization in an acidic medium. Fifteen minutes after the introduction of tubocurarine-loaded polysorbate 80-coated nanoparticles into the perfusate, epileptiform spikes in the EEG appeared. Intraventricular injection of tubocurarine caused the appearance of the EEG seizures 5 min after administration. Neither tubocurarine solution nor tubocurarine-loaded nanoparticles without polysorbate 80 or a mixture of polysorbate 80 and tubocurarine were able to influence the EEG. Thus only the loading of tubocurarine onto the polysorbate 80-coated nanoparticles appears to enable the transport of this quaternary ammonium compound through the blood-brain barrier. Anderson, S. A., R. K. Rader, et al. (2000). "Magnetic resonance contrast enhancement of neovasculature with alpha(v)beta(3)-targeted nanoparticles." Magnetic Resonance in Medicine 44(3): 433-9. Site-directed contrast enhancement of angiogenic vessels in vivo was demonstrated using antibody targeting of an MRI contrast agent to the alpha(v)beta(3) integrin, a molecular marker characteristic of angiogenic endothelium. The agent was tested in a rabbit corneal micropocket model, in which neovasculature is induced in the cornea using basic fibroblast growth factor. The targeted contrast agent consists of Gd-perfluorocarbon nanoparticles linked to alpha(v)beta(3) integrin antibody DM101. The animal group receiving the targeted contrast agent displayed a 25% increase in the average MR signal intensity after 90 min. Control groups in which the nanoparticles are either used alone, linked to an isotype-matched antibody, or linked to DM101 and administered following receptor blocking did not display MR contrast enhancement at similar dose levels. These findings indicate that the antibody-targeted agent enhances MR signal intensity in the capillary bed in a corneal micropocket model of angiogenesis, and is selectively retained within the angiogenic region via specific interaction with the alpha(v)beta(3) epitope. Anisimova, Y. V., S. I. Gelperina, et al. (2000). "Nanoparticles as antituberculosis drugs carriers: Effect on activity against Mycobacterium tuberculosis in human monocyte-derived macrophages." Journal of Nanoparticle Research 2: 165-171. Arangoa, M. A., G. Ponchel, et al. (2000). "Bioadhesive potential of gliadin nanoparticulate systems." European Journal of Pharmaceutical Sciences 11(4): 333-341. The objective of this work was to prepare, characterise and evaluate the adhesive potential of gliadin nanoparticulate carriers. Firstly, lectin-nanoparticle conjugates were obtained by the carbodiimide (CDI) covalent binding of Dolichos biflorus lectin (DBA) to the surface of gliadin nanoparticles (NP) containing carbazole (as a model lipophilic drug). The DBA binding efficiency was favoured in mild acidic conditions. Similarly, a CDI concentration of about 0.63 mg/mg nanoparticles, acting during at least 1 h, provided binding efficiencies of about 50% bulk lectin. Under optimised experimental conditions, the DBA conjugates showed a size of around 500 nm and the amount of loaded carbazole and the DBA content were calculated to be around 15 and 23.5 mug/mg, respectively. The bioadhesive activity of NP and DBA conjugates was determined in samples of small and large rat intestinal mucosa. The amount of adsorbed NP was calculated to be around 8 and 4 g/m2 in the small and large intestine, respectively. This high capacity to interact with the mucosa may be explained by gliadin composition. In fact, gliadin is rich in neutral and lipophilic residues. Neutral amino acids can promote hydrogen bonding interactions with the mucosa, while the lipophilic components can interact with the biological tissue by hydrophobic interactions. The bioadhesive activity of DBA conjugates was calculated to be about 2 g/m2 in the small intestine and greater than 4 g/m2 in the caecum and distal colon. These degrees of interaction were always significantly higher than those obtained with controls. Finally, DBA did not provide the specificity for interaction with Peyer's patches. In summary, gliadin nanoparticles show a high capacity of non-specific interaction with the intestine, whereas DBA binding to the surface of these carriers provided a greater specificity for colonic mucosa. Araujo, L., R. Lobenberg, et al. (1999). "Influence of the surfactant concentration on the body distribution of nanoparticles." Journal of Drug Targeting 6(5): 373-85. The rapid reticuloendothelial system (RES) uptake of nanoparticles after i.v. injection, especially by the liver, can be reduced and the body distribution can be altered by coating them with non-ionic surfactants. In the present work 2-14C-poly(methyl methacrylate) nanoparticles were coated with poloxamine 908 and polysorbate 80, and the influence of different surfactant concentrations on the body distribution was investigated. These surfactants were chosen because earlier studies showed that poloxamine 908 was very effective in decreasing the liver uptake and keeping the nanoparticles in circulation, whereas polysorbate 80 was the most effective surfactant to

direct the particles to organs that do not belong to the RES. Above nanoparticles were injected i.v. to rats and the animals were sacrificed after 30 min. Below a surfactant concentration of 0.1% the nanoparticle preparations behaved like uncoated particles. At a 0.1% concentration a very sudden and significant change in the body distribution occurred with poloxamine 908. The liver concentration decreased from about 75% of the dose to 13% and stayed at this level at higher surfactant concentrations. This decrease was combined with a similar sudden complementary increase in blood and other organ and tissue concentrations. With polysorbate 80 the decrease in liver concentration and increase in the blood and the other organ levels was gradual and became important only above 0.5% surfactant concentration. The results indicate that the type of interaction and the strength of the adsorptive binding to the nanoparticles are different with different surfactants. This in turn leads to different body distribution patterns after i.v. injection of surfactant coated nanoparticles. Arias-Gonzilez, J. R. and M. Nieto-Vesperinas (2000). "Near-field distributions of resonant modes in small dielectric objects on flat surfaces." Optics Letters 25(11): 782-4. We report numerical simulations of the coupling of waves, either propagating or evanescent, with the eigenmodes of dielectric nanocylinders and nanospheres upon substrates. The multiple interaction of light between these objects and the dielectric surface at which the evanescent waves are created is taken into account. In this way, we present an accurate procedure for predicting and controlling the creation of large field enhancements concentrated both within and near the nanoparticle compared with the angle of incidence and the state of polarization. (14 References). Arien, A. and B. Dupuy (1997). "Encapsulation of calcitonin in liposomes depends on the vesicle preparation method." Journal of Microencapsulation 14(6): 753-60. Calcitonin-loading was studied in liposomes composed of phosphatidylcholine, cholesterol and stearylamine in relation to the vesicle preparation method. Liposomes entrapping calcitonin were prepared by extrusion, sonication or from mixed micelles through the elimination of cholate by gel filtration. To understand the mode of calcitonin encapsulation in the vesicles, riboflavin was entrapped within the vesicles and taken as a simple model for the encapsulation of molecules in the aqueous phase. Interactions of calcitonin with the liposomal membranes were evaluated by studying the fixation of radiolabelled calcitonin to the outer surface of empty liposomes, and by preparing calcitonin-loaded LDL-like nanoparticles composed of phosphatidylcholine and cholesteryloleate. Calcitonin entrapment in the vesicles depends largely on the vesicle preparation method. When vesicles are prepared by removal of cholate from mixed micelles, relatively little calcitonin entrapment in the liposomes is obtained. In this type of vesicle, calcitonin is exclusively embedded in the vesicle bilayer. When vesicles are prepared by extrusion or sonication, calcitonin is found both in the aqueous and lipidic phases of the vesicles. Optimal calcitonin encapsulation was obtained when the liposomes were prepared by sonication. Armstrong, T. I., M. C. Davies, et al. (1997). "Human serum albumin as a probe for protein adsorption to nanoparticles: relevance to biodistribution." Journal of Drug Targeting 4(6): 389-98. A range of poloxamers and poloxamines were adsorbed to biodegradable poly(lactide-co-glycolide) (PLGA) and non-biodegradable polystyrene (PS) particulate systems in order to alter their surface characteristics and produce potential drug targeting systems. Human serum albumin (HSA) was chosen as a model protein to investigate protein adsorption to the above systems and was quantified by two techniques. I125 radiolabelled HSA proved to be a useful probe for determining protein adsorption but was limited by a modification that occurred on storage. Also, HSA eluted from the particle surface was quantified by densitometry following it's development on an SDSPAGE gel. Both techniques produced similar results. For cleaned coated PS particles it was found that the PEO chain length and the molecular structure of the block copolymer were important in preventing protein adsorption. The presence of excess block copolymer in the uncleaned preparations resulted in further suppression of HSA adsorption, which was thought to be due to their detergent properties. Due to the different results obtained with similarly coated PLGA particles, it was concluded that the block copolymers adsorb onto the surface of the PLGA particles in a different conformation to those adsorbed onto PS particles. Correlating in vivo biodistribution in terms of the prevention of protein (opsonin) adsorption was of only limited success and it was concluded that adsorption data for a single model protein can only be used with caution to predict the in vivo behaviour of colloidal targeting systems. Arnedo, A., M. A. Campanero, et al. (2000). "Determination of oligonucleotide ISIS 2922 in nanoparticulate delivery systems by capillary zone electrophoresis." Journal of Chromatography 871(1-2): 311-320. ISIS 2922 is an antisense oligonucleotide with antiviral activity against cytomegalovirus. However, its rapid degradation in biological fluids and its low capacity for diffusion across cell membranes limit its therapeutical use. One possibility to overcome these drawbacks consists of using nanoparticles as drug carriers. The aim of this study was to develop an analytical method for determining the amount of ISIS 2922 loaded into albumin nanoparticles. For this purpose, capillary zone electrophoresis (CZE) was performed on a fused-silica capillary filled with borate buffer (12.5 mM, pH 9.5). Paracetamol was used as an internal standard and a diode-array detection system was set at 270 nm. Under these conditions, the limit of quantitation of ISIS 2922 was 1.27 mug

and the precision and accuracy of the method did not exceed 7%. Moreover, the use of paracetamol as internal standard and the quantification by means of a 'corrected area' procedure enabled us to reduce the peak variability and accurately determine the amount of oligonucleotide loaded in the albumin nanoparticles. In summary, this assay is a selective and sensitive CZE method for the accurate quantitation of ISIS 2922 oligonucleotide in albumin nanoparticles. Arnold, T., T. Zorn, et al. (2001). "Sorption behavior of U(VI) on phyllite: experiments and modeling." Journal of Contaminants and Hydrology 47(2-4): 219-31. The sorption of U(VI) onto low-grade metamorphic rock phyllite was modeled with the diffuse double layer model (DDLM) using the primary mineralogical constituents of phyllite, i.e. quartz, chlorite, muscovite, and albite, as input components, and as additional component, the poorly ordered Fe oxide hydroxide mineral, ferrihydrite. Ferrihydrite forms during the batch sorption experiment as a weathering product of chlorite. In this process, Fe(II), leached from the chlorite, oxidizes to Fe(III), hydrolyses and precipitates as ferrihydrite. The formation of ferrihydrite during the batch sorption experiment was identified by Mossbauer spectroscopy, showing a 2.8% increase of Fe(III) in the phyllite powder. The ferrihydrite was present as Fe nanoparticles or agglomerates with diameters ranging from 6 to 25 nm, with indications for even smaller particles. These Fe colloids were detected in centrifugation experiments of a ground phyllite suspension using various centrifugal forces. The basis for the successful interpretation of the experimental sorption data of uranyl(VI) on phyllite were: (1) the determination of surface complex formation constants of uranyl with quartz, chlorite, muscovi te, albite, and ferrihydrite in individual batch sorption experiments, (2) the determination of surface acidity constants of quartz, chlorite, muscovite, and albite obtained from separate acid-base titration, (3) the determination of surface site densities of quartz, chlorite, muscovite, and albite evaluated independently of each other with adsorption isotherms, and (4) the quantification of the secondary phase ferrihydrite, which formed during the batch sorption experiments with phyllite. The surface complex formation constants and the protolysis constants were optimized by using the experimentally obtained data sets and the computer code FITEQL. Surface site densities were evaluated from adsorption isotherms at pH 6.5. The uranyl(VI) sorption onto phyllite was accurately modeled with these newly determined constants and parameters of the main mineralogical constituents of phyllite and the secondary mineralization phase ferrihydrite. The modeling indicated that uranyl sorption to ferrihydrite clearly dominates uranyl sorption, showing the great importance of secondary iron phases for sorption studies. Arshady, R. (1988). "Preparation of polymer nano- and microspheres by vinyl polymerization techniques." Journal of Microencapsulation 5(2): 101-14. The methodologies and techniques of producing polymer particles (nano- and microspheres) from vinyl monomers are described, with an emphasis on laboratory preparations. Five different techniques are employed in the preparation of polymer micro- and nanoparticles from vinyl monomers. Emulsion polymerization provides particles of about 50-200 nm in diameter, emulsifier free emulsion polymerization produces particles of about 1001000 nm (0.1-1.0 micron), dispersion polymerization gives particles in the region of 0.3-10 micron, and suspension polymerization leads to the formation of particles of about 20 micron-2 mm. The gap in the 10-20 micron region may be filled by either seeded polymerization or by more elaborately performed suspension polymerization. All of the four techniques mentioned above produce regular, spherical particles. Precipitation polymerization, on the other hand, gives irregularly shaped particles in the range of 0.1-10 micron. An attempt is made to clarify the underlying differences between these techniques and to say how they are practised in the laboratory. Arshady, R. (1989). "Preparation of nano- and microspheres by polycondensation techniques." Journal of Microencapsulation 6(1): 1-12. Particle-forming polycondensation techniques can be divided into two main categories, namely normal polycondensation and interfacial polycondensation. Various normal polycondensation procedures employed for the preparation of nano- and microspheres are covered by this review, and are described under suspension polycondensation, dispersion polycondensation and precipitation polycondensation. Among these, suspension polycondensation procedures are generally applicable for the preparation of both nano- and microspheres. They are employed for the production of industrially important polycondensates such as phenolics, polyesters and polyurethanes, as well as for novel polymeric materials such as polycyclodextrins, mercury-binding polymercaptals, and polyurea microcapsules. Dispersion polycondensation leads to the formation of monodisperse nanoparticles, but it is not widely employed. Precipitation polycondensation produces non-spherical and polydisperse particles, and it is useful only if low molecular weights of the polymer and polydispersity of the particles do not adversely affect the intended application of the product. Arshady, R. (1996). "in vivo targeting of colloidal carriers by novel graft copolymers." Journal of Molecular Recognition 9(5-6): 536-42. One of the major obstacles to the targeted delivery of colloidal carriers (nanocapsules) is the body's own defence mechanism in capturing foreign particles by the reticuloendothelial system (RES). This means that following

intravenous administration, practically all nanometer size particles are captured by the RES (mainly the liver). This paper draws attention to a recent initiative on the design of 'macromolecular homing devices' which seem to disguise nanoparticles from the RES, and hence are of potential interest for the targeted delivery of nanocapsular carriers. The idea is based on a graft copolymer model embodying a link site for attachment (binding) to the carrier, a floating pad for maintaining the particles afloat in the blood stream, an affinity ligand for site-specific delivery and a structural tune for balancing the overall structure of the homing device. A general synthetic scheme for the preparation of such graft copolymers is given, and preliminary biological evaluations relating to the floating pad concept are discussed. Ascencio, J. A., M. Perez, et al. (2000). "A truncated icosahedral structure observed in gold nanoparticles." Surface Science 447: 1-3. Describes a new type of gold nanoparticle. The particle shape corresponds to a truncated icosahedron which in some orientations appears as an asymmetric decahedron. The particle structure is discussed and the corresponding high resolution electron microscopy images are calculated for the optimum defocusing condition in several orientations. Experimental images of gold nanoparticles are shown that corroborate the truncated icosahedron structure. The evidence suggest that indeed this particle is formed in experimental growth conditions in which the equilibrium shape is achieved. (30 References). Aucouturier, J., L. Dupuis, et al. (2001). "Adjuvants designed for veterinary and human vaccines." Vaccine 19(17-19): 2666-72. Adjuvants play an important role in the efficacy of vaccines as the antigens become more and more purified. Indeed recombinant proteins or synthetic peptides are safer than crude inactivated micro-organism, but less immunogenic. This can be balanced by specific adjuvants. But there is no universal adjuvants and their action is not yet clear and rely on different mechanisms. Then, they must be adapted according to several criteria, like the target species, the antigens, the type of immune response, the route of inoculation, or the duration of immunity. For this purpose different type of emulsions have been developed. Water in oil (W/O) emulsions induce a strong and long term immune response. Those based on mineral oils are known to be very efficient but can sometimes induce local reactions with reactive antigens. Non mineral oils are well tolerated but less efficient with poor immunogens. Multiphasic (W/O/W) emulsions can induce short and long term immune responses with various antigens and oil in water (O/W) emulsions are well tolerated and induce a short term immune response. New generation of adjuvants are based on a new concept called 'immunosol' and stem from the association of nanoparticles with a new immunostimulant. They can be used when emulsions are not suitable to obtain a good balance between safety and immunogenicity. Aynie, I., C. Vauthier, et al. (1996). "Development of a quantitative polyacrylamide gel electrophoresis analysis using a multichannel radioactivity counter for the evaluation of oligonucleotide-bound drug carrier." Analytical Biochemistry 240(2): 202-9. A quantitative polyacrylamide gel electrophoresis (PAGE) analysis using a multichannel radioactivity counter was designed for the evaluation of 33P-labeled antisense oligonucleotide associated with polymeric drug carrier (nanoparticles). The proposed analytical method was first validated. The criteria of specificity, linearity, reliability, detection and quantification limits, and resolution power were determined. Results were compared to those obtained using liquid scintillation counting of crude samples or after solubilization of gel slices. The proposed method gave a better linearity and reliability than liquid scintillation counting of solubilized gel slices. In comparison with the liquid scintillation counting of crude samples, the method presented the advantage of being able to directly separate oligonucleotides differing by only one nucleotide in length. This method was applied for the separation of free oligonucleotides and oligonucleotides bound onto nanoparticles, allowing quantification of the amount of free and bound oligonucleotides without any further separation steps. Thus, because it is easy and rapid, the quantitative PAGE analysis using a multichannel radioactivity counter offers interesting possibilities for the characterization of oligonucleotide nanoparticles. Aynie, I., C. Vauthier, et al. (1999). "Spongelike alginate nanoparticles as a new potential system for the delivery of antisense oligonucleotides." Antisense Nucleic Acid Drug Development 9(3): 301-12. The aim of this study was to design a new antisense oligonucleotide (ON) carrier system based on alginate nanoparticles and to investigate its ability to protect ON from degradation in the presence of serum. Pharmacokinetics and tissue distribution of ON-loaded nanoparticles have been determined after intravenous administration. An original and dynamic process for ON loading into polymeric nanoparticles has been applied. It is based on the diffusion of ON or ON/polylysine complex into the nanoparticle or the alginate gel, respectively. Indeed, the single coincubation of ON with nanoparticles led, within a few days, to an extremely efficient association. The diffusion kinetic of ON was shown to be dependent on several parameters, incubation temperature, ON concentration, presence or absence of polylysine, polylysine molecular weight, and nanoparticle preparation procedure. This new alginate-based system was found to be able to protect [33P]-radiolabeled ON from degradation in bovine serum medium and to modify their biodistribution, as an important accumulation of

radioactivity was observed in the lungs, in the liver, and in the spleen after intravenous administration into mice. ON may be associated efficiently with calcium alginate in a colloidal state. Such nanosponges are promising carriers for specific delivery of ON to lungs, liver, and spleen. Bachels, T., H. J. Guntherodt, et al. (2000). "Melting of isolated tin nanoparticles." Physical Review Letters 85(6): 1250-3. The melting of isolated neutral tin cluster distributions with mean sizes of about 500 atoms has been investigated in a molecular beam experiment by calorimetrically measuring the clusters' formation energies as a function of their internal temperature. For this purpose the possibility to adjust the temperature of the clusters' internal degrees of freedom by means of the temperature of the cluster source's nozzle was exploited. The melting point of the investigated tin clusters was found to be lowered by 125 K and the latent heat of fusion per atom is reduced by 35% compared to bulk tin. The melting behavior of the isolated tin clusters is discussed with respect to the occurrence of surface premelting. Bader, G., A. Hache, et al. (2000). "High-resolution MRI characterization of human thrombus using a novel fibrin-targeted paramagnetic nanoparticle contrast agent." Magnetic Resonance in Medicine 44(6): 867-72. In this study, the sensitivity of a novel fibrin-targeted contrast agent for fibrin detection was defined in vitro on human thrombus. The contrast agent was a lipid-encapsulated perfluorocarbon nanoparticle with numerous GdDTPA complexes incorporated into the outer surface. After binding to fibrin clots, scanning electron microscopy of treated clots revealed dense accumulation of nanoparticles on the clot surfaces. Fibrin clots with sizes ranging from 0.5-7.0 mm were imaged at 4.7 T with or without treatment with the targeted contrast agent. Regardless of sizes, untreated clots were not detectable by T/sub 1/-weighted MRI, while targeted contrast agent dramatically improved the detectability of all clots. Decreases in T/sub 1/ and T/sub 2/ relaxation times (20-40%) were measured relative to the surrounding media and the control clots. These results suggest the potential for sensitive and specific detection of microthrombi that form on the intimal surfaces of unstable atherosclerotic plaque. (32 References). Balabanova, E. (2000). "Mechanism of nanoparticle generation by high-temperature methods." Vacuum 58: 2-3. The mechanism of silica nanoparticle generation by high-temperature (flame and thermal arc plasma) methods is studied by modelling. Processes responsible for particle formation and growth are considered. Parameters such as temperature, characteristic coagulation and coalescence time and residence time-influencing particle structure are investigated. It is found that the thermal arc plasma method allows production of unaggregated particles while the flame method creates large particle aggregates. (22 References). Baldelli, S., A. S. Eppler, et al. (2000). "Surface enhanced sum frequency generation of carbon monoxide adsorbed on platinum nanoparticle arrays." Journal of Chemical Physics 113(13): 5432-8. Sum frequency generation (SFG) vibrational spectroscopy is used to study the adsorption of CO at ~1 atm pressure on Pt nanoparticle arrays and Pt thin films. The SFG signal of CO adsorbed on platinum particles of 45 nm diameter is ~10 000 times larger than from CO on smooth Pt films. The large enhancement is explained by plasmon resonance and Maxwell-Garnett theory. The Pt arrays are prepared using electron beam lithography to produce particles with uniform spacing and sizes on an oxidized Si(100) wafer. Further, as the Pt coverage increases the SFG signal shows a polarization dependence that is explained considering the dielectric properties of a metal film on a dielectric surface. In addition, SFG permits investigation of the CO adsorbed on the particles at ~1 atm, which is not possible with most surface analytical techniques, that will allow for the study of the reaction of small molecules on surfaces relevant in heterogeneous catalysis. (32 References). Balland, O., H. Pinto-Alphandary, et al. (1994). "The uptake of ampicillin-loaded nanoparticles by murine macrophages infected with Salmonella typhimurium." Journal of Antimicrobial Chemotherapy 33(3): 509-22. The purpose of this study was to investigate the in-vitro interaction between [3H]ampicillin-loaded polyisohexylcyanoacrylate nanoparticles and murine macrophages (peritoneal and J774) infected with Salmonella typhimurium. The multiplicity of infection was ten bacteria to each macrophage and the mean (+/- S.D.) diameter of the nanoparticles was 220 (+/- 20 nm), corresponding to an ampicillin concentration of 2 g/L. The uptake of nanoparticle-bound [3H]ampicillin by non-infected J774 and peritoneal macrophages was six- and 24-fold greater respectively than that of free [3H]ampicillin. For infected cells, uptake by J774 and peritoneal macrophages was nine- and 20-fold greater respectively. However, there was no difference between nanoparticle-bound ampicillin and free ampicillin in terms of bactericidal activity against intracellular S. typhimurium. This unexpected observation might be accounted for by bacterium-induced inhibition of phagosome-lyosome fusion within the macrophages, thereby preventing contact between the bacteria in the phagosomes and the nanoparticles in the secondary lysosomes. Balland, O., H. Pinto-Alphandary, et al. (1996). "Intracellular distribution of ampicillin in murine macrophages infected with Salmonella typhimurium and treated with (3H)ampicillin-loaded nanoparticles." Journal of Antimicrobial Chemotherapy 37(1): 105-15.

The intracellular distribution of (3H)ampicillin-loaded polyisohexylcyanoacrylate nanoparticles was studied in murine macrophages (peritoneal cells and the J774 cell line) infected by Salmonella typhimurium C5, using ultrastructural autoradiography. Ampicillin penetration and retention into the cells obviously increased by means of nanoparticles. After short-term (2-4 h) treatment with the nanoparticle formulation, numerous intracellular bacteria were seen to be in the process of destruction. The tritium labelling was located in the cell cytoplasm and inside vacuoles in which bacteria undergoing degradation were often present. After long-term (12 h) treatment, numerous spherical bodies (d: 100 nm to 500 nm) and larger forms (2 microns) were seen in the vacuoles. Radioactivity was mainly found to be localized on the spherical bodies, indicating marked damaging action of the ampicillin on the bacterial walls. The targeting of ampicillin therefore allowed its penetration into the macrophages and vacuoles infected with S. typhimurium. Banai, S., Y. Wolf, et al. (1998). "PDGF-receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine." Circulation 97(19): 1960-9. BACKGROUND: Signaling through protein tyrosine kinases (PTKs) is a major contributor to the transmission of mitogenic stimuli to the interior of the cell and nucleus. The present study was designed to determine the effect of the tyrphostin AG1295, a selective blocker of PDGF-receptor PTK, on the growth of porcine and human smooth muscle cells (SMCs) in culture, on the outgrowth kinetics of SMCs from porcine and human arterial explants, and on neointimal formation after balloon injury in pigs. METHODS AND RESULTS: SMCs for culture were obtained from porcine abdominal aortas, human internal mammary arteries, and endarterectomy tissue from a single human carotid artery. Addition of AG1295 to SMCs before PDGF stimulation completely inhibited PDGF-betareceptor tyrosine phosphorylation without affecting the level of PDGF-beta-receptor. AG1295 resulted in a selective, reversible inhibition of SMC proliferation in culture (76%) with only mild (13.5%) inhibition of endothelial cell proliferation. The number of SMCs accumulating around explants of porcine carotid arteries and human endarterectomy specimens 12, 15, 19, 22, and 24 days after plating was reduced by 82% to 92% in AG1295treated compared with nontreated specimens, and initiation of SMC outgrowth was markedly delayed. The numbers of cells accumulated 10 days after initiation of outgrowth were significantly lower in treated versus control explants. Local intravascular delivery of AG1295-impregnated polylactic acid-based nanoparticles (130+/25 nm) to the site of balloon injury to porcine femoral arteries resulted in significant reductions in intima/media area ratio and luminal cross-sectional area narrowing by neointima compared with contralateral control arteries to which empty nanoparticles were applied (0.15+/-0.07 versus 0.09+/-0.03, P=.046 and 20+/-4% versus 10+/-4%, P=.0009, n=6 for both). CONCLUSIONS: The tyrphostin AG1295, a selective blocker of PDGF-receptor kinase, exerts a marked inhibitory effect on the activation, migration, and proliferation of porcine and human SMCs in vitro and an approximately 50% inhibitory effect on neointimal formation after balloon injury in porcine femoral arteries when delivered via biodegradable nanoparticles. Further studies appear to be warranted to evaluate the applicability of this novel approach to the interventional setting. Bargoni, A., R. Cavalli, et al. (1998). "Solid lipid nanoparticles in lymph and plasma after duodenal administration to rats." Pharmacetical Research 15(5): 745-50. PURPOSE: To evaluate the uptake and transport of solid lipid nanoparticles (SLN), which have been proposed as alternative drug carriers, into the lymph and blood after duodenal administration in rats. METHODS: Single doses of two different concentrations of aqueous dispersions of unlabelled and labelled SLN (average diameter 80 nm) were administered intraduodenally to rats. At different times, samples of lymph were withdrawn by cannulating the thoracic duct and blood was sampled from the jugular vein. Monitoring continued for 45 and 180 minutes, for unlabelled and labelled SLN respectively. The biological samples were analysed by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM) and gamma-counting. RESULTS: TEM analysis evidenced SLN in lymph and blood after duodenal administration to rats: the size of SLN in lymph did not change markedly compared to that before administration. The labelled SLN confirmed the presence of SLN in lymph and blood. CONCLUSIONS: The uptake and transport of SLN in the lymph, and to a lesser extent in the blood, were evidenced. The in vivo physical stability of SLN may have important implications in designing drug-carrying SLN. Bargoni, A., R. Cavalli, et al. (2001). "Transmucosal transport of tobramycin incorporated in solid lipid nanoparticles (sln) after duodenal administration to rats. Part II-Tissue distribution." Pharmacology Research 43(5): 497-502. Tobramycin-loaded solid lipid nanoparticles (SLN) were prepared and administered by duodenal and intravenous (i.v.) routes to rats and the tissue distributions were determined successively at fixed times (30 min, 4 h and 24 h) and compared to those of the tobramycin solution after i.v. administration. The tissue distribution between tobramycin-loaded SLN administered duodenally and i.v. was different. A marked difference between tobramycinloaded SLN administered duodenally and tobramycin solution administered i.v. was also evidenced. In particular, the amounts of tobramycin in the kidneys after tobramycin-loaded SLN administration either duodenally or i.v. were lower than after administration of i.v. solution. Tobramycin-loaded SLN were able to pass across the bloodbrain barrier in rats to a greater extent after i.v. injection than after duodenal administration. Copyright 2001 Academic Press.

Barichello, J. M., M. Morishita, et al. (1999). "Encapsulation of hydrophilic and lipophilic drugs in PLGA nanoparticles by the nanoprecipitation method." Drug Development and Industrial Pharmacy 25(4): 471-6. The purpose of this study was to assess the relative advantages and drawbacks of the nanoprecipitation-solvent displacement method for a range of drugs with respect to the particle size and drug encapsulation in polylactic-coglycolic acid (PLGA) nanoparticles. The particle size analysis indicated a unimodal particle size distribution in all systems, with a mean diameter of 160-170 nm, except for insulin nanoparticles, which showed a smaller particle size. The results of the encapsulation efficiency analysis demonstrated that more lipophilic drugs, such as cyclosporin and indomethacin, do not suffer from the problems of drug leakage to the external medium, resulting in improved drug content in the nanoparticles. In spite of the fact that valproic acid is a liquid that is very sparingly soluble in water, very low encapsulation efficiency was obtained. Ketoprofen, a drug sparingly soluble in water, demonstrated intermediate values of encapsulation that were well correlated with its intermediate lipophilicity. More hydrophilic drugs, such as vancomycin and phenobarbital, were poorly encapsulated in PLGA nanoparticles. Insulin was preferentially surface bound on the PLGA nanoparticles. However, a strong hypoglycemic effect of the insulin was observed after administration of the suspension of PLGA nanoparticles with surface-bound insulin to the ileum loop of male Wistar rats. Barichello, J. M., M. Morishita, et al. (1999). "Absorption of insulin from pluronic F-127 gels following subcutaneous administration in rats." International Journal of Pharmacy 184(2): 189-98. The main objective of this work was to evaluate the use of Pluronic (PF127) gels, polylactic-co-glycolic acid (PLGA) nanoparticles and their combination for parenteral delivery of peptides and proteins having short half-lives using insulin as a model drug. The in vitro insulin release profiles of various PF127 formulations were evaluated at 37 degrees C using a membraneless in vitro model. In vivo evaluation of the serum glucose and insulin levels was performed following subcutaneous administration of various insulin formulations in normal rats. The in vitro results demonstrated that the higher the concentration of PF127 in the gel, the slower the release of insulin from the matrices, independent of the vehicle used. The acute hypoglycemic peak resulting from administration of an insulin solution between 0.5 and 2.0 h after administration (peak at 1 h) is replaced after administration of insulinPLGA nanoparticles by an almost constant hypoglycemic effect with a slower recovery of the serum glucose levels at about 2 h after administration. By loading insulin into PF127 gels, a slower and more prolonged hypoglycemic effect of insulin was obtained in inverse proportion to the polymer concentration. PF127 gel formulations containing insulin-PLGA nanoparticles had the most long-lasting hypoglycemic effects of all formulations. From the current in vitro and in vivo study, we concluded that PF127 gel formulations containing either drug or drug-nanoparticles could be useful for the preparation of a controlled delivery system for peptides and proteins having short half-lives. Copyright Baszkin, A., P. Couvreur, et al. (1987). "Monolayer studies on poly(isobutylcyanoacrylate)-ampicillin association." Journal of Pharmacy and Pharmacology 39(12): 973-7. Surface pressure-area isotherms (pi-A) of poly(isobutylcyanoacrylate) monolayers with or without glucose and dextran as polymerization adjuvants used in the preparation of nanoparticles have been derived from measurements made at the air-water interface with the subphase pH at 2.7, 5.5 or 8.8. The isotherms were characteristic of the expanded type of polymer monolayer curves, yielding unusually low limiting area values compared with those of other known poly(acrylate) derivatives. This behaviour may be explained by the folding of polar moieties of the polymer groups in the water subphase. Ampicillin incorporated during preparation of nanoparticles had a negligible effect on the general behaviour of adjuvant-free monolayers, but a significant one on the adjuvant-loaded polymer monolayer system which showed an increase in surface area throughout the compression cycle, as compared with the surface area of the adjuvant-free polymer system although the collapse pressure was practically the same at 67 mN m-1. Bayer, M., O. Stern, et al. (2000). "Hidden symmetries in the energy levels of excitonic 'artificial atoms'." Nature 405(6789): 923-6. Quantum dots or 'artificial atoms' are of fundamental and technological interest--for example, quantum dots may form the basis of new generations of lasers. The emission in quantum-dot lasers originates from the recombination of excitonic complexes, so it is important to understand the dot's internal electronic structure (and of fundamental interest to compare this to real atomic structure). Here we investigate artificial electronic structure by injecting optically a controlled number of electrons and holes into an isolated single quantum dot. The charge carriers form complexes that are artificial analogues of hydrogen, helium, lithium, beryllium, boron and carbon excitonic atoms. We observe that electrons and holes occupy the confined electronic shells in characteristic numbers according to the Pauli exclusion principle. In each degenerate shell, collective condensation of the electrons and holes into coherent many-exciton ground states takes place; this phenomenon results from hidden symmetries (the analogue of Hund's rules for real atoms) in the energy function that describes the multi-particle system. Breaking of the hidden symmetries leads to unusual quantum interferences in emission involving excited states.

Bazile, D. V., C. Ropert, et al. (1992). "Body distribution of fully biodegradable [14C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats." Biomaterials 13(15): 1093-102. Fully biodegradable polylactic acid (PLA) nanoparticles (90-250 nm) coated with human serum albumin (HSA) were prepared by high-pressure emulsification and solvent evaporation, using the protein as surfactant. A new analytical tool was developed, based on Mie's law and size exclusion chromatography, to establish that, after evaporation of the solvent, the protein saturates the surface of the nanoparticles, masking the PLA core. According to this technique, no HSA is encapsulated in the polymer matrix. A radiolabelled [14C]-PLA50 was synthesized to follow the fate of this new drug carrier after i.v. administration to rats. The time necessary to clear the albumin-coated nanoparticles from the plasma was significantly longer than for the uncoated ones but not extended enough to target cells other than mononuclear phagocytes. As deduced from whole-body autoradiography and quantitative distribution experiments, the 14C-labelled polymer is rapidly captured by liver, bone marrow, lymph nodes, spleen and peritoneal macrophages. Nanoparticle degradation was addressed following 14C excretion. The elimination of the 14C was quick on the first day (30% of the administered dose) but then slowed down. In fact, if the metabolism of the PLA proceeds to lactic acid which is rapidly converted into CO2 via the Krebs cycle (80% of the total excretion was fulfilled by the lungs), anabolism from the lactic acid may also have taken place leading to long-lasting radioactive remnants, by incorporation of 14C into endogenous compounds. Bazile, D., C. Prud'homme, et al. (1995). "Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system." Journal of Pharmaceutical Sciences 84(4): 493-8. Nanoparticles were prepared from methoxy poly(ethylene glycol)poly(d,l-lactic acid) block copolymers (Me.PEGPLA) or blends of Me.PEG-PLA and PLA by the precipitation-solvent diffusion method. These nanoparticles, labeled by introducing [14C]PLA in the formulation, were shown to be more slowly captured by cultured THP-1 monocytes than F68-coated PLA nanoparticles, in a PEG chain-length-dependent manner. In vivo, the half-life in plasma of the Me.PEG-PLA nanoparticles that were intravenously administered to rats is increased by a factor 180 compared with the F68-coated PLA nanoparticles. This mononuclear phagocytes system avoidance was explained according to a conformation model in which the PEG density at the surface of the particles is a key parameter. Beaucage, G., J. Hyeon-Lee, et al. (1999). "Aero-sol-gel reactor for nano-powder synthesis." Journal of Nanoparticle Research 1: 379-392. Beck, P., D. Scherer, et al. (1990). "Separation of drug-loaded nanoparticles from free drug by gel filtration." Journal of Microencapsulation 7(4): 491-6. A suitable method for separating free drug and other residual compounds from drug-loaded, colloidal polymeric particles was developed. The objective of this separation procedure was to purify particle suspensions on a preparative scale by a rapid, simple, and exact method without changing the properties of the particles. The gel filtration method described in this paper using a middle-pressure chromatographic system is able to meet all these requirements. The separation process could be optimized by using only water as an eluent in combination with Sephadex G 50 medium. The purified particles appeared after 12-13 min in the eluate. Neither dispersity nor particle size or loading rate were influenced to a considerable extent. Beck, P., J. Kreuter, et al. (1993). "Influence of polybutylcyanoacrylate nanoparticles and liposomes on the efficacy and toxicity of the anticancer drug mitoxantrone in murine tumour models." Journal of Microencapsulation 10(1): 101-14. Polybutylcyanoacrylate (PBCA) nanoparticles were prepared and loaded with mitoxantrone, a highly effective anticancer drug. The proportion of mitoxantrone bound to the particles was analysed to be about 15 per cent of the initial drug concentration with the incorporation method and about 8 per cent with the adsorption method. Selected nanoparticle formulations were tested in leukaemia- or melanoma-bearing mice after intravenous injection. Efficacy and toxicity of mitoxantrone nanoparticles were compared with a drug solution and with a mitoxantrone-liposome formulation (small unilamellar vesicles with a negative surface charge). Furthermore, influence of an additional coating surfactant, poloxamine 1508, which has been shown to change body distribution of other polymeric nanoparticles, was investigated. It was shown that PBCA nanoparticles and liposomes influenced the efficacy of mitoxantrone in cancer therapy differently: liposomes prolonged survival time in P388 leukaemia, whereas nanoparticles led to a significant tumour volume reduction at the B16 melanoma. Neither nanoparticles nor liposomes were able to reduce the toxic side-effects caused by mitoxantrone, namely leucocytopenia. A slight additional influence of the coating surfactant was observed with only one preparation. Behan, N., C. Birkinshaw, et al. (2001). "Poly n-butyl cyanoacrylate nanoparticles: a mechanistic study of polymerisation and particle formation." Biomaterials 22(11): 1335-44. Poly n-butyl cyanoacrylate has been used in the synthesis of nanoparticles by dispersion polymerisation in aqueous media. Following establishment of a thermometric procedure for assessment of monomer reactivity, the relationships between monomer-polymer conversion reactions and particle development at various pH values was

investigated. Particle size was measured during the synthesis process using a laser diffraction technique and final particle character was assessed by scanning electron microscopy. Optimum conditions for particle production were a dispersion medium of pH 2.5 at a temperature of 65 degrees C, with dextran 70 used as a steric stabiliser. In the presence of dextran, following a period of equilibration, colloidally stable particles form, but in the absence of dextran particles are colloidally unstable and rapidly coalesce. Measurement of molecular weight changes through the synthesis process show an upward shift consistent with the initial formation of oligomers, which then further polymerise through a re-initiation re-polymerisation process until an equilibrium molecular weight is reached. Bell, S. E. and S. J. Spence (2001). "Disposable, stable media for reproducible surface-enhanced Raman spectroscopy." Analyst 126(1): 1-3. Large numbers of identical and stable SE(R)RS [surface-enhanced (resonance) Raman]-active media, which are convenient to handle and manipulate but sufficiently inexpensive that they can be used once and then discarded, have been prepared by isolating nanoparticles from Ag and Au sols in hydrophilic polymer gels. The preparation simply involves mixing a suitable polymer with the sol to give a viscous suspension that can be coated onto a substrate and dried to form a hard translucent film. The films remain inactive until they are treated with aqueous analyte solution, which causes the film to swell and brings the analyte into contact with the active metal particles. The swollen films give strong SERS spectra which are effectively identical to those obtained from simple sols. The advantage of this method is that the dried polymers can be stored indefinitely before use and that they give a high degree of spectral reproducibility. Bender, A., V. Schfer, et al. (1994). "Inhibition of HIV in vitro by antiviral drug-targeting using nanoparticles." Res Virol 145(3-4): 215-20. Nanoparticles are known to accumulate in the phagocytic cells of the mononuclear phagocyte system. Therefore, the use of this carrier system for the targeting of antiviral drugs to monocytes/macrophages (MO/MAC) is an attractive concept in the treatment of diseases involving MO/MAC, e.g. infection with HIV. In this study, the ability of macrophages isolated from peripheral blood of healthy blood donors to phagocytose and metabolize human serum albumin microspheres was investigated by transmission electron microscopy. Furthermore, nanoparticles manufactured using human serum albumin or polyhexylcyanoacrylate were loaded with nucleoside analogues (AZT and ddC) and tested for their ability to prevent HIV infection in MO/MAC cultures. Our results demonstrate the effectiveness of this drug-targeting system to one of the major target cells for HIV. Bender, A. R., H. von Briesen, et al. (1996). "Efficiency of nanoparticles as a carrier system for antiviral agents in human immunodeficiency virus-infected human monocytes/macrophages in vi tro." Antimicrobial Agents and Chemotherapy 40(6): 1467-71. Polyhexylcyanoacrylate nanoparticles loaded with either the human immunodeficiency virus (HIV) protease inhibitor saquinavir (Ro 31-8959) or the nucleoside analog zalcitabine (2',3'-dideoxycytidine) were prepared by emulsion polymerization and tested for antiviral activity in primary human monocytes/macrophages in vitro. Both nanoparticulate formulations led to a dose-dependent reduction of HIV type 1 antigen production. While nanoparticle-bound zalcitabine showed no superiority to an aqueous solution of the drug, a significantly higher efficacy was observed with saquinavir-loaded nanoparticles. In acutely infected cells, an aqueous solution of saquinavir showed little antiviral activity at concentrations below 10 nM, whereas the nanoparticulate formulation exhibited a good antiviral effect at a concentration of 1 nM and a still-significant antigen reduction at 0.1 nM (50% inhibitory concentrations = 4.23 nM for the free drug and 0.39 nM for the nanoparticle-bound drug). At a concentration of 100 nM, saquinavir was completely inactive in chronically HIV-infected macrophages, but when bound to nanoparticles it caused a 35% decrease in antigen production. Using nanoparticles as a drug carrier system could improve the delivery of antiviral agents to the mononuclear phagocyte system in vivo, overcoming pharmacokinetic problems and enhancing the activities of drugs for the treatment of HIV infection and AIDS. Benderbous, S. and B. Bonnemain (1995). "Superparamagnetic nanoparticles as blood-pool contrast agents. Contribution to MRI preclinical investigations." Radiologe 35(11 Suppl 2): S248-52. Benderbous, S. and B. Bonnemain (1996). "[Magnetic resonance contrast agents and perfusion imaging]." Journal des Maladies Vasculaires 21(1): 16-21. Contrast agents may be categorised as non-specific or specific agents. Non-specific agents are freely diffusible in the extracellular and extravascular compartment with the exception of the brain where only blood brain barrier lesions enables the contrast agent to pass. In the specific agent group, a new class of products has been developed, that of blood pool contrast agent, which are distributed in the total intravascular volume and are slowly cleared from the blood. Crossing the healthy capillary wall is limited and depends both on the pathological state of the endothelial permeability tissue of the organ under interest and on the characteristics of the contrast agent (size, charge, molecular shape...). The diagnostic efficacy in perfusion imaging including cerebral perfusion is modulated by the pharmacokinetic profile of the blood pool contrast agent. One way to improve the vascular

residence time, consists in binding a vector such as synthetic polymer or a biological macromolecule and a lanthanide like Gd3+, Mn2+, Dy3+ or metal ions. A second way is the synthesis of ultrasmall iron oxide nanoparticles which could escape rapid recognition by the monocyte macrophage phagocytic system mainly of liver and spleen. Because of their cristalline structure and the large number of non-paired spins, five electrons for the iron metal, the nanoparticles behave as magnetic domain when an external field is applied. They consequently have a high dipolar magnetic moment, and can produce a T2 effect in vivo, resulting in a drop in the magnetic resonance signal. Possible interests and developments toward perfusion imaging are demonstrated in experimental models studies. Bennis, S., C. Chapey, et al. (1994). "Enhanced cytotoxicity of doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres against multidrug-resistant tumour cells in culture." European Journal of Cancer 1: 89-93. We have studied the cytotoxicity and accumulation of doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres in a model of doxorubicin-resistant rat glioblastoma variants differing by their degree of resistance to this drug. We observed that the particulate form of doxorubicin was always more cytotoxic than free doxorubicin, whereas coadministration of drug-unloaded nanospheres with free doxorubicin did not modify significantly doxorubicin cytotoxicity. In C6 0.001 cells, which were 6-fold resistant and present a pure multidrug-resistant phenotype, the reversal of doxorubicin resistance was complete. In C6 0.1 cells, which were 60-fold resistant, as with C6 1V cells (selected with vincristine), the reversal of doxorubicin resistance was almost complete, with a residual resistance factor of 2-3. In C6 0.5 cells, which were 600-fold resistant to doxorubicin, the reversal of resistance was only partial and, in all cases, not above the expected participation of P-glycoprotein to the phenotype of resistance. Intracellular drug accumulation after 2-h exposure to 17.2 mumol/l doxorubicin was systematically reduced by a factor of 2-3 when doxorubicin was incubated under the form of nanospheres; doxorubicin accumulation after a 2-h exposure to IC50 was also highly reduced in all cell lines for doxorubicinloaded nanospheres. This work shows that association of doxorubicin with nanoparticles could provide a useful tool for circumventing multidrug resistance, probably by a bypass of P-glycoprotein rather than by an inhibition of this pump. Benoit, E., O. Prot, et al. (1994). "Adsorption of beta-blockers onto polyisobutylcyanoacrylate nanoparticles measured by depletion and dielectric methods." Pharmacetical Research 11(4): 585-8. Berrabah, M., D. Andre, et al. (2000). "Preparation and evaluation of benzyl benzoate-loaded poly-epsilon-caprolactone nanoparticles." Pharmazie 55(4): 322-3. Bertling, W. M., M. Gareis, et al. (1991). "Use of liposomes, viral capsids, and nanoparticles as DNA carriers." Biotechnology and Applied Biochemistry 13(3): 390-405. We tested a variety of liposomes for parameters such as DNA binding capacity and DNase I protection of incorporated and attached DNA to elucidate their use as vehicles for DNA transfer into cells and animals. The results were compared to other potential DNA vehicles, empty viral capsids, and nanoparticles. Maximal binding capacity was achieved for positively charged nanoparticles, DNase I protection was observed for most preparations with neosome preparations being least efficient. The uptake of radiolabeled DNA by cells in culture was determined for cationic and nonionic surfactant vesicles, viral capsids, and nanoparticles. Cellular DNA uptake was best for dioleoyl-derived positively charged liposomes (N-[1-(2,3-dioleoyloxy)propyl]-N,N,Ntrimethylammonium chloride; DOTMA) and the DNA could be shown to be physiologically active. The recombination rate for DNA fragments transfected in polyoma capsids in live mice was higher than for liposome mediated transfection. Homologous recombination could be observed for both DOTMA and polyoma-mediated DNA transfer. Berton, M., E. Allemann, et al. (1999). "Highly loaded nanoparticulate carrier using an hydrophobic antisense oligonucleotide complex." European Journal of Pharmaceutical Science 9(2): 163-70. Antisense oligonucleotides, and particularly those with phosphorothioate backbones, have emerged as potential gene specific therapeutic agents and are currently undergoing evaluation in clinical trials for a variety of diseases. In the area of HIV-1 therapeutics, targeting of oligonucleotides to infected cells, such as macrophages, would be highly desirable. The present study was designed to prepare and characterize oligonucleotide-loaded nanoparticles for this purpose. Due to their hydrophilic characteristics, oligonucleotides are difficult to entrap in polymeric particles. Here, the oligonucleotides were first complexed with cetyltrimethylammonium bromide. The oligonucleotide-loaded nanoparticles were prepared by the emulsification-diffusion method and subsequently purified. In comparison with previous studies, a high oligonucleotide-loading was achieved; 2.5, 5 and 10% oligonucleotide loading were assessed. If the initial oligonucleotide content was 4%, this method produced a final oligonucleotide loading of 1.9% with an entrapment efficiency of 47%. The integrity of the oligonucleotide and of the polymer, in the final freeze-dried product, was retained. Berton, M., L. Benimetskaya, et al. (1999). "Uptake of oligonucleotide-loaded nanoparticles in prostatic cancer cells and

their intracellular localization." European Journal of Pharmaceutics and Biopharmaceutics 47(2): 119-23. The development of antisense biotechnology is dependent, in part, on creating improved methods for delivering oligonucleotides to cells. In this study, we investigated a colloidal system (nanoparticles (NP) of poly (D,L) lactic acid) that affects the intracellular delivery of oligonucleotides. We have examined the intracellular compartmentalization in DU145 cells of fluorescein labeled phosphorothioate oligonucleotides, both in the free state and when loaded into NP. Fluorescent oligonucleotides were incubated for 18 h with DU145 cells and the mean intracellular fluorescence was determined by flow cytometry. After the addition of monensin, an increase in signal intensity was observed, indicating that free oligonucleotides were resident in an acidic intracellular environment, whereas oligonucleotides from the NP did not reside in an acidic compartment. Free and NP loaded with oligonucleotides effluxed from DU145 cells from two intracellular compartments. This preliminary report indicates that colloidal carriers such as NP could prove to be useful in affecting intracellular trafficking of oligonucleotides in DU145 and in other cells. Berven, C. A., M. N. Wybourne, et al. (2000). "The use of biopolymer templates to fabricate low-dimensional gold particle structures." Superlattices and Microstructures 27: 5-6. We report the current-voltage characteristics of gold nanoparticle-biopolymer networks at room temperature. The characteristics have features that are indicative of single-electron charging in ordered, one-dimensional chains of nanoparticles. From capacitance estimates and numerical simulations, we argue that the observed electrical behavior is related to the low size dispersion of the nanoparticles and the uniformity of the biopolymer lengths embedded within the network. (20 References). Betbeder, D., S. Sperandio, et al. (2000). "Biovector nanoparticles improve antinociceptive efficacy of nasal morphine." Pharmacetical Research 17(6): 743-8. PURPOSE: We have studied the antinociceptive activity and blood and brain delivery of nasal morphine with or without Biovector nanoparticles in mice. METHODS: A tail flick assay was used to evaluate the antinociceptive activity. The kinetics of morphine were evaluated in blood and brain, using tritiated morphine as tracer. RESULTS: These nanoparticles were shown to increase the duration of the antinociceptive activity of morphine after nasal administration. This effect was not due to an increase of morphine in the blood; and the analgesic activity of morphine in association with nanoparticles was reversed by naloxone. The ED50 value was 33.6+/-15.6 mg/kg for morphine alone and 14.4+/-7.6 mg/kg in presence of nanoparticles. They were only effective at low doses (1.5 to 2.5 microg), a higher or a lower dose had no effect. No interaction was found between nanoparticles and morphine. NaDOC, a permeation enhancer, was unable to improve nasal morphine activity. CONCLUSIONS: These results show the presence of nanoparticles only at a very specific dose increases the antinociceptive activity of nasal morphine in mice. The occurrence of a direct transport of morphine from the nasal mucosa to the brain is discussed. Bigot, J., J. Merle, et al. (1995). "Electron dynamics in copper metallic nanoparticles probed with femtosecond optical pulses." Physical Review Letters 75(25): 4702-4705. Billsten, P., P. O. Freskgard, et al. (1997). "Adsorption to silica nanoparticles of human carbonic anhydrase II and truncated forms induce a molten-globule-like structure." FEBS Lett 402(1): 67-72. Human carbonic anhydrase II pseudo-wild type (HCAIIpwt) and two truncated variants were adsorbed to approximately 9 nm silica nanoparticles. Ellipsometry was used as an indirect measure of protein adsorption. The structural changes of adsorbed proteins were investigated with the use of circular dichroism (CD), intrinsic fluorescence, ANS binding ability and inhibitor binding capacity. It was found that the variants that were truncated at positions 5 and 17 in the N-terminal end attain a molten-globule-like state after interaction with the silica nanoparticles. In contrast, the more stable HCAIIpwt retained most of its native structure after 24 h adsorption to silica nanoparticles. The result suggests that surface induced unfolding may give rise to intermediates similar to those for unfolding induced by, for example GuHCl. Thus, the intermediate observed has some features of the molten globule. Birnbaum, D. T., J. D. Kosmala, et al. (2000). "Optimization of preparation techniques for poly(lacticacid-Co-glycolic acid) nanoparticles." Journal of Nanoparticle Research 2: 173-181. Birtcher, R. C., S. E. Donnelly, et al. (2000). "Nanoparticle ejection from Au induced by single Xe ion impacts." Physical Review Letters 85(23): 4968-71. In situ transmission electron microscopy has been used to observe sputtered Au during Xe ion irradiation in transmission geometry. The sputtered Au was collected on an electron transparent carbon foil. Nanoparticles were observed on the collector foil after they were ejected by single ion impacts. The ejection is from the melt zone formed during the thermal spike phase of a displacement cascade produced near the surface by a single ion impact. Such single ion impacts are also capable of producing craters. Ejected nanoparticles can make a significant contribution to sputtering. (29 References).

Blagoeva, P. M., R. M. Balansky, et al. (1992). "Diminished genotoxicity of mitomycin C and farmorubicin included in polybutylcyanoacrylate nanoparticles." Mutation Research 268(1): 77-82. The genotoxic effects of mitomycin C (MMC) and farmorubicin (FR) in a free form and included in polybutylcyanoacrylate nanoparticles (PBCN) were studied employing the Salmonella/microsome mutagenicity assay and the micronucleus test in mouse bone marrow as well as in mouse fetal liver. The data obtained clearly indicated that MMC (0.25-2.00 micrograms/plate) was a strong mutagen in S. typhimurium TA102, while the same concentrations of this compound in PBCN were ineffective in inducing his+ revertant mutations in bacterial cells. A similar total suppression of mutagenic activity of FR (1.0-20.0 micrograms/plate) was registered in S. typhimurium TA98 when the drug was included in PBCN. Furthermore, the incorporation of MMC (2.0 or 4.0 mg/kg, i.p.) into PBCN strongly diminished or even abolished its clastogenic activity in the bone marrow of virgin and pregnant mice as well as in mouse fetal liver, respectively. In addition, a lack of genotoxic effect of PBCN only was also established. The toxic activity of MMC in mouse bone marrow was significantly reduced or completely abolished after its inclusion in PBCN. A conclusion might be drawn that the genotoxic activity of some antitumor drugs might be markedly diminished or even abolished after their incorporation in PBCN. Blum, J., N. Tymiak, et al. (1999). "The effect of substrate temperature on the properties of nanostructured silicon carbide films deposited by hypersonic plasma particle deposition." Journal of Nanoparticle Research 1: 31-42. Boal, A. K., F. Ilhan, et al. (2000). "Self-assembly of nanoparticles into structured spherical and network aggregates." Nature 404(6779): 746-8. Multi-scale ordering of materials is central for the application of molecular systems in macroscopic devices. Selfassembly based on selective control of non-covalent interactions provides a powerful tool for the creation of structured systems at a molecular level, and application of this methodology to macromolecular systems provides a means for extending such structures to macroscopic length scale. Monolayer-functionalized nanoparticles can be made with a wide variety of metallic and non-metallic cores, providing a versatile building block for such approaches. Here we present a polymer-mediated 'bricks and mortar' strategy for the ordering of nanoparticles into structured assemblies. This methodology allows monolayer-protected gold particles to self-assemble into structured aggregates while thermally controlling their size and morphology. Using 2-nm gold particles as building blocks, we show that spherical aggregates of size 97 +/- 17 nm can be produced at 23 degrees C, and that 0.5-1 microm spherical assemblies with (5-40) x 10(5) individual subunits form at -20 degrees C. Intriguingly, extended networks of approximately 50-nm subunits are formed at 10 degrees C, illustrating the potential of our approach for the formation of diverse structural motifs such as wires and rods. These findings demonstrate that the assembly process provides control over the resulting aggregates, while the modularity of the 'bricks and mortar' approach allows combinatorial control over the constituents, providing a versatile route to new materials systems. Bodker, F., S. Morup, et al. (1994). "Surface effects in metallic iron nanoparticles." Physical Review Letters 72(2): 282285. Bodmeier, R., H. G. Chen, et al. (1989). "A novel approach to the oral delivery of micro- or nanoparticles." Pharmacetical Research 6(5): 413-7. A novel oral multiple-unit dosage form which overcame many of the problems commonly observed during the compression of microparticles into tablets was developed in this study. Micro- or nanoparticles were entrapped in beads formed by ionotropic gelation of the charged polysaccharide, chitosan or sodium alginate, in solutions of the counterion, tripolyphosphate (TPP) or calcium chloride (CaCl2), respectively. The described technique did not change the physical properties of the microparticles, and it allowed a high microparticle loading (up to 98%). The ionic character of the polymers allowed pH-dependent release of the microparticles. Chitosan beads disintegrated and released the microparticles in 0.1 N HCl, while calcium alginate beads stayed intact in 0.1 N HCl but rapidly disintegrated in simulated intestinal fluids. Coating the calcium alginate beads with cellulose acetate phthalate resulted in an enteric drug delivery system. Scanning electron microscopy and dissolution and disintegration tests were used to characterize the microparticle-containing beads. The disintegration time of the beads was studied as a function of the solution viscosity of the polysaccharide, gelation time, counterion concentration, and method of drying. Bodmeier, R., H. Chen, et al. (1991). "Spontaneous formation of drug-containing acrylic nanoparticles." Journal of Microencapsulation 8(2): 161-70. Nanoparticles containing ibuprofen, indomethacin or propranolol were formed spontaneously after the addition of solutions of the drugs and acrylic polymers (Eudragit RS or RL 100) in the water-miscible solvents, acetone or ethanol, to water without sonication or microfluidization. The colloidal dispersions were stabilized by quaternary ammonium groups and did not require the addition of surfactants or polymeric stabilizers. The nanoparticles were compared to nanoparticles prepared either by a microfluidization-solvent evaporation method with a waterimmiscible organic solvent, methylene chloride, or by a melt method with respect to particle size and

redispersibility of freeze- or spray-dried samples. Nanoparticles prepared by microfluidization or the melt method were easily redispersed while Eudragit RS nanoparticles prepared by spontaneous emulsification were not redispersible. Flexible films were formed from the nanosuspensions after the addition of 15 per cent triethyl citrate, a water-soluble plasticizer. The release of propranolol from the films increased with increasing proportion of RL, but was independent of the order of mixing of the two polymers or nanosuspensions during film preparation. The drug release from indomethacin films was increased by adding water-soluble polymers to the nanosuspension. Bonafos, C., B. Garrido, et al. (2000). "An electron microscopy study of the growth of Ge nanoparticles in SiO2." Applied Physics Letters 76(26): 3962-4. Ion implantation followed by high temperature annealing can be used to synthesize group IV semiconducting nanoparticles in SiO/sub 2/. The density and the size distribution of these nanocrystals obviously depend on the implantation and annealing conditions. While their size can be measured by "classical" transmission electron microscopy techniques, their density cannot because no diffraction occurs in the amorphous matrix. In this letter, we use electron energy loss spectroscopy to overcome this problem. We have measured the evolution of the size distribution, the density, and the atomic fraction occupied by the Ge precipitates during annealing. We show that the nanocrystals grow in size and reduce their density, while the overall number of atoms they contain remains constant. This observation proves that the nanoparticles undergo a conservative ripening during annealing. (12 References). Bonduelle, S., C. Foucher, et al. (1992). "Association of cyclosporin to isohexylcyanoacrylate nanospheres and subsequent release in human plasma in vitro." Journal of Microencapsulation 9(2): 173-82. Polyisohexylcyanoacrylate nanocapsules containing cyclosporin were prepared by mixing in a 1:2 ratio an oil/ethanol solution of monomer and drug with an aqueous phase. Drug nanoencapsulation rate was controlled by its partition coefficient between the inner (organic) and outer (aqueous) phases. Thus highest encapsulation yields (88 per cent) were achieved by reducing cyclosporin solubility in the aqueous phase, i.e. by reducing ethanol concentration under reduced pressure, achieving a 3-fold volume reduction. Due to the relative insolubility of cyclosporin in water, no drug was released from the nanocapsules during storage in this injectable vehicle. Upon a 1/5 dilution in human plasma at 37 degrees C in vitro around 40 per cent of the initially encapsulated cyclosporin diffused quickly out of the capsules and an equilibrium was reached, the drug being most likely dissolved in the fatty compartment of the plasma such as lipoproteins, etc. This release mechanism is different from plain polymeric nanoparticles. Indeed, in this case the drug was released in two phases: an initial burst (around 60 per cent) of adsorbed drug as a result of the dilution, followed by a slow release (around 20 per cent over 3 h) which is likely to result from the progressive enzymatic erosion of the polymer. The initial burst was markedly more pronounced (around 80 per cent) when nanoparticle suspensions were evaporated to 1/3 of their initial volume under reduced pressure. Finally, experiments performed at 0 degree C allowed a reduction of the fraction released immediately from both types of nanospheres, probably because of a reduced solubility in plasma. In the case of nanoparticles the second phase of slow release is also inhibited at 0 degree C, in agreement with an enzymatically controlled release mechanism. Bonet Orozco, E., W. Wernsdorfer, et al. (2000). "Uniform rotation of magnetization measured in single nanometer-sized particles." Journal of Applied Physics 87(9): 1-3. We show in this article the first full three dimensional measurements of switching fields of a nanometer-scale magnetic particle. The field direction dependence of the switching fields can be successfully described by the uniform rotation model. Nevertheless, we could see that the Stoner-Wohlfarth form for the anisotropy function, which is often assumed together with the uniform rotation model, is an oversimplification. In order to reproduce the measured fields, one has to take into account higher order anisotropy terms. The complete form of the anisotropy function seems to be accessible only by magnetic measurements on each individual nanoparticle. (12 References). Bonnemain, B. (1998). "Superparamagnetic agents in magnetic resonance imaging: physicochemical characteristics and clinical applications. A review." Journal of Drug Targeting 6(3): 167-74. Superparamagnetic agents in magnetic resonance imaging: physico-chemical characteristics and clinical applications. Superparamagnetic agents have been the subject of extensive research over the last decade. They consist of iron oxide nanoparticles which are highly effective in Magnetic Resonance Imaging (MRI). The particle size varies widely and influences their physicochemical and pharmacokinetic properties. Their main present and future applications by the parenteral route are: imaging of gastrointestinal tract, liver and spleen, lymph nodes. Ultrasmall superparamagnetic iron oxide particles (USPIO) are also blood pool agents which could be used for perfusion imaging (i.e. brain or myocardial ischemic diseases) as well as for imaging of vessels in Magnetic Resonance Angiography. These agents open up an important field of research into more specific agents adapted to clinicians' needs in diagnostic imaging.

Borchard, G. and J. Kreuter (1993). "Interaction of serum components with poly(methylmethacrylate) nanoparticles and the resulting body distribution after intravenous injection in rats." Journal of Drug Targeting 1(1): 15-9. Radiolabelled poly(methylmethacrylate) (PMMA) nanoparticles were coated with rat serum albumin (RSA), serum and inactivated serum, to examine the influence of these blood components on the body distribution of a model colloidal drug carrier. The particles were incubated overnight at 37 degrees C either in a 1% solution of RSA in phosphate buffered saline (PBS) or in serum obtained from the rats. A suspension of nanoparticles in PBS was used as a control. Serum complement inactivation was achieved by storage at 56 degrees C for 30 min. The suspensions were then injected intravenously via the tail vein of Wistar rats. The animals were sacrificed at five different time points (30 min, 2 h, 6 h, 24 h, and 7 d after injection) and two samples of each organ and two blood samples were weighed into scintillation vials. The radioactivity of each sample was then measured in a Beckman scintillation counter. Coating with RSA led to no significant change in the body distribution of the particles, whereas incubation in serum, especially with complement inactivation prior to injection, very significantly reduced the uptake of particles into the organs of the reticuloendothelial system (RES), e.g., liver, spleen, and bone marrow. At the same time, much higher concentrations of nanoparticles were observed in the serum and in nonRES organs and peripheral tissues (kidneys, muscles, and intestine). This effect was most pronounced after 30 min, but was still observable after 7 d. Borchard, G. and J. Kreuter (1996). "The role of serum complement on the organ distribution of intravenously administered poly (methyl methacrylate) nanoparticles: effects of pre-coating with plasma and with serum complement." Pharmacetical Research 13(7): 1055-8. PURPOSE: The organ distribution of radiolabeled poly (methyl methacrylate) (PMMA) nanoparticles coated with plasma proteins and serum complement in rats was studied in order to determine the effect of serum complement on the particle phagocytosis by the organs of the reticulo-endothelial system (RES). METHODS: PMMAnanoparticles were coated overnight with plasma proteins or serum complement, and injected into Wistar rats. The body distribution of nanoparticles was measured by means of scintillation counting of organ samples. In addition, proteins adsorbed to the particle surface were inactivated by heat treatment prior to injection, and the particle's distribution was measured as described above. RESULTS: Whereas uncoated nanoparticles (control group) were mainly taken up by the Kupffer cells in the liver, incubation of the particles in plasma for 12 h followed by heat inactivation reduced the particle concentrations in the liver to merely 22% after 30 min. After 120 min, liver concentrations were still lower than the control group, and almost 30% of the administered dose of the heatinactivated particle group was present in non-RES organs and tissues. Particles with non-inactivated complement were accumulated in the lung at concentrations of 29% after 30 min, which increased to 71% after 120 min, whereas those coated with inactivated complement reached lung concentrations above 70% already after 30 min. CONCLUSIONS: Particles coated with plasma components are able to avoid uptake by the RES, especially after heat inactivation of the plasma components adsorbed. Adsorption and heat inactivation of complement proteins alone, however, does not have the same result as coating with plasma proteins followed by heat inactivation. Therefore, it is concluded that plasma components other than complement proteins take part in the process of RES activation and phagocytosis of injected nanoparticles. Borchardt, G., S. Brandriss, et al. (1994). "Body distribution of 75Se-radiolabeled silica nanoparticles covalently coated with omega-functionalized surfactants after intravenous injection in rats." Journal of Drug Targeting 2(1): 61-77. Silica nanoparticles, radiolabeled with 75Selenium were coated with 14 types of omega-functionalized surfactants covalently bound to the particle surface. The particles were suspended in phosphate buffered saline (PBS) and injected intravenously via the tail vein of Wistar rats. The animals were sacrificed after 5 different time points (30 min, 2 h, 6 h, 24 h, and 7 d), and two samples of each organ and two blood samples were weighed into vials. The radioactivity of each sample was measured in a LKB-Wallac CliniGamma counter. Coated silica nanoparticles accumulated in the liver at much lower levels than other colloidal drug carriers after short time periods (30 min). The liver accumulation increased after longer time periods due to a natural redistribution process. Surface modification by increasing the hydrophilicity and thickness of coating yielded higher and longer persisting concentrations in the intestine, blood, and the muscles. Initially increased lung concentrations were decreasing with time, probably due to migration of the alveolar phagocytes. Bordat, C., M. Sich, et al. (2000). "Distribution of iron oxide nanoparticles in rat lymph nodes studied using electron energy loss spectroscopy (EELS) and electron spectroscopic imaging (ESI)." Journal of Magnetic Resonance Imaging 12(3): 5059. Superparamagnetic iron nanoparticles have been developed as contrast agents for magnetic resonance lymphography. The kinetics of uptake of these particles has not yet been accurately determined. We have therefore monitored the distribution of individual iron particles (ferumoxtran, AMI-227, Sinerem) in rat lymph nodes 1.5, 3, 6, 12, and 24 hours after i.v. injection (two rats per time point). The ultrastructural distribution of the iron was determined by energy-filtered transmission electron microscopy (EFTEM). This method allows the identification of elements using element-specific energy-loss electrons. Iron was identified by the Fe-L(2,3) edge (EELS), and iron maps were obtained using iron-specific electrons for imaging (ESI). The background was

calculated by simplex optimization (EELS) and by the two-window method (ESI). Ferumoxtran particles were regularly observed at the periphery of the lymph nodes but not in their centers. Isolated iron particles were seen extracellularly within lymph vessels and, 3 hours after injection, as small dots in phagocytic cells. Numerous dense clusters appeared within the cells at later times (6 and 12 hours after injection). These results suggest that the contrast agent moves rapidly across the capillary wall to the lymph and is then taken up by phagocytic cells. J. Magn. Reson. Imaging 2000;12:505-509. Borgobain, K., J. B. Singh, et al. (2000). "Quantum size effects in CuO nanoparticles." Physical Review B Condensed Matter 61(16): 11093-6. Size effects in cupric oxide nanocrystals, synthesized using a novel electrochemical route, having average diameters of about 4 and 6 nm, are probed by X-ray photoelectron spectroscopy. Cu-O bond ionicity was found to increase with reduction in nanocrystallite size. Formation of pure CuO phase was confirmed from X-ray diffraction, infrared spectrophotometry and photoelectron spectroscopy. This report also disproves the earlier conjecture that nanometer sized CuO phase is unstable below 25 nm. (39 References). Borner, K., H. Hartwig, et al. (1999). "HPLC determination of clofazimine in tissues and serum of mice after intravenous administration of nanocrystalline or liposomal formulations." International Journal of Antimicrobial Agents 11(1): 75-9. A simple HPLC method is described for the determination of clofazimine in mouse tissues and in serum. The main application of the method was the determination of the drug in mouse tissues after i.v. administration of nanocrystalline suspensions or liposomal encapsulated clofazimine. Tissues were extracted with a 10-fold (w/v) volume of an extraction solution consisting of methanol/glacial acetic acid 9:1 (v/v). Serum proteins were precipitated with a 2-fold volume of acetonitrile. Isocratic chromatography was performed using an anion exchange column (Nucleosil 100-5 SA, Macherey & Nagel) for separation. The mobile phase was a mixture of acetonitrile and 0.1 mol/l aqueous phosphoric acid (75:25, v/v), adjusted to pH 2.9 with sodium hydroxide solution. Absorption of the eluate was monitored at 495 nm. The assay was precise, simple to perform and fast. Recovery from tissues was > or = 98%, from nanoparticles > or = 98%, and from liposomes > or = 96%. No interference was observed in extracts from mouse liver, spleen, lungs and human serum. Bornschein, M., P. Melegari, et al. (1989). "[Micro- and nanoparticles as carrier systems with special consideration of the preparation methods]." Pharmazie 44(9): 585-93. Boudad, H., P. Legrand, et al. (2001). "Combined hydroxypropyl-beta-cyclodextrin and poly(alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir." Interntional Journal of Pharmacology 218(1-2): 113-24. The aim of this study was to prepare and characterize an hydroxypropyl-beta-cyclodextrin-saquinavir inclusion complex with the purpose of incorporating this complex into poly(alkylcyanoacrylate) nanoparticles in order to increase the drug loading. Hydroxypropyl-beta-cyclodextrin-saquinavir complex was characterized by thermal (differential scanning calorimetry), crystallographic (X-ray diffractography) and spectroscopic methods (circular dichroism, H(1)-NMR). Nanoparticles were prepared by polymerization of alkylcyanoacrylate monomers (isobutyland isohexylcyanoacrylate) in a water solution of the complex and further characterized. The apparent solubility of saquinavir was increased 400-fold at pH 7.0 in presence of hydroxypropyl-beta-cyclodextrin owing to the formation of a drug-cyclodextrin complex as demonstrated mainly by 1H NMR and confirmed by other techniques. Saquinavir-loaded nanoparticles could be easily prepared in the presence of a drug-cyclodextrin complex. It was found that large amounts of cyclodextrins remained associated with the particles, resulting in a 20-fold increase in saquinavir loading compared to nanoparticles prepared in the absence of cyclodextrins. This study has shown that the loading in saquinavir of poly(alkylcyanoacrylate) nanospheres could be dramatically improved by simultaneously increasing the apparent solubility of the drug in the preparation medium and the amount of cyclodextrin associated with the particles, making these nanospheres a promising system for oral application. Bourel, D., A. Rolland, et al. (1988). "A new immunoreagent for cell labeling. CD3 monoclonal antibody covalently coupled to fluorescent polymethacrylic nanoparticles." Journal of Immunological Methods 106(2): 161-7. The preparation and application of immunonanospheres are described. CD3 monoclonal antibodies were covalently coupled to fluorescent polymethacrylic nanoparticles by the glutaraldehyde reaction and the resultant conjugate purified by gel filtration on a Sepharose 4B column. Peripheral blood mononuclear cells labeled with this immunoreagent were observed by both fluorescence microscopy and scanning electron microscopy in order to evaluate the technique. Bousquet, Y., P. J. Swart, et al. (1999). "Molecular mechanisms of the adsorption of a model protein (human serum albumin) on poly(methylidene malonate 2.1.2) nanoparticles." Pharmacetical Research 16(1): 141-7. PURPOSE: To understand the molecular mechanisms involved in protein-methylidene malonate 2.1.2 polymer interactions. METHODS: To assess the importance of electrostatic forces in polymer-protein interactions use was made of HSA and its derivatives, which were anionized by succinylation and aconitylation. Surface plasmon resonance measurements, using the three HSA molecules as immobilized ligands and polymer nanoparticles as

analytes in the liquid phase, allowed the determination of initial kinetic constants and affinity constants at equilibrium at two different temperatures. RESULTS: Saturation of binding for the three proteins occurred at approximately 900 protein molecules/nanoparticle. The apparent affinity decreased with increasing electronegativity of the proteins. Surface plasmon resonance measurement of proteins, covalently linked to the chip matrix, showed a high affinity for the nanoparticles (K(A) approximately 10(10) M(-1) and confirmed the moderate decrease of affinity with increasing electronegativity of the modified albumins. Measurements at 25 and 37 degrees C showed no significant increase in the albumin-nanoparticle interactions. Dissociation of the proteins from the nanoparticles could only be realized with chaotropic salt solutions. CONCLUSIONS: These results suggest the molecular forces initiating the protein-nanoparticle interactions are mainly of electrostatic nature followed by stabilization by hydrophobic forces. The high affinity confirms the nanoparticles as excellent carriers for protein delivery. Bovin, J. O., T. Huber, et al. (2000). "A new view on chemistry of solids in solution--cryo energy-filtered transmission electron microscopy (cryo-EFTEM) imaging of aggregating palladium colloids in vitreous ice." Chem 6(1): 129-32. It is shown that by using cryo-transmission electron microscopy (cryo-TEM) it is possible to image the aggregation behaviour of nanoparticles while they are still in solution. This technique has allowed the study of the arrangement of colloidal palladium particles in solution by preparing the specimen by the plunge-freezing technique. This method of rapidly cooling the specimen avoids rearrangement of the particles during specimen preparation. The palladium particles were identified by energy-filtered cryo-TEM. The aggregation of particles in solution was studied as a function of pH and ionic strength. The results can be used as recommendations for colloidal solutions intended for deposition of single particles. Brabers, V. A. (1992). "Comment on Size-dependent Curie temperature in nanoscale MnFe2O4 particles." Physical Review Letters 68(20): 3113. Bragg, W. D., V. P. Safonov, et al. (1999). "Near-field optical studies of local photomodification in nanostructured materials." Journal of Microscopy 194(Pt 2-3)(1-2): 574-7. Fractal aggregates of silver nanoparticles are studied experimentally using atomic force microscopy and photon scanning tunnelling microscopy. Large changes in the near-field optical response of fractal aggregates are observed after the irradiation of samples with nanosecond laser pulses. The threshold energy density for photomodification using a 532 nm laser is measured to be 9 mJcm(-2). It is shown that photomodification-induced changes in the local optical response can be two orders of magnitude larger than changes in far-field absorption. Brasseur, F., P. Couvreur, et al. (1980). "Actinomycin D absorbed on polymethylcyanoacrylate nanoparticles: increased efficiency against an experimental tumor." European Journal of Cancer 16(11): 1441-5. Braunstein, P., H. P. Kormann, et al. (2000). "Strategies for the anchoring of metal complexes, clusters, and colloids inside nanoporous alumina membranes." Chemistry 6(24): 4637-46. Two complementary strategies are presented for the anchoring of molecular palladium complexes, of cobalt or platinum clusters or of gold colloids inside the nanopores of alumina membranes. The first consists in the one step condensation of an alkoxysilyl functional group carried by the metal complex with the hydroxy groups covering the surface of the membrane pores. Thus, using the short-bite alkoxysilyl-functionalized diphosphane ligands (Ph2P)2N(CH2)3Si(OMe)3 (1) and (Ph2P)2N(CH2)4SiMe2(OMe)] (2) derived from (Ph2P)2NH (dppa) (dppa bis(diphenylphosphanyl)amine), the palladium complexes [Pd(dmba)(kappa2-P,P(Ph2P)2N(CH2)3Si(OMe)3)] Cl (3) and [Pd(dmba)[kappa2-P,P-(Ph2P)2N(CH2)4SiMe2(OMe)]]Cl (4) (dmba-H = dimethylbenzylamine). respectively, were tethered to the pore walls. After controlled thermal treatment. confined and highly dispersed palladium nanoparticles were formed and characterized by transmission electron microscopy (TEM). This method could not be applied to the cobalt cluster [Co4(CO)8(mu-dppa)[mu-P,P(Ph2P)2N(CH2)4SiMe2(OMe)]] (7) owing to its too limited solubility. However, its anchoring was achieved by using the second method which consisted of first derivatizing the pore walls with 1 or 2. The covalent attachment of the diphosphane ligands provides a molecular anchor that allows subsequent reaction with the cluster [Co4(CO)10(mu-dppa)] 6 to generate anchored 7 and this step was monitored by UV/Vis spectroscopy. In addition, the presence of carbonyl ligands in the cluster provides for the first time a very sensitive spectroscopic probe in the IR region which confirms both cluster incorporation and the retaining of its molecular nature inside the membrane. The presence of the bridging dppa ligand in 6 provides additional stabilization and accounts for the selectivity of the procedure. Using this method, platinum clusters (diameter ca. 2 nm) and gold colloids (diameter ca. 13 nm) were immobilized after passing their solution through the functionalized membrane pores. The resulting membranes were characterized by TEM which demonstrated the efficiency of the complexation and showed the high dispersion of the metal loading. The successful application of these methods has demonstrated that nanoporous alumina membranes are not only unique supports to incorporate metal complexes, clusters, or colloids but can also be regarded as functional matrices or microreactors, thus opening new fields for applications.

Brendle, M., P. Diss, et al. (2000). "Nanoparticle detachment: a possible link between macro- and nanotribology?" Baltzer. Tribology Letters 9: 1-2. Although particle detachment is a common phenomenon associated with most tribological processes, it seldom occurs that each piece of elemental debris can be considered as the result of a single event. Such an association has been revealed by the systematic study of a specific system, where a pin of graphite is made to rub against thoroughly polished steel. While the discontinuous nature of the transfer film allows a quantitative assessment of the volume of transfer h, to be made by 3D optical-profilometry, the linear dependence of the rate of particle detachment dh/sub e//dn (n=number of rubbing cycles) with the logarithm of sliding speed v strongly suggests the existence of a particular type of stick-slip, where each stick may lead to the detachment of a debris particle. The variations in size of these debris with environment as revealed by AFM, further suggest that the global rate of particle detachment is of the form: dh/sub e//dn=Nx epsilon /sub i/, where N is the number of stick-slip events per rubbing cycle, x the proportion of stick events leading to a cohesive rupture, and epsilon /sub i/ the mean volume of an elemental particle. While this relation is apparently supported by most experimental results, its actual validation can only be made by experiments at the level of single (nanoscale) asperities, carried out under wellcontrolled experimental conditions. (12 References). Breton, P., X. Guillon, et al. (1998). "Physico-chemical characterization, preparation and performance of poly (methylidene malonate 2.1.2) nanoparticles." Biomaterials 19(1-3): 271-81. The present investigation confirms that initially implemented procedure to produce poly(methylidene malonate 2.1.2) (PMM 2.1.2) nanoparticles (Lescure et al. Pharm Res 1994;11:1270-77) lead to products mostly containing plasticizing oligomers which strongly lowered glass-transition temperature (Tg), dramatically reduced nanoparticle consistency and rendered them too sensitive to solubilization when diluted in an aqueous medium. From MALDITOF spectroscopy analysis, performed on intact colloids, emerged some structural information about these oligomeric species which could result from an intramolecular cyclization mechanism occurring soon in the course of the polymerization process. Thus, with the objective of overcoming these drawbacks, this contribution deals with the variations of manufacturing specifications such as pH and magnetic stirring speed to try and modulate molecular weight (MW) of nanoparticle constituents and reduce oligomer concentration. Although the analyses performed on these new nanoparticles were rather encouraging, the colloid formation yield became so low that it required the development of other methodologies, excluding a previous emulsion step, and allowing a controlled production of PMM 2.1.2-made nanoparticles having better physico-chemical characteristics while keeping good pharmaceutical capabilities. Breulmann, M., S. A. Davis, et al. (2000). "Polymer-gel templating of porous inorganic macro-structures using nanoparticle building blocks." Advanced Materials 12(7): 502-7. 3D inorganic monoliths with sponge-like texture have been produced using polymer-gel templates. Colloidal suspensions of magnetite or titanium dioxide nanoparticles were diffused into swellable gels composed of acrylic acid-based copolymers, and possessing 3D channels. Hybrid composites were produced that could be subsequently transformed into ceramic monoliths with macroporous structure. (12 References). Brigger, I., P. Chaminade, et al. (2000). "Near infrared with principal component analysis as a novel analytical approach for nanoparticle technology." Pharmaceutical Research 17(9): 1124-1132. Purpose. To progress in the characterization of a poly(MePEGcyanoacrylate-co-hexadecylcyanoacrylate) (poly(PEGCA-co-HDCA) copolymer and the nanoparticles formed from this copolymer. Methods. Poly(PEGCAco-HDCA) at a MePEG/hexadecyl ratio of 1:4 was investigated by 1H-NMR and near infrared spectroscopy. The nanoparticle suspensions, obtained by the methods of nanoprecipitation or emulsion-solvent evaporation, as well as the crude nanoparticles and their dispersion medium-were analyzed by MePEG measurement, 1H-NMR, and near infrared spectroscopy. Results. The 1H-NMR results showed that the (poly(PEGCA-co-HDCA) copolymer obtained bore lateral hydrophilic MePEG chains and lateral hydrophobic hexadecyl chains in a final ratio of 1:4. However, this ratio, although reproducible from batch to batch, represented only a mean value for different molecular species. Indeed, our results demonstrated the formation of more hydrophobic poly(alkylcyanoacrylate) oligomers (with a higher content of hexadecyl chains) and other more hydrophilic oligomers (with a higher MePEG content). Only the more hydrophobic oligomers were able to form solid pegylated nanoparticles. As far as these nanoparticles were concerned, determination of their MePEG content allowed the calculation of a distance of 1.2 nm and 1.05 nm between 2 grafted MePEG chains at the nanoparticle surface, when obtained by nanoprecipitation and emulsion-solvent evaporation, respectively. Moreover, when the same copolymer batch was used, different nanoparticles were obtained according to the preparation method, as seen by near infrared spectroscopy. Conclusions. The nanoparticles obtained by nanoprecipitation or emulsion-solvent evaporation of poly(PEGCA-co-HDCA) 1:4 copolymer displayed a different supramolecular organization, as evidenced by the near infrared spectroscopy results. Moreover, these nanoparticles showed surface characteristics compatible with a long circulating carrier.

Brigger, I., P. Chaminade, et al. (2001). "Tamoxifen encapsulation within polyethylene glycol-coated nanospheres. A new antiestrogen formulation." International Journal of Pharmacology 214(1-2): 37-42. When dealing with solid tumors in vivo, pegylated long-circulating carrier systems show, after intravenous administration, an attractive extravasation profile with an enhanced localization in the tumoral interstitium. These systems could be of help for the delivery of cancer fighting drugs, such as Tamoxifen, a well known antiestrogen used in breast cancer therapy that possesses an extended biodistribution in vivo. This work aimed at encapsulating Tamoxifen in long-circulating poly(MePEGcyanoacrylate-co-hexadecylcyanoacrylate) 1:4 nanospheres. Tamoxifen-loaded poly(MePEGcyanoacrylate-co-hexadecylcyanoacrylate) nanospheres were successfully synthesized and characterized in terms of hydrophilicity/hydrophobicity by a model made up from near infrared spectra using principal component analysis. Zeta potential, drug loading, encapsulation efficiency, as well as biological effect, in vitro release and nanospheres integrity were also investigated. Even though near infrared spectroscopy could not detect Tamoxifen, it revealed that Pluronic F68 was associated with the pegylated nanospheres. HPLC measurements demonstrated that Tamoxifen was encapsulated in the pegylated nanospheres following a partition equilibrium between the polymeric and the aqueous phases. The Tamoxifen encapsulated in the nanospheres still showed a transcription inhibitory activity in ex vivo experiments. However, zeta potential and in vitro release suggested that Tamoxifen was essentially localized at the nanoparticles surface, resulting in an important and immediate drug release. Brongersma, M. L., J. W. Hartman, et al. (2000). "Electromagnetic energy transfer and switching in nanoparticle chain arrays below the diffraction limit." Physical Review B Condensed Matter 62(24). Electromagnetic energy transfer in plasmon wires consisting of chains of closely spaced metal nanoparticles can occur below the diffraction limit by means of coupled plasmon modes. Coherent propagation with group velocities that exceed 0.1 c is possible in straight wires and around sharp corners (bending radius much less than wavelength of visible light). Energy transmission through chain networks is possible at high efficiencies and is a strong function of the frequency and polarization direction of the plasmon mode. Although these structures exhibit transmission losses due to heating of about 3 dB/500 nm, they have optical functionality that cannot be obtained in other ways at a length scale <<1 mu m. (25 References). Bronstein, L. M., D. M. Chernyshov, et al. (2000). "Metal nanoparticles grown in the nanostructured matrix of poly(octadecylsiloxane)." Langmuir 16(22): 8221-5. Metal nanoparticles grown within the nanostructured matrix of the amphiphilic polymer poly(octadecylsiloxane) (PODS) are investigated here by transmission electron microscopy. Due to its silanol groups and alkyl chain, PODS forms a bilayered nanostructure containing an intercalated layer of water within an aqueous environment, replacement of water molecules with metal ions within the siloxy bilayers, followed by reduction, results in the formation of metal nanoparticles. The increase in electron density upon nanoparticle formation permits direct visualization of these bilayers, as well as the individual nanoparticles residing within them. These nanoparticles measure about 1-2 nm in diameter and possess a relatively narrow size distribution due presumably to volume availability within the ordered bilayers of PODS. (15 References). Bronstein, L. M., D. M. Chernyshov, et al. (2000). "IRS and ESR characterizations of nanocomposite thin films derived from alkanethiolates and gold nanoparticles." Nondestructive Methods for Materials Characterization. Symposium 591: 255-60. A key to the ultimate technological applications of core-shell nanoparticle materials is the understanding of the structure-property correlation. This work focuses on the characterizations of the structural properties for composite thin films derived from gold nanoparticles and thiolates using infrared reflectance spectroscopic (IRS) and electron spin resonance (ESR) techniques. IRS provides information on molecular packing and ordering of the shell components in the films, which relates to the molecular interactions and interfacial reactivities. ESR probes the conduction electron spin resonance properties of the nanosized cores, which can be correlated with the network or environmental electronic effects on the crystal cores. Results are discussed in terms of their correlation with the nanoparticle core sizes and the organic shell functionality. (13 References). Brown, J. E., M. J. Clayton, et al. (2000). "Comparison of the particle size distribution of heavy -duty diesel exhaust using a dilution tailpipe sampler and an in-plume sampler during on-road operation." Journal of Air and Waste Management Association 50(8): 1407-16. Originally constructed to develop gaseous emission factors for heavy -duty diesel trucks, the U.S. Environmental Protection Agency's (EPA) On-Road Diesel Emissions Characterization Facility has been modified to incorporate particle measurement instrumentation. An electrical low-pressure impactor designed to continuously measure and record size distribution data was used to monitor the particle size distribution of heavy -duty diesel truck exhaust. For this study, which involved a high-mileage (900,000 mi) truck running at full load, samples were collected by two different methods. One sample was obtained directly from the exhaust stack using an adaptation of the University of Minnesota's air-ejector-based mini-dilution sampler. The second sample was pulled from the plume just above the enclosed trailer, at a point approximately 11 m from the exhaust discharge. Typical dilution ratios of

about 300:1 were obtained for both the dilution and plume sampling systems. Hundreds of particle size distributions were obtained at each sampling location. These were compared both selectively and cumulatively to evaluate the performance of the dilution system in simulating real-world exhaust plumes. The data show that, in its current residence-time configuration, the dilution system imposes a statistically significant bias toward smaller particles, with substantially more nanoparticles being collected than from the plume sample. Brugger, C., S. Tasch, et al. (2000). "Electroluminescence devices with CdS and CdS:Mn nanoparticles and polymer blends." Nanophase and Nanocomposite Materials III. Symposium 581: 405-10. We have investigated the photophysical properties of surface capped CdS and CdS:Mn nanoparticles in the form of spin coated thin films of the pure nanoparticles and nanoparticle polymer blends. The organic capping reagent was p-thiocresol. Electroluminescence (EL) devices were fabricated and characterized by their current/voltage characteristics and EL emission performance. This is to our knowledge the first report on Mn doped CdS nanoparticles applied in EL devices with a single layer device structure (ITO/CdS:Mn/Al). Photoluminescence (PL) and PL excitation measurements were performed on CdS:Mn nanoparticles in pyridine dispersion and on thin films. The PL excitation spectrum shows a narrow peak at 390 nm. Excitation at this wavelength yields a broad PL spectrum spanning from about 450 to 700 nm, which is dominated by a strong emission band at 585 nm. This emission is attributed to transitions involving Mn levels in previous works. The EL emission peak is shifted to the red compared to the PL emission spectra. The characteristics and performance of these new types of EL devices are presented and discussed. (20 References). Bulavchenko, A. I., E. K. Batishcheva, et al. (2000). "Direct potentiometric titration of chloride and fluoride ions in reversed micelles of an ethoxylated surfactant." Fresenius Journal of Analytical Chemistry 366(1): 59-63. The possibility of the potentiometric titration of Cl- and F- ions directly in reversed micelles of the ethoxylated surfactant (Neonol APh9-4) in n-decane is shown. The potential change of the indicator electrode (silver chloride and lanthanum fluoride) only depends on the ion concentration in the aqueous pseudophase of the reversed micelles and is independent of the aqueous phase concentration in n-decane in the region of concentrations from 4 to 0.2 vol %. The determination of the micelle size of Neonol APh9-4 in the precipitation titration of Cl- and F ions by photon correlation spectroscopy showed the formation of nanoparticles of AgCl and LaF3 of dimensions limited by original micelle size (r(hd) = 6 to 11 nm). The growth of AgCl and LaF3 nanoparticles was studied at a shortage and excess of the titrant and in the point of equivalence. Bulte, J. W., R. A. Brooks, et al. (1998). "T1 and T2 relaxometry of monocrystalline iron oxide nanoparticles (MION-46L): theory and experiment." Academic Radiology 5 Suppl 1(3): S137-40; discussion S145-6. Bulte, J. W., S. Zhang, et al. (1999). "Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination." Proceedings of the National Academy of Sciences U S A 96(26): 15256-61. Demyelination is a common pathological finding in human neurological diseases and frequently persists as a result of failure of endogenous repair. Transplanted oligodendrocytes and their precursor cells can (re)myelinate axons, raising the possibility of therapeutic intervention. The migratory capacity of transplanted cells is of key importance in determining the extent of (re)myelination and can, at present, be evaluated only by using invasive and irreversible procedures. We have exploited the transferrin receptor as an efficient intracellular delivery device for magnetic nanoparticles, and transplanted tagged oligodendrocyte progenitor cells into the spinal cord of myelin-deficient rats. Cell migration could be easily detected by using three-dimensional magnetic resonance microscopy, with a close correlation between the areas of contrast enhancement and the achieved extent of myelination. The present results demonstrate that magnetic resonance tracking of transplanted oligodendrocyte progenitors is feasible; this technique has the potential to be easily extended to other neurotransplantation studies involving different precursor cell types. Bunjes, H., M. Drechsler, et al. (2001). "Incorporation of the model drug ubidecarenone into solid lipid nanoparticles." Pharmacology Research 18(3): 287-93. PURPOSE: The impact of drug incorporation on melt-homogenized tripalmitin nanoparticles is investigated with ubidecarenone as a model drug. The dispersions are studied with respect to their drug loading capacity, localization and physical state of the drug as well as to potential changes of the nanoparticle properties due to interactions between drug and triglyceride matrix. METHODS: The investigations were carried out using photon correlation spectroscopy, differential scanning calorimetry, synchrotron radiation X-ray diffraction, ultracentrifugation, and cryo- and freeze-fracture transmission electron microscopy. RESULTS: Ubidecarenone can be incorporated into the dispersions in concentrations higher than 50% of the dispersed phase. The drug is associated with the nanoparticles such that small drug amounts are bound tightly to the carrier matrix while excess drug adheres as a liquid phase to the crystalline particles. Drug incorporation lowers the crystallization and melting temperature of the particle matrix and accelerates the transition of the triglyceride into the stable beta-polymorph after crystallization. CONCLUSIONS: Drug incorporation may significantly alter important

physicochemical parameters of solid lipid nanoparticles. Slow release of ubidecarenone may only be possible for the fraction of drug which is tightly bound to the matrix while the liquid fraction should be rapidly released. Cabot, A., J. Arbiol, et al. (2000). "Dynamic response of the 2Ag state in nanopolyacetylene on the time scale from femtoseconds to milliseconds." Conference on Lasers and Electro Optics 39(IEEE Cat. No.00CH37088). Nanopolyacetylene (nano-(CH)/sub x/) is a pi conjugated material in which 10-nm polyacetylene nanoparticles are dispersed in a polyvinylbutyral matrix. Each nanoparticle comprises of packed pi -conjugated chains of length about 30 double bond (C=C). The absorption spectrum of nano-(CH)/sub x/ has a well-resolved vibronic structure with the zero-phonon line at 1.7 eV. Nano-(CH)/sub x/ has a excellent long-term stability and reveals no symptoms of photooxidization. We present results obtained on nonoriented films of trans-cis blend of nano(CH)/sub x/ at 300 K. (0 References). Callender, R. L. and A. R. Barron (2000). "Facile synthesis of aluminum-containing mixed-metal oxides using doped carboxylate alumoxane nanoparticles." Journal of the American Ceramic Society 83(7): 1777-89. A simple and rapid process has been developed that allows the formation of highly crystalline main-group, lanthanide, and transition-metal aluminates, including CaAl/sub 12/O/sub 19/ (hibonite), Y/sub 3/Al/sub 5/O/sub 28/ (yttrium aluminum garnet, YAG), LaAl/sub 11/O/sub 18/, LaAlO/sub 3/, Ce/sub 2/Al/sub 3/O/sub 8/, NdAlO/sub 3/, Er/sub 6/Al/sub 10/O/sub 24/, and Al/sub 2/TiO/sub 5/. Carboxylate-stabilized alumina nanoparticles (carboxylate alumoxanes) are reacted with the appropriate metal acetylacetonate complexes to form metal-doped carboxylate alumoxanes and aluminum acetylacetonate via a facile transmetalation reaction. Thermolysis of the metal-doped carboxylate alumoxanes, up to a temperature of 1400 degrees C, yields crystalline aluminates, as confirmed by X-ray diffractometry, electron microprobe analysis, and scanning electron microscopy. The synthesis of different phases (i.e., LaAlO/sub 3/O/sub 18/ versus LaAlO/sub 3/) is controlled by the stoichiometry of the transmetalation reaction. A new, distorted, perovskite phase (with lattice parameters of a=5.47 AA and c=13.3 AA) of LaAlO/sub 2/ is formed. The alumoxane methodology results in multicomponent aluminate materials that are obtained in shorter processing times and with greater phase purity than previously reported. This observation is undoubtedly due to the atomic-scale mixing that is inherent in the alumoxane nanoparticle approach. (23 References). Calvo, P., J. L. Vila-Jato, et al. (1996). "Comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules, and nanoemulsions, as ocular drug carriers." Journal of Pharmaceutical Sciences 85(5): 530-6. Three different colloidal carriers, namely, nanoparticles and nanocapsules made of poly-epsilon-caprolactone and submicron emulsions, were designed, and their capacity for increasing the comeal penetration of drugs was investigated. The three systems differed in their inner structure and composition, but they had a similar size (200250 nm) and a negative superficial charge (-16 to -42 mV). Indomethacin, which was used as a model drug, was dispersed at a molecular level within the colloidal systems, no chemical interaction between the polymer and the drug being detected. Release of the encapsulated indomethacin occurred very rapidly upon high dilution in a buffered medium and was independent of the composition of the system. The in vitro comeal penetration of the encapsulated indomethacin was more than 3-fold that of the commercial eye drops. This increased penetration was similar for the three formulations investigated, which therefore excludes the influence of the inner structure or chemical composition of the colloidal systems on the comeal penetration of indomethacin. Thus, it could be stated that the main factor responsible for the favorable comeal transport of indomethacin is the colloidal nature of these carriers rather than their inner structure or composition. Calvo, P., M. J. Alonso, et al. (1996). "Improved ocular bioavailability of indomethacin by novel ocular drug carriers." Journal of Pharmacy and Pharmacology 48(11): 1147-52. The ability of different drug carriers to improve the ocular bioavailability of drugs was investigated in the rabbit eye. The assayed drug carriers were suspensions of nanoparticles, nanocapsules and microparticles made of poly-epsilon-caprolactone (PECL) and a submicron emulsion. Results indicated that the three submicron systems, nanoparticles, nanocapsules and emulsion, increased more than 3-fold the indomethacin concentration in the cornea, aqueous humour and iris-ciliary body at 0.5 and 1 h post-instillation. Furthermore, an increased indomethacin ocular bioavailability of 300% was observed after instillation of the submicron systems in comparison with the value obtained for a commercial solution. In contrast, the microparticles hardly increased the ocular bioavailability of indomethacin. The mechanism of interaction of the colloidal carriers with the corneal epithelium was investigated by confocal laser scanning microscopy. Confocal images indicated that submicron particles penetrate into the corneal epithelium cells by an endocytic mechanism. The similar behaviour of the three colloidal carriers suggests that any of their specific ingredients (PCEL, lecithin and oil) acts as a penetration enhancer or an endocytotic stimulator. On the other hand, the favourable ocular penetration of indomethacin when encapsulated in the colloidal carriers, but not in the microparticles, led us to assume that the colloidal nature of these carriers is the main factor responsible for the increased ocular bioavailability of indomethacin. PECL nanoparticles and nanocapsules as well as submicron emulsions are shown to be novel corneal drug carriers, thus representing a useful approach for increasing the ocular bioavailability of drugs.

Calvo, P., J. L. Vila-Jato, et al. (1997). "Effect of lysozyme on the stability of polyester nanocapsules and nanoparticles: stabilization approaches." Biomaterials 18(19): 1305-10. The efficacy of colloidal particles as drug carriers is closely related to their interaction with proteins and enzymes in different body fluids. In the present work, we analysed the interaction phenomenon between lysozyme (LZM), a positively charged enzyme that is highly concentrated in mucosas, and two different drug carriers: nanocapsules made of an oily core coated by the polymer poly-epsilon-caprolactone (PECL) and nanoparticles made solely of PECL. Results showed that the interaction of LZM with these colloidal drug carriers is highly affected by their surface charge. Nanocapsules, because of their important negative charge (-40 mV), adsorbed a great amount of LZM, which is positively charged. This adsorption process, which was also evidenced by the significant reduction of the nanocapsules' negative surface charge, led to the degradation of the polymer coating and the aggregation of the nanocapsules. In contrast, nanoparticles had a low negative surface charge (-8 mV) and adsorbed only a small amount of LZM, which did not cause the destabilization of the system. Furthermore, the molecular weight of the polymer forming the nanoparticles did not change. Finally, it was observed that the destabilizing effects caused by the adsorption of LZM onto the nanocapsules can be prevented by previous adsorption of the cationic poly(amino acid) poly-L-lysine. Using this approach the adsorption of LZM was hindered and its consequences avoided. Calvo, P., C. Remunan-Lopez, et al. (1997). "Chitosan and chitosan/ethylene oxide-propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines." Pharm Res 14(10): 1431-6. PURPOSE: The aim of this study was to investigate the interaction between the components of novel chitosan (CS) and CS/ethylene oxide-propylene oxide block copolymer (PEO-PPO) nanoparticles and to evaluate their potential for the association and controlled release of proteins and vaccines. METHODS: The presence of PEOPPO on the surface of the nanoparticles and its interaction with the CS was identified by X-ray photoelectron spectroscopy (XPS). The mechanism of protein association was elucidated using several proteins, bovine serum albumin (BSA), and tetanus and diphtheria toxoids, and varying the formulation conditions (different pH values and concentrations of PEO-PPO), and the stage of protein incorporation into the nanoparticles formation medium. RESULTS: BSA and tetanus and diphtheria toxoids were highly associated with CS nanoparticles partly due to electrostatic interactions between the carboxyl groups of the protein and the amine groups of CS. PEO-PPO also interacted electrostatically with CS, thus competing with the proteins for association with CS nanoparticles. A visible amount of PEO-PPO was projected towards the outer phase of the nanoparticles. Proteins were released from the nanoparticles at an almost constant rate, the intensity of which was closely related to the protein loading. Furthermore, the tetanus vaccine was released in the active form for at least 15 days. CONCLUSIONS: CS and CS/PEO-PPO nanoparticles prepared by a very mild ionic crosslinking technique are novel and suitable systems for the entrapment and controlled release of proteins and vaccines. Canali, C. M. and A. H. MacDonald (2000). "Theory of tunneling spectroscopy in ferromagnetic nanoparticles." Physical Review Letters 85(26): 5623-6. We present a theory of the low-energy excitations of a ferromagnetic metal nanoparticle. In addition to the particle-hole excitations, which occur in a paramagnetic metal nanoparticle, we predict a branch of excitations involving the magnetization-orientation collective coordinate. Tunneling matrix elements are in general sizable for several different collective states associated with the same band configuration. We point out that the average change in ground state spin per added electron differs from noninteracting quasiparticle expectations, and that the change in the spin polarization, due to Zeeman coupling, is strongly influenced by Coulomb blockade physics. (18 References). Cappel, M. J. and J. Kreuter (1991). "Effect of nanoparticles on transdermal drug delivery." Journal of Microencapsulation 8(3): 369-74. The purpose of the present study was to assess by in vitro means the effect of poly (methylmethacrylate) nanoparticles and poly (butylcyanoacrylate) nanoparticles on transdermal drug delivery. Methanol and octanol were chosen as test permeants. In order to distinguish between thermodynamic effect and those due to biological consequences, two different membranes were employed, i.e., full thickness hairless mouse skin and silicone elastomer sheeting (175 microns). It is evident that poly (methylmethacrylate) nanoparticles and poly (butylcyanoacrylate) nanoparticles increase the permeability of methanol through hairless mouse skin by a factor of 1.2-2. The permeability of lipophilic octanol is either unaffected by nanoparticles or decreases as a function of nanoparticle concentration depending on the lipophilicity of the polymer material. Carpignano, R., M. R. Gasco, et al. (1991). "Optimization of doxorubicine incorporation and of the yield of polybutylcyanacrylate nanoparticles." Pharmaceutica Acta Helvetiae 66(1): 28-32. The preparation from w/o microemulsion of polybutylcianacrylate nanocapsules incorporating doxorubicine was optimized applying a multivariate experimental design. Different variables were investigated; the responses were polymer yield, concentration of the drug in the particles and percentage of the drug incorporated. A preliminary

study was carried out with the strategy of fractional factorial design; the following step was a central composite design in order to study the most important causal variables. The information collected were treated by the response surface method (REGFAC package). The optimization allowed to maximize the responses; an incorporation of about 10% of doxorubicine and a yield of about 95% were obtained, starting from values notably lower of both incorporation and yield. Carreno-Gomez, B., J. F. Woodley, et al. (1999). "Studies on the uptake of tomato lectin nanoparticles in everted gut sacs." International Journal of Pharmacy 183(1): 7-11. Tomato lectin (TL) is a bioadhesive glycoprotein that has been shown to bind selectively to the small intestine epithelium. When bound to polystyrene microspheres, intestinal uptake occurs not only through the gut associated lymphoid tissue (GALT) but also through normal enterocytes. In this study, the everted gut sac model was used to compare the rates and quantities of intestinal uptake of tomato lectin and that of TL coupled to microspheres. Using bovine serum albumin (BSA) and BSA coupled to microspheres as comparators. Uptake is time and concentration dependent. Transfer of TL from the lumen to the serosa was 3.9 ng/mg per h whereas that of BSA was 0.5 ng/mg per h. Hence uptake of tomato lectin was 7-fold higher than BSA. The rate of uptake of TL coupled microspheres was 41.5 ng/mg per h, which was 4-fold higher than microspheres coupled to BSA (11.8 ng/mg per h). The uptake of TL conjugated microspheres was shown to be inhibited by N-acetyl-d-glucosamine tetramer [GlcNac]4. Caruso, F., R. A. Caruso, et al. (1998). "Nanoengineering of inorganic and hybrid hollow spheres by colloidal templating." Science 282(5391): 1111-4. Hollow silica and silica-polymer spheres with diameters between 720 and 1000 nanometers were fabricated by consecutively assembling silica nanoparticles and polymer onto colloids and subsequently removing the templated colloid either by calcination or decomposition upon exposure to solvents. Scanning and transmission electron microscopy images demonstrate that the wall thickness of the hollow spheres can be readily controlled by varying the number of nanoparticle-polymer deposition cycles, and the size and shape are determined by the morphology of the templating colloid. The hollow spheres produced are envisioned to have applications in areas ranging from medicine to pharmaceutics to materials science. Castignolles, N., S. Morgeaux, et al. (1996). "A new family of carriers (biovectors) enhances the immunogenicity of rabies antigens." Vaccine 14(14): 1353-60. Biovectors (BV) are a new family of protein carriers. They are nanoparticles of polymerized polysaccharides substituted with phosphate residues and surrounded by covalently bound lipid molecules (palmitic acid). The effect of BV was tested on the immunogenicity of rabies antigens. Biovectors enhanced the production of antibody induced by both rabies glycoprotein and ribonucleoprotein. Moreover, they enhanced the protective activity of an experimental rabies vaccine composed of inactivated and purified virus. The isotype profile of antibody produced in vivo was not modified when BV were mixed with rabies antigens. To clarify the mechanism of the adjuvant/ immunostimulation effect of BV, two types of approach were used: (1) analysis of the antibody response when antigen and BV were injected separately; (2) determination of the nature of cells involved in the proliferation in vitro of murine splenocytes in the presence of BV. The enhancing effect of BV on antibody production was highest when mixed with antigens. In vitro BV induced the proliferation of B cells. These findings suggest that BV have immunostimulating properties in addition to their probable depot and/or antigen-presentation effect which explain in part their adjuvant activity. Cavalli, R., E. Peira, et al. (1999). "Solid lipid nanoparticles as carriers of hydrocortisone and progesterone complexes with beta-cyclodextrins." International Journal of Pharmacy 182(1): 59-69. Inclusion complexes of hydrocortisone and progesterone were formed with beta-cyclodextrin or 2-hydroxypropylbeta-cyclodextrin. The formation of the complexes was confirmed by differential scanning calorimetry (DSC). The inclusion complexes were incorporated in two types of solid lipid nanoparticles (SLN). In the presence of the complexes the sizes of SLN remained below 100 nm. DSC analysis showed that hydrocortisone and progesterone are dispersed in SLN in an amorphous state. Using the beta-cyclodextrin complexes the incorporation of the more hydrophilic drug, hydrocortisone, was higher than that of progesterone. Release of hydrocortisone and progesterone from SLN was lower when they were incorporated as inclusion complexes than as free molecules. Copyright Chacon, M., J. Molpeceres, et al. (1999). "Stability and freeze-drying of cyclosporine loaded poly(D,L lactide-glycolide) carriers." European Journal of Pharmaceutical Sciences 8(2): 99-107. The present paper describes the stability of poly (D, L-lactide-glycolide) nanoparticles (PLGA NP) and microspheres (MS), either alone or loaded with cyclosporine (CyA), stored at 8 degrees C and room temperature (RT). Freeze-drying of these formulations was evaluated as an alternative method to achieve long term stability. A significant polymer rupture was detected during PLGA MS preparation by solvent evaporation, which correlated with the stirring rates used for the formation of the primary emulsion. On the other hand, the polymer remained

unchanged during NP formation. After 6 months of storage, PLGA NP of a size below 80 nm aggregated when stored at RT whereas no changes of particle size were observed for the remaining formulations and experimental conditions. Drug entrapment significantly increased by about 9.5% only during PLGA NP storage at RT. The PLGA molecular weight of NP dropped at RT being these changes related to the initial particle size and amount of CyA incorporated. The same effect was observed at 8 degrees C but only the particle size showed a significant influence. The drop of PLGA molecular weight observed during storage of MS was not dependent on the storage temperature but it was directly related to the molecular weights obtained after MS preparation. Freeze-drying studies revealed that it was not feasible to maintain the initial PLGA NP characteristics after reconstitution. On the other hand, MS lyophilized in the absence of cryoprotectants retained the drug initially entrapped; however, the presence of at least 5% cryoprotectant was essential to keep the initial particle size. Therefore, PLGA NP and MS show a significant instability when stored as suspensions. Freeze-drying offers a good alternative to stabilize polymeric MS but the preservation of the PLGA NP characteristics by freeze-drying needs for further investigations. Chan, D. C., H. W. Titus, et al. (1999). "Radiopacity of tantalum oxide nanoparticle filled resins." Dental Materials 15(3): 219-22. OBJECTIVES: Radiopacity of composite resins allows radiographic distinction of existing restorations and recurrent caries. Current composites must be supplemented with heavy metal-containing glasses or minerals to achieve a desired radiopacity. The purpose of this study was to evaluate the radiopacity of Tantalum oxide (Ta2O5) filled resins at varying percentage loadings. METHODS: Methacrylate functionalized Ta2O5 nanoparticles (&lt; 50 nm) in methanol-dissolved or powder forms were mixed into either glycerol dimethacrylate (GDMA) or a bisGMA, TEGDMA, bisEMA mixture (GTE). Specimens were made in a split brass mold (2 x 2 x 15 mm) and compared with an aluminum stepwedge (99.5% pure Al) and a dentin slice of the same thickness. Kodak Ultraspeed periapical X-ray film on a lead plate at a target distance of 45 cm was exposed at 70 kVp and 10 mA, for 0.5 s and processed automatically. Optical density was measured (n = 3) with an RMI Processor Control Densitometer. Radiopacity was calculated as percent relative linear attenuation coefficient (Alpha). ANOVA and Student-Newman-Keuls comparisons were used to determine significance at the 95% confidence level. RESULTS: Radiopacity increased significantly with Ta2O5 loading (p = 0.001). Ta2O5 nanoparticle filled resins enter the optimal range of diagnostic detectability (alpha = 150-250) at 50 wt.% and approach equivalence with enamel at approximately 70 wt.%. SIGNIFICANCE: The introduction of tantalum oxide nanoparticle filler has potential as a miscible component of a resin composite to provide radiopacity for microfiller-type restorative materials and to circumvent the need for hydrolysis-prone glass reinforcing fillers. Chang, C. L., C. L. Dong, et al. (2000). "Valence state of CeAl 2 nanoparticles studied by Ce L3-edge X-ray absorption spectroscopy." Journal of Applied Physics 87(7): 3349-50. We report measurements of the Ce L/sub 3/-edge X-ray absorption near-edge structure on CeAl/sub 2/ nanoparticles with average diameters of 80 AA. The Ce exhibits a mixed valence with a small amount of tetravalent Ce, which is in contrast to the purely trivalent Ce observed in bulk CeAl/sub 2/. A shift in the absorption edge to higher energy and a narrower linewidth are also observed in the nanoparticle samples. These spectral differences are attributed to surface effects caused by the small particle size, including a lower coordination number and higher surface pressure. The observation of nonmagnetic tetravalent Ce with the 4f/sup 0/ configuration is in good agreement with the small values of magnetic entropy seen in low temperature specific heat measurements. (15 References). Chavany, C., T. Le Doan, et al. (1992). "Polyalkylcyanoacrylate nanoparticles as polymeric carriers for antisense oligonucleotides." Pharm Res 9(4): 441-9. Adsorption of oligothymidylates on polyisobutyl- or polyisohexylcyanoacrylate nanoparticles was achieved in the presence of hydrophobic cations such as tetraphenylphosphonium chloride or quaternary ammonium salts. Results suggested that oligonucleotide adsorption on the nanoparticles was mediated by the formation of ion pairs between the negatively charged phosphate groups of the nucleic acid chain and the hydrophobic cations. The adsorption efficiency of oligonucleotide-cation complexes on nanoparticles was found to be highly dependent upon several parameters: oligonucleotide chain length, nature of the cyanoacrylic monomer, hydrophobicity of cations used as ion-pairing agents, and ionic concentration of the medium. Carrier capacity of polyisohexylcyanoacrylate nanoparticles for oligothymidylates (16 nucleotides) complexed with cetyltrimetylammonium bromide in the presence of 0.15 M NaCl was determined to be 5 mumol/g polymer. The in vitro protection of oligothymidylates adsorbed to nanoparticles against degradation by a 3'-exonuclease (snake venom phosphodiesterase) was also demonstrated. These results showed that nanoparticles can be considered as convenient carriers for the protection and delivery of oligonucleotides to cells in culture and for future applications in vivo. Chavany, C., T. Saison-Behmoaras, et al. (1994). "Adsorption of oligonucleotides onto polyisohexylcyanoacrylate nanoparticles protects them against nucleases and increases their cellular uptake." Pharm Res 11(9): 1370-8.

Oligonucleotides can be adsorbed on polyisohexylcyanoacrylate nanoparticles in the presence of hydrophobic quarternary ammonium salts. Oligonucleotides bound to nanoparticles are protected from nuclease attack both in buffer and in cell culture media. Cellular uptake of oligonucleotides is increased when they are adsorbed onto nanoparticles as a result of the capture of nanoparticles by an endocytic phagocytic pathway. Intracellular stability towards nucleolytic degradation is increased in the presence of nanoparticles. These results show that nanoparticles can be considered as convenient carriers for the protection and delivery of oligonucleotides to cells. Chemla, Y. R., H. L. Grossman, et al. (2000). "Ultrasensitive magnetic biosensor for homogeneous immunoassay." Proceedings of the National Academy of Sciences of the United States of America 97(26): 14268-14272. A technique is described for specific, sensitive, quantitative, and rapid detection of biological targets by using superparamagnetic nanoparticles and a "microscope" based on a high-transition temperature dc superconducting quantum interference device (SQUID). In this technique, a mylar film to which the targets have been bound is placed on the microscope. The film, at room temperature and atmospheric pressure, is typically 40 mum from the SQUID, which is at 77 K in a vacuum. A suspension of magnetic nanoparticles carrying antibodies directed against the target is added to the mixture in the well, and 1-s pulses of magnetic field are applied parallel to the SQUID. In the presence of this aligning field the nanoparticles develop a net magnetization, which relaxes when the field is turned off. Unbound nanoparticles relax rapidly by Brownian rotation and contribute no measurable signal. Nanoparticles that are bound to the target on the film are immobilized and undergo Neel relaxation, producing a slowly decaying magnetic flux, which is detected by the SQUID. The ability to distinguish between bound and unbound labels allows one to run homogeneous assays, which do not require separation and removal of unbound magnetic particles. The technique has been demonstrated with a model system of liposomes carrying the FLAG epitope. The SQUID microscope requires no more than (5 +- 2) X 104 magnetic nanoparticles to register a reproducible signal. Chen, X. Y., J. R. Li, et al. (1998). "A new step to the mechanism of the enhancement effect of gold nanoparticles on glucose oxidase." Biochemical and Biophysical Research Communications 245(2): 352-5. Quantum size effect was strongly supported by the experiment on correlation between size of gold nanoparticles (below 10 nm) and activity of glucose oxidase attached to them. The attractive enhancement effect of gold nanoparticles on the activity of glucose oxidase was then satisfactorily explained. In this experiment, 2 nm and 6 nm (average diameter) particles were obtained on monolayer matrix. The 2 nm particles proved to be much more able to increase the activity of glucose oxidase. Chen, S., R. S. Ingram, et al. (1998). "Gold nanoelectrodes of varied size: transition to molecule-like charging." Science 280(5372): 2098-101. A transition from metal-like double-layer capacitive charging to redox-like charging was observed in electrochemical ensemble Coulomb staircase experiments on solutions of gold nanoparticles of varied core size. The monodisperse gold nanoparticles are stabilized by short-chain alkanethiolate monolayers and have 8 to 38 kilodaltons core mass (1.1 to 1.9 nanometers in diameter). Larger cores display Coulomb staircase responses consistent with double-layer charging of metal-electrolyte interfaces, whereas smaller core nanoparticles exhibit redox chemical character, including a large central gap. The change in behavior is consistent with new nearinfrared spectroscopic data showing an emerging gap between the highest occupied and lowest unoccupied orbitals of 0.4 to 0.9 electron volt. Chen, X., J. Li, et al. (2000). "Anisotropic optical constants of aggregated gold films by reflection and transmission ellipsometry." Thin Solid Films 375: 1-2. Studies of optical properties of aggregated films have usually been performed by considering the properties in the direction parallel to the film surface and, therefore, information on the films was not complete. The techniques of spectroscopic reflection and transmission ellipsometry (RTELL) at variable incident angles developed by our laboratory were particularly suitable for obtaining the anisotropic optical constants for such films with good precision, thus fully characterizing the optical behavior of films. In the present study, aggregated gold films were prepared using solutions containing gold nanoparticles, giving films with a very low filling factor. With the help of an automated RTELL system, the anisotropic optical constants have been determined in the spectral range from 300 to 800 nm. The results obtained showed a striking difference between the parallel and the perpendicular optical constants. This difference was well accounted for by using an effective-medium theory, approximating the nanoparticle clusters to rotational ellipsoids. (10 References). Chen, S. (2000). "Two-dimensional crosslinked nanoparticle networks." Advanced Materials 12(3): 186-9. Monolayer-protected nanoclusters exhibit good stability both in solution and dry forms and as such are promising materials for nanocircuits and nanodevices. In this article, an efficient method for fabricating 2D crosslinked nanoparticle networks using the Langmuir-Blodgett technique and dithiols as bifunctional linkers is reported. (31 References).

Chen, G. (2000). "Particularities of heat conduction in nanostructures." Journal of Nanoparticle Research 2: 199-204. Chen, W., W. Cai, et al. (2001). "Sonochemical processes and formation of gold nanoparticles within pores of mesoporous silica." Journal of Colloid and Interface Science 238(2): 291-295. Mesoporous silica with gold nanoparticles inside its pores was prepared by the soaking and ultrasound-induced reduction method. This new composite was characterized by X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET), and high-resolution transmission electron microscopy (HRTEM) techniques. The results showed that nearly spherical-shaped gold nanoparticles, with mean size in diameter of 5.2 nm, are located in the pores, most of which are less than 6 nm in diameter. The ultrasonic irradiation time dependence of optical absorption for the soaked porous solid sample, as suggested by the variation in absorbance at 310 and 544 nm, indicated the reduction of Au (III) ions, and the nucleation and aggregation of gold nanoparticles within pores of mesoporous silica. Additionally, the reaction rates estimated phenomenologically by the absorbance decay at 310 nm for both the porous sample and the corresponding soaking solution presented the enhancement of the sonochemical reduction rate of Au (III) ions within pores of mesoporous silica. It is assumed that the extensive liquid-solid interfacial zones in the pores, due to the high specific surface areas and great porosity of the mesoporous solid, are the major regions where the efficient sonochemical reduction induced by the cavitation takes place. Copyright 2001 Academic Press. Cherian, A. K., A. C. Rana, et al. (2000). "Self-assembled carbohydrate-stabilized ceramic nanoparticles for the parenteral delivery of insulin." Drug Development and Industrial Pharmacy 26(4): 459-63. The insulin-bearing aquasomes were fabricated by first preparing the nanosize calcium phosphate dihydrate core. The calcium phosphate dihydrate core was prepared by colloidal precipitation and sonication of disodium hydrogen phosphate solution and calcium chloride solution at low temperature. This core was coated with cellobiose, pyridoxal-5-phosphate, or trehalose under sonication and was further loaded with the drug at low temperature by a partial adsorption mechanism. The prepared systems were characterized for size, shape, size distribution, drug loading efficiency, and in vivo performance. The in vivo performance of the formulated aquasome was compared with standard porcine insulin solution, and better results were observed compared to insulin solution. Cherng, J. Y., P. van de Wetering, et al. (1996). "Effect of size and serum proteins on transfection efficiency of poly ((2dimethylamino)ethyl methacrylate)-plasmid nanoparticles." Pharm Res 13(7): 1038-42. PURPOSE: The aim of this study was to gain insight into the relation between the physical characteristics of particles formed by a plasmid and a synthetic cationic polymer (poly(2-dimethylamino)ethyl methacrylate, PDMAEMA) and their transfection efficiency. METHODS: The PDMAEMA-plasmid particles were characterized by dynamic light scattering (size) and electrophoretic mobility measurements (charge). The transfection efficiency was evaluated in cell culture (COS-7 cells) using a pCMV-lacZ plasmid coding for beta-galactosidase as a reporter gene. RESULTS: It was shown that the optimal transfection efficiency was found at a PDMAEMAplasmid ratio of 3 (w/w), yielding stable and rather homogeneous particles (diameter 0.15 micron) with a narrow size distribution and a slightly positive charge. Particles prepared at lower weight ratios, showed a reduced transfection efficiency and were unstable in time as demonstrated by DLS measurements. Like other cationic polymers, PDMAEMA is slightly cytotoxic. This activity was partially masked by complexing the polymer with DNA. Interestingly, the transfection efficiency of the particles was not affected by the presence of serum proteins. CONCLUSIONS: PDMAEMA is an interesting vector for the design of in vivo and ex vivo gene transfection systems. Chhowalla, M. and G. A. Amaratunga (2000). "Thin films of fullerene-like MoS2 nanoparticles with ultra-low friction and wear." Nature 407(6801): 164-7. The tribological properties of solid lubricants such as graphite and the metal dichalcogenides MX2 (where M is molybdenum or tungsten and X is sulphur or selenium) are of technological interest for reducing wear in circumstances where liquid lubricants are impractical, such as in space technology, ultra-high vacuum or automotive transport. These materials are characterized by weak interatomic interactions (van der Waals forces) between their layered structures, allowing easy, low-strength shearing. Although these materials exhibit excellent friction and wear resistance and extended lifetime in vacuum, their tribological properties remain poor in the presence of humidity or oxygen, thereby limiting their technological applications in the Earth's atmosphere. But using MX2 in the form of isolated inorganic fullerene-like hollow nanoparticles similar to carbon fullerenes and nanotubes can improve its performance. Here we show that thin films of hollow MoS2 nanoparticles, deposited by a localized high-pressure arc discharge method, exhibit ultra-low friction (an order of magnitude lower than for sputtered MoS2 thin films) and wear in nitrogen and 45% humidity. We attribute this 'dry' behaviour in humid environments to the presence of curved S-Mo-S planes that prevent oxidation and preserve the layered structure. Chiang, C. L. (2001). "Controlled growth of gold nanoparticles in AOT/C12E4/isooctane mixed reverse micelles." Journal of Colloid and Interface Science 239(2): 334-341.

Stable anisotropic gold nanoparticles were prepared by the reduction of a relatively high concentration of tetrachloroauric acid with hydrazine in mixed reverse micelles formed with anionic surfactant AOT and nonionic surfactant tetraethylene glycol dodecyl ether (C(12)E(4)) in isooctane. It was found that the C(12)E(4) serves not only as a structure modifier but also as a stabilizer for Au particles, to prevent their further growth and precipitation. By the analyses of a high-resolution electron microscope, electron diffraction patterns, and energydispersive X-ray analysis (EDX), the resultant particles have been found to be pure gold of face-centered cubic structure. In the presence of C(12)E(4), the Au particle size is larger than that in the absence of C(12)E(4), while the particle size decreases with increases in the concentration of C(12)E(4). The molar ratio of hydrazine to HAuCl(4) was found to be an important parameter in the control of size and shape for the production of gold nanoparticles. A decrease in the molar ratio of hydrazine to HAuCl(4) resulted in larger Au particles with significantly more polydispersity. When the HAuCl(4) was injected directly into the mixed reversed micelles containing hydrazine, anisotropic gold nanoparticles, such as cylinders and trigons, were obtained at the molar ratio of hydrazine to HAuCl(4) of less than 0.5. Copyright 2001 Academic Press. Chiannilkulchai, N., Z. Driouich, et al. (1989). "[Nanoparticles of doxorubicin: colloidal vectors in the treatment of hepatic metastases in animals]." Bull Cancer 76(8): 845-8. Chiannilkulchai, N., Z. Driouich, et al. (1989). "Doxorubicin-loaded nanoparticles: increased efficiency in murine hepatic metastases." Sel Cancer Ther 5(1): 1-11. Free doxorubicin and doxorubicin associated with polyisohexlycyanoacrylate were tested for their therapeutic efficiency in hepatic metastasis-bearing mice. The metastases originated from the M 5076 reticulum cell sarcoma. Irrespective of the dose and the administration schedule, the reduction of the number of metastases was much larger with the doxorubicin-loaded nanoparticles than with free doxorubicin. This was clearly confirmed by histological examination. Although pharmacological and pharmacokinetic data indicated a strong capture of the nanoparticles by the hepatic issue, the mechanism of nanoparticle therapeutic efficiency remains unclear. Chiannilkulchai, N., N. Ammoury, et al. (1990). "Hepatic tissue distribution of doxorubicin-loaded nanoparticles after i.v. administration in reticulosarcoma M 5076 metastasis-bearing mice." Cancer Chemotherapy and Pharmacology 26(2): 122-6. In our previous studies, doxorubicin-loaded polyisohexylcyanoacrylate nanoparticles have been proven to increase dramatically the antitumoral activity of the cytotoxic agent in metastasis-bearing mice. The experimental model consisted of metastases induced by i.v. inoculation of reticulosarcoma M 5076 cell suspension to C57BL/6 mice. The improved efficacy of the drug was noted in terms of either metastasis count or survival. Therefore, tissue-distribution studies of this drug delivery system within the metastatic liver after i.v. administration were undertaken to gain more insight into the mechanism of action. Doxorubicin measurements in healthy hepatic or neoplastic tissue were carried out together with histological examinations using transmission electron microscopy. These results demonstrated the hepatic tissue to be an efficient reservoir of the drug when it was injected associated with nanoparticles. Accumulation of biodegradable nanoparticles with associated doxorubicin in Kupffer cells created a gradient of drug concentration for a massive and prolonged diffusion of the free drug towards the neoplastic tissue. Cho, C. S., Y. I. Jeong, et al. (1997). "Simple preparation of nanoparticles coated with carbohydrate-carrying polymers." Biomaterials 18(4): 323-6. Nanoparticles bearing carbohydrate chains on the surface can be prepared by the simple diafiltration method. The nanoparticles prepared by the present method displayed high yield, no-aggregation formation, small size, narrow size distribution, and one-step procedure. Also, the high density carbohydrate chains on the particles can be recognized by liver cells. Choe, S., Y. Y. Chang, et al. (2000). "Kinetics of reductive denitrification by nanoscale zero-valent iron." Chemosphere 41(8): 1307-11. Zero-valent iron powder (Fe0) has been determined to be potentially useful for the removal of nitrate in the water environment. This research is aimed at subjecting the kinetics of denitrification by nanoscale Fe0 to an analysis of factors affecting the chemical denitrification of nitrate. Nanoscale iron particles with a diameter in the range of 1100 nm, which are characterized by the large BET specific surface area to mass ratio (31.4 m2/g), removed mostly 50, 100, 200, and 400 mg/l of nitrate within a period of 30 min with little intermediates. Compared with microscale (75-150 microm) Fe0, end product is not ammonia but N2 gas. Kinetics analysis from batch studies revealed that the denitrification reaction with nanoscale Fe0 appeared to be a pseudo first-order with respect to substrate and the observed reaction rate constant (k(obs)) varied with iron content at a relatively low degree of application. The effects of mixing intensity (rpm) on the denitrification rate suggest that the denitrification appears to be coupled with oxidative dissolution of iron through a largely mass transport-limited surface reaction (&lt;40 rpm).

Choe, S., S. H. Lee, et al. (2001). "Rapid reductive destruction of hazardous organic compounds by nanoscale Fe0." Chemosphere 42(4): 367-72. Fe0-mediated reductive destruction of hazardous organic compounds such as chlorinated organic compounds (COCs) and nitroaromatic compounds (NACs) in the aqueous phase is one of the latest innovative technologies. In this paper, rapid reductive degradation of COCs and NACs by synthesized nanoscale Fe0 in anaerobic batch systems was presented. The nanoscale Fe0, characterized by high specific surface area and high reactivity, rapidly transformed trichloroethylene (TCE), chloroform (CF), nitrobenzene (NB), nitrotoluene (NT), dinitrobenzene (DNB) and dinitrotoluene (DNT) under ambient conditions, which results in complete disappearance of the parent compounds from the aqueous phase within a few minutes. GC analysis reported that the main products of the dechlorination of TCE and CF were ethane and methane as well as that most of the nitro groups in NACs were reductively transformed to amine groups. These results suggest that the rapid reductive destruction by nanoscale Fe0 is potentially a viable in situ or aboveground treatment of groundwater contaminated with hazardous organic compounds including COCs and NACs. Chognot, D., M. F. Zambaux, et al. (1999). "Identification of protein C epitopes altered during its nanoencapsulation." Journal of Protein Chemistry 18(7): 779-84. Protein C is a plasmatic inhibitor which regulates the blood coagulation mechanism by modulating the anticoagulant response. The improvement of its bioavailability would be beneficial for the treatment of the disorders caused by its homozygous deficiency or by an other plasmatic inhibitor deficiency. In this context, the protein C encapsulation into biodegradable nanoparticles could be used to approach the problem. However, the method used to prepare the nanoparticles requires the use of ultrasonication and of an organic solvent such as methylene chloride which interferes with protein activity. Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed that neither ultrasonication nor methylene chloride, singly or in combination, led to protein C aggregation or cleavage. Thus, a binding study using an ELISA assay with four characterized monoclonal antibodies was carried out to identify the epitopes damaged by these experimental constraints. The correlation between the immunological assay and a functional one i.e. by the means of the assay of its anticoagulant activity (activated partial thromboplastin time) made it possible to show that protein C amino acids 166-169 of the activation peptide were probably altered after ultrasonication and methylene chloride treatment. Indeed, it is likely that these residues were no longer surface-exposed but had moved inside the protein core. Choi, M., J. Cho, et al. (1999). "Measurements of silica aggregate particle growth using light scattering and thermophoretic sampling in a coflow diffusion flame." Journal of Nanoparticle Research 1: 169-183. Chouly, C., L. Bordenave, et al. (1994). "In vitro study of the hemocompatibility of superparamagnetic contrast agent for magnetic resonance imaging." Clin Mater 15(4): 293-301. Five different nanoparticles, potentially useful in magnetic resonance imaging (MRI) after venous administration, were studied for their hemocompatibility. The in vitro methodology evaluated these materials by several parameters: cytotoxicity towards cells cultured in vitro, aggregation ability of platelets, hemolysis inducibility, intrinsic and extrinsic coagulation pathway activation, and complement activation. With the proposed clinical dose, regardless of the cell type used (murine cell line or human endothelial cells) no toxicity was observed. The presence of the particles in blood did not produce any considerable damage: either hemolysis or platelet aggregation or blood coagulation were recorded. However, a slight decrease in aggregation ability of platelets was noticed as well as an increase in partial thromboplastin time. Because of the quick removal of the particles from the bloodstream, these phenomena must be short-lived, thus avoiding significant adverse clinical effects. Chouly, C., D. Pouliquen, et al. (1996). "Development of superparamagnetic nanoparticles for MRI: effect of particle size, charge and surface nature on biodistribution." Journal of Microencapsulation 13(3): 245-55. Twelve superparamagnetic Magnetite-Dextran (MD) nanoparticles potentially useful as contrast agents for Magnetic Resonance Imaging (MRI), with different sizes, charges and surface natures, were produced and internally labelled with (59)Fe in order to investigate the effect of their physicochemical properties on their biodistribution in mice. In a first step, neutral MD particles of a size 33-90.6 nm were studied. Next, the influence of charge was investigated with negative and positive particles (MDL, MDD, MDDEAE). The former (-25, -30 mV) were small, around 30 nm in size whereas the latter (+20 mV) were larger (104 nm). The effect of surface nature was evaluated using MD particles coated with polyoxyethylene-polyoxypropylene copolymers (Synperonic: these MDP particles were neutral and larger in size (65.9-76.4 nm). Experiments showed that 20 min post-injection (2 mg Fe/kg), liver uptake was enhanced when the mean diameter increased: 22% for the smallest and 42% for the largest. It was up to 3 X lower for electrically neutral particles than for charged particles. Coated particles presented higher vascular persistence. The diagnostic potential for liver, lymph node or vascular imaging were discussed. Chu, B. and T. Liu (2000). "Characterization of nanoparticles by scattering techniques." Journal of Nanoparticle Research 2(1): 29-41.

Basic principles and applications of different scattering techniques (including static and dynamic light scattering (SLS and DLS), small-angle X-ray scattering (SAXS), wide-angle X-ray diffraction (WAXD) and small-angle neutron scattering (SANS)) on the characterization of nanoparticles are reviewed in this paper. By choosing a suitable scattering technique or a combination of different techniques for nanoparticle characterization, the particles' molecular weight, radius of gyration, hydrodynamic radius, size distribution, shape and internal structure as well as interparticle interactions of nanoparticles, can be determined. Examples, including some sophisticated colloidal systems, are presented. (39 References). Chu, X., H. Chen, et al. (2000). "Studies of aggregation of copper phthalocyanine nanoparticles." Zhenkong Kexue Yu Jishu Xuebao/Vacuum Science and Technology 20(1): 63-5. Semiconductive copper phthalocyanine (CuPc) nano-particles, approximately 20-100 nm in diameter, have been successfully grown with the gas condensation technique. The influence of various growth parameters, including thermofield distribution and heating temperature, on the nanoparticle sizes and aggregation was discussed. (8 References). Chudnovsky, E. M. and J. R. Friedman (2000). "Macroscopic quantum coherence in a magnetic nanoparticle above the surface of a superconductor." Physical Review Letters 85(24): 5206-9. We study macroscopic quantum tunneling of the magnetic moment in a single-domain particle placed above the surface of a superconductor. Such a setup allows one to manipulate the height of the energy barrier, preserving the degeneracy of the ground state. The tunneling amplitude and the effect of the dissipation in the superconductor are computed. (21 References). Clement, O., R. Guimaraes, et al. (1994). "Magnetic resonance lymphography. Enhancement patterns using superparamagnetic nanoparticles." Investigative Radiology 29 Suppl 2(6): S226-8. Clement, O., F. Rety, et al. (1998). "MR lymphography: evidence of extravasation of superparamagnetic nanoparticles into the lymph." Academic Radiology 5 Suppl 1(3): S170-2; discussion S183-4. Clement, O., N. Siauve, et al. (1998). "Liver imaging with ferumoxides (Feridex): fundamentals, controversies, and practical aspects." Topics in Magnetic Resonance Imaging 9(3): 167-82. Superparamagnetic nanoparticles (Feridex) have been recently made available to the radiological community as a contrast agent for MR imaging of the liver. This article reviews the principal physicochemical characteristics of this new compound, with an emphasis on the explanation of the contrast obtained (either positive or negative enhancement) that depends on the local concentration and the sequence used. The clinical use of Feridex is detailed, both for lesion detection and characterization. Finally, some guidelines for image optimization are given. Coester, C., J. Kreuter, et al. (2000). "Preparation of avidin-labelled gelatin nanoparticles as carriers for biotinylated peptide nucleic acid (PNA)." International Journal of Pharmaceutics 196(2): 147-149. The possibility of preparing uniform nanoparticles consisting of proteins such as gelatin followed by covalent linkage of avidin was investigated. Gelatin nanoparticles were prepared by two step desolvation. Functional groups at the surface of the particulate system were quantified with site-specific reagents. The surface of the nanoparticles was thiolated and avidin was covalently attached to the nanoparticles via a bifunctional spacer at high levels. Biotinylated peptide nucleic acid (PNA) was effectively complexed by the avidin-conjugated nanoparticles. Avidin-conjugated protein nanoparticles should prove as potential carrier system for biotinylated drug derivatives in antisense therapy. Coester, C. J., K. Langer, et al. (2000). "Gelatin nanoparticles by two step desolvation--a new preparation method, surface modifications and cell uptake." Journal of Microencapsulation 17(2): 187-93. A new two-step desolvation method for manufacturing gelatin nanoparticles was developed. After the first desolvation step, the low molecular gelatin fractions present in the supernatant were removed by decanting. The high molecular fractions present in the sediment were redesolved and then desolvated again at pH 2.5 in the second step. The resulting particles can then be easily purified by centrifugation and redispersion. The different fractions obtained during the process were analysed by gel permeation chromatography (GPC). Based on these results, it can be concluded that the molecular weight of gelatin has a decisive influence on the stability of the manufactured gelatin nanoparticles. In addition, two fluorescent dyes (Texasred and fluoresceinamine) were coupled to the nanoparticles for cell uptake studies. The fluorescent nanoparticles showed a high uptake into monocytes/macrophages. Coffin, M. D. and J. W. McGinity (1992). "Biodegradable pseudolatexes: the chemical stability of poly(D,L-lactide) and poly(epsilon-caprolactone) nanoparticles in aqueous media." Pharm Res 9(2): 200-5. Pseudolatexes of the biodegradable polyesters poly(D,L-lactide) (PLA) and poly(epsilon-caprolactone) (PCL) have been developed as potential aqueous coatings for sustained release. Since PLA and PCL are known to

hydrolyze, the influence of the surfactant system, temperature, pH, and particle size on the chemical stability of the polymers as aqueous colloidal dispersions was investigated. Pseudolatexes of PLA and PCL formulated with a nonionic surfactant system were the most stable. When these dispersions were stored in unbuffered media for 350 days at 5 degrees C, only small changes in the weight-average molecular weights (Mw) of the polymers were observed. At 37 degrees C there was rapid degradation of both polymers in the dispersions. Arrhenius plots for the degradation of PLA and PCL resulted in a linear relationship for PCL. The nonlinear relationship for PLA was attributed to the polymer being in two different physical states within the 5 to 37 degrees C range which was used for the Arrhenius plots. PCL was in the rubbery state at all temperatures studied. Storage of the pseudolatexes in pH 1.65 buffer at 37 degrees C catalyzed the rates of degradation of both PLA and PCL. However, refrigeration of the pseudolatexes stabilized the polymers even at pH 1.65 for up to 4 months. Particle size had an insignificant effect on PLA and PCL stability in pseudolatexes prepared with either a nonionic or an anionic surfactant system. Cohen, H., R. J. Levy, et al. (2000). "Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles." Gene Therapy 7(22): 1896-905. Sustained release polymeric gene delivery systems offer increased resistance to nuclease degradation, increased amounts of plasmid DNA (pDNA) uptake, and the possibility of control in dosing and sustained duration of pDNA administration. Furthermore, such a system lacks the inherent problems associated with viral vectors. Biodegradable and biocompatible poly(DL-lactide-co-glycolide) polymer was used to enacapsulate pDNA (alkaline phosphatase, AP, a reporter gene) in submicron size particles. Gene expression mediated by the nanoparticles (NP) was evaluated in vitro and in vivo in comparison to cationic-liposome delivery. Nano size range (600 nm) pDNA-loaded in poly(DL-lactide-co-glycolide) polymer particles with high encapsulation efficiency (70%) were formulated, exhibiting sustained release of pDNA of over a month. The entrapped plasmid maintained its structural and functional integrity. In vitro transfection by pDNA-NP resulted in significantly higher expression levels in comparison to naked pDNA. Furthermore, AP levels increased when the transfection time was extended, indicating sustained activity of pDNA. However, gene expression was significantly lower in comparison with standard liposomal transfection. Seven days after i.m. injections in rats, naked pDNA and pDNA-NP were found to be significantly more potent (1-2 orders of magnitude) than liposomal pDNA. Plasmid DNA-NP treatment exhibited increased AP expression after 7 and 28 days indicating sustained activity of the NP. Colfen, H. and L. Qi (2001). "A systematic examination of the morphogenesis of calcium carbonate in the presence of a double-hydrophilic block copolymer." Chemistry 7(1): 106-16. In this paper, a systematic study of the influence of various experimental parameters on the morphology and size of CaCO3 crystals after room-temperature crystallization from water in the presence of poly(ethylene glycol)block-poly(methacrylic acid) (PEG-b-PMAA) is presented. The pH of the solution, the block copolymer concentration, and the ratio [polymer]/[CaCO3] turned out to be important parameters for the morphogenesis of CaCO3, whereas a moderate increase of the ionic strength (0.016 M) had no influence. Depending on the experimental conditions, the crystal morphologies can be tuned from calcite rhombohedra via rods, ellipsoids or dumbbells to spheres. A morphology map is presented which allows the prediction of the crystal morphology from a combination of pH, and CaCO3 and polymer concentration. Morphologies reported in literature for the same system but under different crystallization conditions agree well with the predictions from the morphology map. A closer examination of the growth of polycrystalline macroscopic CaCO3 spheres by TEM and time-resolved dynamic light scattering showed that CaCO3 macrocrystals are formed from strings of aggregated amorphous nanoparticles and then recrystallize as dumbbell-shaped or spherical calcite macrocrystal. Colin de Verdiere, A., C. Dubernet, et al. (1994). "Uptake of doxorubicin from loaded nanoparticles in multidrug-resistant leukemic murine cells." Cancer Chemotherapy and Pharmacology 33(6): 504-8. Previous studies have clearly demonstrated that polyisobutylcyanoacrylate (PIBCA) doxorubicin-loaded nanoparticles (NS-Dox PIBCA) can overcome the resistance of P388/ADR cells. In the present paper, we found that overcoming multidrug resistance with the aid of doxorubicin (Dox) loaded onto these nanoparticles was associated with an increased intracellular drug content. Indeed, after a 6-h incubation period, the amount of cellassociated drug was 5 times higher when the cells were incubated with NS-Dox PIBCA as compared with free Dox. Further experiments, such as uptake studies in the presence of cytochalasin B or efflux studies, indicated a possible mechanism of nanoparticle/cell interaction. These results suggested that nanoparticles did not enter the cells by an endocytic process, in contrast to a previous hypothesis. Couvreur, P., B. Kante, et al. (1979). "Adsorption of antineoplastic drugs to polyalkylcyanoacrylate nanoparticles and their release in calf serum." Journal of Pharmaceutical Sciences 68(12): 1521-4. Conditions are described for attaching anticancer drugs to polyalkylcyanoacrylate nanoparticles, a new drug delivery system for cells that exhibit endocytic uptake. They are ultrafine, metabolizable, and able to associate with various drugs in a nonspecific manner. Data are given for the in vitro degradation and for drug release from this new drug carrier system.

Couvreur, P., B. Kante, et al. (1980). "Tissue distribution of antitumor drugs associated with polyalkylcyanoacrylate nanoparticles." Journal of Pharmaceutical Sciences 69(2): 199-202. Polymethylcyanoacrylate nanoparticles, polyethylcyanoacrylate nanoparticles, and free 3H-dactinomycin and 3Hvinblastine were studied with emphasis on their distribution pattern in rat tissues after intravenous administration. The adsorption of cytostatic drugs to polyalkylcyanoacrylate nanoparticles can modify drug distribution in tissues. Particularly with vinblastine, modification of drug disposition is important. Data are given concerning the formation and stability of nanoparticle--drug complexes. Polyalkylcyanoacrylate nanoparticles seem to be an interesting drug carrier owing to their size, structure, degradability, and drug sorptive properties. Couvreur, P., B. Kante, et al. (1982). "Toxicity of polyalkylcyanoacrylate nanoparticles II: Doxorubicin-loaded nanoparticles." Journal of Pharmaceutical Sciences 71(7): 790-2. Couvreur, P. (1988). "Polyalkylcyanoacrylates as colloidal drug carriers." Critical Reviews in Therapeutic Drug Carrier Systems 5(1): 1-20. A considerable amount of energy has been spent in creating new colloidal drug delivery systems that are acceptable for general systemic use. Among these new systems, nanoparticles made with biodegradable polymers are gaining more and more interest. The aim of this paper is to describe the preparation and characterization of these nanoparticles and their in vivo behavior and to show the possibilities of using them in various fields of human medicine. The interaction of polyalkylcyanoacrylate nanoparticles with cells in culture is also discussed, as well as the possibility of improving the specificity of the carrier by coating it with monoclonal antibodies. Couvreur, P., E. Fattal, et al. (1991). "Liposomes and nanoparticles in the treatment of intracellular bacterial infections." Pharm Res 8(9): 1079-86. The treatment of infections caused by obligate or facultative intracellular microorganisms is difficult because most of the available antibiotics have either poor intracellular diffusion and retention or reduced activity at the acidic pH of the lysosomes. The need for antibiotics with greater intracellular efficacy led to the development of endocytosable drug carriers, such as liposomes and nanoparticles, which mimic the entry path of the bacteria by penetrating the cells into phagosomes or lysosomes. This Review assesses the potential of liposomes and nanoparticles in the targeted antibiotic therapy of intracellular bacterial infections and diseases and the pharmaceutical advantages and limitations of these submicron delivery systems. Cremaschi, D., C. Porta, et al. (1999). "Different kinds of polypeptides and polypeptide-coated nanoparticles are accepted by the selective transcytosis shown in the rabbit nasal mucosa." Biochimica et Biophysica Acta 1416(1-2): 31-8. The specific transcytosis of polypeptides, demonstrated in the nasal respiratory mucosa of the rabbit, seems to be involved in antigen sampling at the airway entry, since absorption has been shown only to occur if lymphoid aggregates are present beneath the epithelium and to be proportional to aggregate volume. Nanoparticles and many polypeptides besides the two previously tested (i.e. carbocalcitonin (CCT) and adrenocorticotropic hormone) should be transportable, in agreement with the vesicular transcytosis and antigen sampling hypothesis. Thus unidirectional mucosa-submucosa and opposite fluxes (Jms, Jsm) and the corresponding net fluxes (Jnet) of uncoated or polypeptide-coated polystyrene nanospheres (diameter: about 0.5 micrometer) have been measured with the aid of spectrophotometry and quantitative dark-field microscopy. No net transport has been observed for uncoated beads, whereas it has always been shown for polypeptide-coated beads, although to different extents. The selectivity sequence for the polypeptides tested is as follows: BSA congruent with enkephalin &lt;&lt; anti-BSA IgG congruent with IgA congruent with CCT congruent with insulin &lt;/=anti-insulin IgG. With the exception of BSA and enkephalin-coated beads, whose Jnet is very small, in all the other cases the apparent affinities for receptors seem to be equal or similar; just over 6% polypeptide coating on the nanosphere is sufficient to elicit maximal transport; finally, transport seems to require many cooperating binding sites between the single nanosphere and receptors or one or many non-cooperating binding sites, but with a threshold number of polypeptide molecules adsorbed on the nanosphere to reach a minimal binding probability. Crooks, R. M., M. Zhao, et al. (2001). "Dendrimer-encapsulated metal nanoparticles: Synthesis, characterization, and applications to catalysis." Accounts of Chemical Research 34(3): 181-90. This Account reports the synthesis and characterization of dendrimer-encapsulated metal nanoparticles and their applications to catalysis. These materials are prepared by sequestering metal ions within dendrimers followed by chemical reduction to yield the corresponding zerovalent metal nanoparticle. The size of such particles depends on the number of metal ions initially loaded into the dendrimer. Intradendrimer hydrogenation and carbon-carbon coupling reactions in water, organic solvents, biphasic fluorous/organic solvents, and supercritical CO2 are also described. Cruz, T., R. Gaspar, et al. (1997). "Interaction between polyalkylcyanoacrylate nanoparticles and peritoneal macrophages: MTT metabolism, NBT reduction, and NO production." Pharm Res 14(1): 73-9.

PURPOSE: The nature of interactions between macrophages and drug carriers is of primordial importance either in the design of more effective therapeutic strategies for macrophage-associated pathogenesis or in establishing new approaches for pharmacological action avoiding macrophages. METHODS: Polyalkylcyanoacrylate nanoparticles (PMCA, PECA, PBCA and PIBCA nanoparticles) were assayed for their toxicity on peritoneal resident and thioglycolate-elicited macrophages. Cellular viability was assessed by MTT tetrazolium salt assay, oxidative burst by NBT reduction and NO production by nitrite evaluation. RESULTS: The nanoparticles tested led to cellular morphological modifications and induced toxicity in both types of macrophages in culture. The polyalkylcyanoacrylate nanoparticles uptake by peritoneal macrophages caused an increase in respiratory burst, as assessed by the NBT reduction assay, and induced the release of soluble toxic factors to the culture medium. The association of LPS with the PMCA nanoparticles significantly stimulated the production of nitric oxide (NO) by resident macrophages. In contrast, the association of PBCA nanoparticles with LPS does not increase the nitrite production as compared with LPS alone, which may be due to a different physico-chemical interaction between LPS and the two types of polymers. CONCLUSIONS: In cultured mice peritoneal macrophages, nanoparticles of PACA induce the production of oxygen reactive products, which cause changes in the cell metabolism of both resident and elicited macrophages. PMCA nanoparticles in association with LPS significantly increase the expression of the inducible isoform of nitric oxide synthase, leading to the release of large amount of NO, which may be highly cytotoxic to the cultured cells in the presence of peroxide generated from the oxidative burst. Curtis, A. and C. Wilkinson (2001). "Nantotechniques and approaches in biotechnology." Trends in Biotechnology 19(3): 97-101. Nanotechnology has enabled the development of an amazing variety of methods for fabricating nanotopography and nanopatterned chemistry in recent years. Some of these techniques are directed towards producing single component particles, as well as multi-component assembly or self-assembly. Other methods are aimed at nanofeaturing and patterning surfaces that have a specific chemistry or topography. This article concentrates mainly on surface-directed nanobiotechnologies because they are nearer to commercial realisation, such as use in tissue engineering, control of biofouling and cell culture, than those directed at producing nanoparticles. D'Acapito, F., G. Battaglin, et al. (2000). "Cu-Ni alloy nanocluster formation by ion implantation in silicate glasses: Structure and optical properties." European Physical Journal D 10(1): 123-9. Sequential ion implantation (copper and nickel) in silica and soda-lime glasses has been performed. The formation of copper-nickel alloy nanocluster in the glass host has been evidenced by synchrotron radiation-based techniques, namely X-ray diffraction and absorption spectroscopy. The nanocrystals' lattice parameter value was estimated, indicating the formation of Cu/sub 55/Ni/sub 45/ alloy particles. Optical absorption spectra are also discussed. (53 References). Darius, J., F. P. Meyer, et al. (2000). "Influence of nanoparticles on the brain-to-serum distribution and the metabolism of valproic acid in mice." Journal of Pharmacy and Pharmacology 52(9): 1043-7. The suitability of nanoparticles as a drug-carrier system for the antiepileptic valproic acid has been studied in mice. The aim of the study was to increase the brain-to-serum ratio of the drug to reduce dose-related side effects in the periphery. The influence of nanoparticles on the metabolism of valproic acid was also investigated. The serum kinetics and the brain tissue levels of valproic acid were not altered by administration with nanoparticles. However, the nanoparticles did inhibit the metabolic degradation of valproic acid via mitochondrial beta-oxidation but did not influence any other metabolic pathway. It can be concluded that nanoparticles loaded with valproic acid may help to reduce the toxic side effects of valproate therapy, not by reducing the therapeutically necessary dosage but by inhibition of formation of toxic metabolites. Using their ability to selectively block a pathway nanoparticles may serve as a tool to investigate the metabolic origin of metabolites and their contribution to therapeutic efficacy and side effects. Darkow, R., T. Groth, et al. (1999). "Functionalized nanoparticles for endotoxin binding in aqueous solutions." Biomaterials 20(14): 1277-83. Nanoparticles consisting of a polystyrene core and a polyglycidyl methacrylate shell were prepared by a two-step emulsion polymerization. The size and surface properties of the particles were characterized by scanning electron microscopy, dynamic light scattering and polyelectrolyte titration techniques. Particles were found to be monodisperse with a mean diameter of about 85 nm. Parent particles were modified with a number of different ligands including diamines of increasing chain length, amino acids and corresponding amines and higher molecular weight ligands like polymyxin B. The modified particles were tested for their endotoxin (ET) binding capacity in water and physiological sodium chloride solution with the Limulus amebocyte lysate (LAL) assay. It was found that the ET binding properties of the different ligands depend both on the ability of the ligand to form Coulomb- and van der Waals-interactions with the ET molecule influenced by the nature of the suspension medium. Therefore, the choice of ligands for particle modification has to consider minutely the conditions under which ET has to be removed, e.g. removal from pure water, dialysis fluids, plasma or blood.

Das, S. K., I. G. Tucker, et al. (1995). "Evaluation of poly(isobutylcyanoacrylate) nanoparticles for mucoadhesive ocular drug delivery. I. Effect of formulation variables on physicochemical characteristics of nanoparticles." Pharmacetical Research 12(4): 534-40. A factorial design was applied to evaluate the effect of formulation variables on physicochemical properties of poly(isobutylcyanoacrylate) nanoparticles. Formulation variables were dextran T40 or T70 and Pluronic F68 or Tween 20 acting as stabilizer and surfactant respectively, and three pH levels (2, 4 and 7). Nanoparticles possessed unimodal particle size distribution with significant effect of dextran, surfactant and pH. A wide range of molecular weight distribution was observed with significant effect of pH and dextran on average molecular weight. NMR studies revealed the presence of dextran, monomer and surfactants in the nanoparticles. Solid state surface analysis using X-ray photoelectron spectroscopy confirmed the presence of three chemical environments to the carbon envelope, O-C = O, C-O/C identical to N and C-C. Dawson, G. F. and G. W. Halbert (2000). "The in vitro cell association of invasin coated polylactide-co-glycolide nanoparticles." Pharmacetical Research 17(11): 1420-5. PURPOSE: To determine the effect of particle size and ligand surface density on the cellular association of poly lactide-co-glycolide nanoparticles covalently coated with bacterial invasin. METHODS: Poly lactide-co-glycolide nanoparticles containing a flourescent probe were prepared at four diameters 155 nm, 200 nm, 375 nm and 600 nm using standard techniques. Bacterial invasin was covalently coupled to the particles surface at varying surface concentrations using a water soluble carbodiimide. The modified particle's cellular association with HEp2 2B cells in tissue culture was determined using flow cytometry. RESULTS: Cellular association of modified nanoparticles was time dependent, abolished at low temperature, competitively inhibited by free invasin or the RGD peptide ligand and saturable. Increased cell association was produced by increasing the particle's surface invasin concentration however, this effect was size dependent. Small particles (155 nm and 200 nm) exhibiting a maximal association with increasing invasin concentration whilst the larger particles (375 nm and 600 nm) provide a minimum at low invasin concentrations. CONCLUSIONS: Modified particle cell association provided results commensurate with a receptor dependent uptake mechanism related to the presence of invasin. The size and surface concentration dependency however illustrate that application of these ligands to particulate drug delivery or targeting systems will be controlled by their natural cellular association properties. De, T. K. and A. S. Hoffman (2001). "A reverse microemulsion polymerization method for preparation of bioadhesive polyacrylic acid nanoparticles for mucosal drug delivery: loading and release of timolol maleate." Artificial Cells Blood Substitutes and Immobilization Biotechnology 29(1): 31-46. Polyacrylic acid nanoparticles were successfully synthesized using a reverse microemulsion polymerization process. They had a narrow size range, averaging approximately 50 nm, and were stable in buffer. The particles were isolated and lyophilized in dry powder form, and were redispersible as individual particles in buffer. The drug timolol maleate was loaded into the nanoparticles from aqueous drug solutions and, when the drug-loaded particles were dispersed in a phosphate buffer solution, the drug slowly released over several hours from the nanoparticles. de Cuyper, M. and M. Joniau (1992). "Binding characteristics and thermal behaviour of cytochrome-C oxidase, inserted into phospholipid-coated, magnetic nanoparticles." Biotechnology and Applied Biochemistry 16(2): 201-10. A strategy for the immobilization of cytochrome-c oxidase, used as a representative membrane-bound enzyme, into so-called magnetoliposomes has been developed. The latter structures consist of a phospholipid bilayer which covers nanometer-sized Fe3O4 colloids. Incorporation of the enzyme into the phospholipid envelope is facilitated by a short sonication step. Upon adsorption, the reaction characteristics of the lipid-depleted enzyme are drastically changed. With double-layered phosphatidylcholine (PC) magnetoliposomes the activity increases by a factor of approximately 5. After a first magnetic fractionation step, approximately 67% of the activity remains with the magnetoliposome retentate. Subsequent magnetophoresis cycles show that the adsorbed enzyme is firmly fixed into the phospholipid coat. Upon immobilization, the thermal behavior is also profoundly affected. The heating inactivation curves show two sigmoidal transition zones. Irrespective of the PC type used, a first inflection point is located near 39 degrees C, whereas a second one, which is located at higher temperatures, clearly depends on the acyl chain length (56 degrees C with dimyristoyl-PC and 60 degrees C for dioleoyl-PC and Ovothin-200). An identical behavior is observed with classical proteoliposomes with an equal phospholipid composition. By contrast, monolayer-coated dimyristoyl-PC magnetic structures are inferior with respect to both their reactivation potency and their ability to strongly affix cytochrome-c oxidase and to improve the thermal stability of the enzyme. De Jaeghere, F., E. Allemann, et al. (1999). "Formulation and lyoprotection of poly(lactic acid-co-ethylene oxide) nanoparticles: influence on physical stability and in vitro cell uptake." Pharmacetical Research 16(6): 859-66. PURPOSE: To investigate the feasibility of producing freeze-dried poly(ethylene oxide) (PEO)-surface modified nanoparticles and to study their ability to avoid the mononuclear phagocytic system (MPS), as a function of the PEO chain length and surface density. METHODS: The nanoparticles were produced by the salting-out method

using blends of poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acidco-ethylene oxide) (PLA-PEO) copolymers. The nanoparticles were purified by cross-flow filtration and freeze-dried as such or with variable amounts of trehalose as a lyoprotectant. The redispersibility of the particles was determined immediately after freeze-drying and after 12 months of storage at -25 degrees C. The uptake of the nanoparticles by human monocytes was studied in vitro by flow cytometry. RESULTS: PLA-PEO nanoparticles could be produced from all the polymeric blends used. Particle aggregation after freeze-drying was shown to be directly related to the presence of PEO. Whereas this problem could be circumvented by use of trehalose, subsequent aggregation was shown to occur during storage. These phenomena were possibly related to the specific thermal behaviours of PEO and trehalose. In cell studies, a clear relationship between the PEO content and the decrease of uptake was demonstrated. CONCLUSIONS: The rational design of freeze-dried PEO-surface modified nanoparticles with potential MPS avoidance ability is feasible by using the polymer blends approach combined with appropriate lyoprotection and optimal storage conditions. De Jaeghere, F., E. Allemann, et al. (2000). "Cellular uptake of PEO surface-modified nanoparticles: evaluation of nanoparticles made of PLA:PEO diblock and triblock copolymers." Journal of Drug Targeting 8(3): 143-53. Nanoparticles with either physically adsorbed or covalently bound poly(ethylene oxide) (PEO) coatings were produced from various combinations of poly(lactic acid) (PLA) and diblock or triblock copolymers of PLA and PEO. The particles were produced by the salting-out process and purified by the cross-flow filtration technique. The amount of PEO at the nanoparticle surface, as well as the residual amount of emulsifier poly(vinyl alcohol) were assessed, with a good correlation with expected values. Stability of the nanoparticulate suspensions was studied at 4 degrees C and after freezing under various conditions for up to 6 months. The nanoparticle redispersibility after storage was related to the thermal behavior of the PEO coatings. The in vitro cellular uptake of the different types of nanoparticles was compared by flow cytometry after incubation with human monocytes in serum and in plasma. The influence of the PEO molecular weight and surface density on the particle uptake was especially marked for the diblock and triblock copolymer formulations, with a decrease in uptake of up to 65% with one of the diblock copolymer formulations. Nanoparticles made of triblock copolymer with short PEO chains at their surface in the postulated "loop conformation" proved to be as resistant to cellular uptake as nanoparticles made of diblock copolymers with PEO chains in the "brush conformation". De Jaeghere, F., E. Allemann, et al. (2000). "Oral bioavailability of a poorly water soluble HIV-1 protease inhibitor incorporated into pH-sensitive particles: effect of the particle size and nutritional state." Journal of Controlled Release 68(2): 291-8. The new chemical entity CGP 70726, a very poorly water-soluble HIV-1 protease inhibitor, was incorporated into pH-sensitive nanoparticles and microparticles made of the poly(methacrylic acid-co-ethylacrylate) copolymer Eudragit((R)) L100-55. The particles were characterized in terms of morphology, size distribution, drug loading, production yield and dispersion state of the drug inside the polymeric matrices. Aqueous dispersions of the particles were administered orally to Beagle dogs against a suspension of free drug (control formulation) all at a dose of 100 mg/kg. Oral administration was conducted in the absence and presence of food. Plasma concentrations and pharmacokinetic parameters were determined within 8 h post-dose. While no measurable absorption of the drug resulted after administration of the control formulation, substantial systemic exposure to the compound was obtained with both kinds of pH-sensitive formulations. The selective release of CGP 70726 in a highly dispersed/amorphous state and creation of high concentrations close to its absorption site was thought to account for this positive result. The largest areas under the plasma concentration-time curve (AUC) were obtained in the fasted state, with slightly better performance of the microparticles over the nanoparticles, in both nutritional states (7.8+/-1.5 versus 5.8+/-0. 8 micromol.h/l in the fasted state; 4.4+/-1.4 versus 2.00+/-0.5 micromol.h/l in the fed state). With these results, the potential of pH-sensitive particles for the oral delivery of HIV-1 protease inhibitors with low water solubility was confirmed. De Jaeghere, F., E. Allemann, et al. (2000). "Freeze-drying and lyopreservation of diblock and triblock poly(lactic acid)poly(ethylene oxide) (PLA-PEO) copolymer nanoparticles." Pharmaceutical Development and Technology 5(4): 473-83. In this study, the formulation and process parameters that determine successful production and long-term stability of freeze-dried poly(lactic acid) (PLA) nanoparticles with &quot;hairy-like&quot; poly(ethylene oxide) (PEO) surfaces were investigated. Nanoparticles with grafted (covalently bound) PEO coatings were produced by the salting-out method from blends of PLA and PLA-PEO diblock or triblock copolymers. PLA nanoparticles with physically adsorbed PEO were also produced. The redispersibility of the nanoparticles after freeze-drying under various conditions was assessed. The surface of the nanoparticles was characterized and classified in terms of &quot;brush&quot; and &quot;loop&quot; conformations. Upon freeze-drying, it appeared that the presence of PEO at the nanoparticle surface could severely impair the redispersibility of the particles, especially in the PEOgrafted systems. This effect was shown to be related to the amount and molecular weight of PEO in the various formulations. In most cases, particle aggregation was prevented by use of trehalose as lyoprotective agent. Increasing the concentration of particles in the suspension to be freeze-dried was shown to induce much less damage to the nanoparticles, and freezing the suspension at a very low temperature (-196 degrees C) was found

to further improve the lyoprotective effect. Most of the lyoprotected nanoparticles remained stable for at least 12 weeks at 4 and -25 degrees C. The production and preservation of freeze-dried PLA-PEO diblock and triblock copolymer nanoparticles is feasible under optimized lyoprotective conditions. De Keyser, J. L., J. H. Poupaert, et al. (1991). "Poly(diethyl methylidenemalonate) nanoparticles as a potential drug carrier: preparation, distribution and elimination after intravenous and peroral administration to mice." Journal of Pharmaceutical Sciences 80(1): 67-70. Polymerization of diethyl methylidenemalonate (DEMM, 1a) in 0.1 M phosphate buffer containing 1% dextran 70 yields nanoparticles of a diameter ranging from 140 to 250 nm depending on the pH value (6.7 to 8.7). The weight-average and number-average molecular weight of the resulting polymer were 3791 and 1084, respectively. Approximately 95% of the 14C-labeled poly(DEMM) nanoparticles were found in liver and spleen 1 h after iv administration. A statistically significant (p less than 0.01) approximately 10% decrease of the radioactivity was observed in the liver over a 3-month period. The poly(DEMM) nanoparticles were not absorbed and were totally cleared from the gastrointestinal tract 24 h after oral dosage. The very slow bioelimination process observed after iv administration limits the usefulness of poly(DEMM) nanoparticles as a systemic drug carrier. Nevertheless, their oral administration as bioavailability enhancers can be envisaged. Moreover, the fact that nanoparticles are readily produced in a medium near neutrality should be emphasized. De Miguel, I., L. Imbertie, et al. (2000). "Proofs of the structure of lipid coated nanoparticles (SMBVTM) used as drug carriers." Pharmaceutical Research 17(7): 817-824. Purpose: Supramolecular Biovectors (SMBVTM) consist of cross-linked cationic nanoparticles surrounded by a lipid membrane. The purpose was to study the structure of the lipid membrane and to characterise its interaction with the nanoparticles in order to differentiate SMBVTM from other polymer/lipid associations. Methods: The interaction of lipids with the nanoparticle surface was studied using zeta potential, Fluorescence Energy Transfer (FET) and Fluorescence Microscopy. SMBVTM were compared to liposomes and mixtures nanoparticles/liposomes. Finally the structure of SMBVTM was visualised by Electron Microscopy. Results: Zeta potential measurements showed that lipids on SMBVTM had a pronounced shielding effect on the surface charge. This was not the case for mixtures of nanoparticles and liposomes. FET experiments confirmed these results indicating that, for SMBVTM, the lipids are much closer to the nanoparticle surface. SMBVTM Fluorescence microscopy on model microparticles showed a lipid crown on SMBVTM that was confirmed by electron microscopy on SMBVTM nanoparticles. Conclusions: Results show that in case of SMBVTM lipids are strongly adsorbed on the polysaccharide core surface probably due to ionic/hydrophobic interactions. The resulting supramolecular structure is a spherical cationic polysaccharide particle surrounded by a phospholipid/cholesterol layer. de Verdiere, A. C., C. Dubernet, et al. (1997). "Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action." British Journal of Cancer 76(2): 198-205. Polyalkylcyanoacrylate (PACA) nanoparticles loaded with doxorubicin allowed multidrug resistance to be overcome in vitro. However, increased cytotoxicity is not always correlated with an increased level of intracellular drug. Although we have previously shown that PACA nanoparticles are not endocytosed by tumour cells, we report here that a direct interaction between nanoparticles and cells is a necessary requirement for overcoming resistance. In addition, the results showed that the degradation products of PACA (mainly polycyanoacrylic acid) in the presence of doxorubicin are able to increase both accumulation and cytotoxicity, thus suggesting the formation of a doxorubicin-polycyanoacrylic acid ion pair. It is therefore concluded that resistance is overcome as a result of both the adsorption of nanoparticles to the cell surface and increased doxorubicin diffusion by the accumulation of an ion pair at the plasma membrane. de Vringer, T. and H. A. de Ronde (1995). "Preparation and structure of a water-in-oil cream containing lipid nanoparticles." Journal of Pharmaceutical Sciences 84(4): 466-72. To obtain a topical dermatological product with a high degree of occlusivity combined with attractive cosmetic properties, a water-in-oil (w/o) cream containing small particles of solid paraffin was developed. Dynamic light scattering, freeze-fracture electron microscopy, polarization microscopy, and differential scanning calorimetry were used to characterize the cream. The preparation method essentially consisted of two steps. First, an aqueous dispersion of solid paraffin particles, with a mean diameter of 200 nm, was prepared with an oil-in-water (o/w) emulsifier. The aqueous dispersion proved to be extremely stable, and the particles had a spherical shape. Second, the aqueous dispersion was incorporated into the water phase of the cream during its production. After production of the cream, 68% of the paraffin was present as particles in the dispersed water phase. The size and shape of these particles did not change by the mechanical treatment during the production of the cream. At least 28% of the paraffin was present in the continuous oily phase, either as solid particles or in the form of a gel structure. At most, 4% of the paraffin was dissolved in this oily phase. The excess o/w emulsifier present in the aqueous phase of the w/o cream did not cause physical instability.

Debuigne, F., J. Cuisenaire, et al. (2000). "Synthesis of monodisperse nimesulide nanoparticles in microemulsions E170/isopropyl myristate/water/n-butanol (or isopropanol)." Journal de Pharmacie de Belgique 55(2): 59-60. Nanoparticles of nimesulide have been synthesized in two systems of microemulsion: E170/isopropyl myristate/water/n-butanol (or isopropanol). Nanoparticles are monodisperse. In the two microemulsions, the size of the nanoparticles is comprised between 45 and 60 A and also seems to be independent of the factor R ([water]/[E170]) and of the concentration of the nimesulide solubilized in chloroform. The constancy of the size suggests that the size is controlled by thermodynamic stabilization of the nanoparticles with the surfactant. The nature of the cosurfactant does not have an obvious influence on the nanoparticle size. The nanoparticles are instantaneously formed and stay stable during a long period of time (several months). Del Fatti, N., F. Vallee, et al. (2000). "Electron dynamics and surface plasmon resonance nonlinearities in metal nanoparticles." Chemical Physics 251: 1-3. The ultrafast surface plasmon resonance nonlinearities and their connection with the conduction band electron dynamics are discussed in metal nanoparticles in the light of the results of high sensitivity femtosecond pumpprobe experiments in silver nanoparticles embedded in a glass matrix. The optical response is interpreted in terms of frequency shift and broadening of the surface plasmon resonance and is related to the changes of the metal nanoparticle dielectric function induced by ultrafast perturbation of the electron distribution. Alteration of the interband absorption is found to be responsible for the observed red shift and very short time delay broadening of the surface plasmon resonance, in agreement with numerical simulations and with measurements in silver films. On a longer time scale, a new nonlinear mechanism due to increase of the electron scattering off the surfaces is demonstrated. This mechanism, specific to confined system, plays an important role in the ultrafast nonlinear optical response of small nanoparticles. (42 References). Delie, F., R. Gurny, et al. (2001). "Fluorescence correlation spectroscopy for the characterisation of drug delivery systems." Biological Chemistry 382(3): 487-90. Fluorescence Correlation Spectroscopy (FCS) offers the possibility to measure molecular interactions between active compounds and drug delivery systems such as cationic peptides or polymeric nanoparticles. In order to investigate the potential of FCS for drug carrier design, a complex made of protamine, a cationic peptide, and a 19mer oligonucleotide was characterised. Protamine was used to form proticles, agglomerates consisting of the oligonucleotide and the cationic peptide. The binding kinetics and proticle formation was studied by FCS. Complete binding of the oligonucleotide to protamine was achieved at a 1:2.5 (w/w) ratio. From the diffusion coefficient, D, a mean value for the hydrodynamic diameter was calculated at 53 nm, which was in agreement with data obtained from photon correlation spectroscopy (PCS). Oligonucleotide loading into cationic monomethylaminoethylmethacrylate (MMAEMA) nanoparticles was also determined by this method at 5.6% (5.6 microg per 100 microg of nanoparticles). Delie, F., M. Berton, et al. (2001). "Comparison of two methods of encapsulation of an oligonucleotide into poly(D,L-lactic acid) particles." International Journal of Pharmacology 214(1-2): 25-30. The aim of this study was to compare two methods to encapsulate a 25-mer-phosphorothioate oligonucleotide (ODN) into poly(D,L-lactic acid) (PLA) particles. Antisense oligonucleotides belong to a new therapeutic class especially attractive for the treatment of cancers and viral diseases. The development of these new drugs suffers, however, from poor stability in biological media and very low cellular uptake. Polymeric particulate systems display interesting features for ODN delivery. ODN are highly hydrophilic and most encapsulation methods are inappropriate for such molecules. Using poly(D,L-lactide) polymer, two methods of encapsulation were compared. First, a double emulsion technique was used to prepare nano- and microparticles. Secondly, the ODN was combined with a quaternary ammonium, the cethyltrimethyl-ammonium bromide (CTAB), to enhance the hydrophobicity of the molecule before entrapment by the emulsification-diffusion method. Both methods led to the formation of individualized and spherical particles loaded with a significant amount of ODN. Similar entrapment efficiencies were obtained for the nanoparticles prepared by both methods (approx. 27% of the theoretical loading) whereas 45% of entrapment efficiency was observed for the microparticles. Seventy five percent of the ODN were released in 60 min with the particles prepared by the emulsification-diffusion method, whereas only 7% were released in 60 h when using the double emulsion method. A viability test on U-937 cells showed better survival rates with the particles prepared by the double emulsion technique. The results suggest that the location of the ODN in the polymeric matrix is affected by the encapsulation method. Particles containing CTAB appeared more toxic than the ones obtained by the double emulsion technique, however, these particles can still be used for antisense activity since high oligonucleotide loading can be achieved. Dellwig, T., G. Rupprechter, et al. (2000). "Bridging the pressure and materials gaps: high pressure sum frequency generation study on supported Pd nanoparticles." Physical Review Letters 85(4): 776-9. Infrared-visible sum frequency generation vibrational spectroscopy is applied for the first time to monitor CO stretching vibrations on alumina supported Pd nanoparticles in a pressure range from 10(-7) to 200 mbar. The adsorption behavior of Pd aggregates with 3 and 6 nm mean size is dominated by surface defects and two

different adsorption sites (twofold bridging and on-top) were identified. The CO adsorption site occupancy on Pd nanocrystals is mainly governed by the gas phase pressure while the structure of the particles and their temperature have a smaller influence. Dembri, A., M. J. Montisci, et al. (2001). "Targeting of 3'-azido 3'-deoxythymidine (AZT)-loaded poly(isohexylcyanoacrylate) nanospheres to the gastrointestinal mucosa and associated lymphoid tissues." Pharmacology Research 18(4): 467-73. PURPOSE: The aim of the studv was to evaluate the capacity of poly(isohexylcyanoacrylate) nanospheres to concentrate 3'-azido 3'-deoxythymidine (AZT) in the intestinal epithelium and associated immunocompetent cells, which are known to be one of the major reservoirs of the human immunodeficiency virus (HIV). METHODS: The tissue concentration of 3H-radiolabeled AZT in the gastrointestinal (GI) tract was obtained 30 and 9() minutes after intragastric administration to rats at a dose of 0.25 mg AZT/100 g of body weight. The distribution along the intestine was determined. AZT concentrations in the lymph were obtained by lymphatic duct cannulation. RESULTS: Unlike the solution. nanoparticles did concentrate AZT very cfficiently in the intestinal mucosa, as well as in the Peyer's patches, and could simultaneously control the release of free AZT. Concentration in Peyer's patches was 4 times higher for nanoparticles, compared with the control solution. The tissue concentration was 30-45 microM, which was much higher than the reported IC50 of AZT (0.06-1.36 microM) and was regularly distributed along the gastrointestinal tract. CONCLUSIONS: Nanoparticles have been shown to be efficient in concentrating AZT in the intestinal epithelium and gut-associated lymphoid tissues, supporting the view that these particles may represent a promising carrier to treat specifically the GI reservoir of HIV. Demers, L. M., C. A. Mirkin, et al. (2000). "A fluorescence-based method for determining the surface coverage and hybridization efficiency of thiol-capped oligonucleotides bound to gold thin films and nanoparticles." Analytical Chemistry 72(22): 5535-41. Using a fluorescence-based method, we have determined the number of thiol-derivatized single-stranded oligonucleotides bound to gold nanoparticles and their extent of hybridization with complementary oligonucleotides in solution. Oligonucleotide surface coverages of hexanethiol 12-mer oligonucleotides on gold nanoparticles (34 +/- 1 pmol/cm2) were significantly higher than on planar gold thin films (18 +/- 3 pmol/cm2), while the percentage of hybridizable strands on the gold nanoparticles (1.3 +/- 0.3 pmol/cm2, 4%) was lower than for gold thin films (6 +/- 2 pmol/cm2, 33%). A gradual increase in electrolyte concentration over the course of oligonucleotide deposition significantly increases surface coverage and consequently particle stability. In addition, oligonucleotide spacer sequences improve the hybridization efficiency of oligonucleotide-modified nanoparticles from approximately 4 to 44%. The surface coverage of recognition strands can be tailored using coadsorbed diluent oligonucleotides. This provides a means of indirectly controlling the average number of hybridized strands per nanoparticle. The work presented here has important implications with regard to understanding interactions between modified oligonucleotides and metal nanoparticles, as well as optimizing the sensitivity of gold nanoparticle-based oligonucleotide detection methods. Demirel, M., Y. Yazan, et al. (2001). "Formulation and in vitro-in vivo evaluation of piribedil solid lipid micro- and nanoparticles." Journal of Microencapsulation 18(3): 359-71. Modification of the dissolution rate and, thus, the enhancement of the bioavailability of a dopaminergic drug, piribedil, which has a low aqueous solubility and short elimination half-life have been the aim in this study. Preparations of micron and submicron particles using solid lipid carriers have been performed for this purpose. For the avoidance of solvent residues resulting from the preparation technique, cold and hot homogenization methods have been used to prepare solid lipid particles. After obtaining an appropriate particle size, piribedil loading and preparation yield by the use of those two methods, various formulations have been prepared with different lipid, drug and surfactant materials. The factors mentioned were found to affect properties of the particles, and the release rate was found to be the fastest in acidic medium. Suspensions of pure piribedil and a formulation, selected according to the results obtained from in vitro dissolution and particle size experiments, were compared using tremor tests in mice. The same suspensions were applied perorally to rabbits and bioavailability of the solid lipid particle was found to be higher than the pure piribedil. After an in vitro-in vivo evaluation of piribedil solid lipid particles developed for Parkinson's disease therapy, it has been determined that release rate could be controlled and piribedil bioavailability could be improved. Demoy, M., S. Gibaud, et al. (1997). "Splenic trapping of nanoparticles: complementary approaches for in situ studies." Pharmacetical Research 14(4): 463-8. PURPOSE: To identify more accurately in the spleen, the areas and the cells where nanoparticulate carriers were taken up from the blood flow, a series of complementary approaches were used. METHODS: First, in and ex vivo examination of the whole spleen led to a global view of all the trapping areas. Then, histological studies on frozen sections of the same organ allowed for a more precise localization of these areas and image analysis gave an evaluation of tissue distribution of the nanoparticles. Finally, immunological and enzymological characteristics of the capturing cells were determined in situ, using monoclonal antibodies (F4/80 and anti-sialoadhesin) and

cytochemical reactions (esterases and acid phosphatase). Furthermore incubation of spleen slices with different nanoparticles was used so as to know if the capture was due to a high capturing capacity of these cells or to a high blood flow in their vicinity. RESULTS: It was shown that more than 90% of the splenic capture was localized in the marginal zone of the follicles. The capturing cells form a special population of macrophages inserted in a reticular meshwork, showing low esterase and acid phosphatase activities, giving faint or no reaction with F4/80 or anti-sialoadhesin antibodies. The circulating nanoparticles were quickly trapped with rather low specificity by these cells. CONCLUSIONS: Combination of coherent approaches allowed for the tracking of capturing cells from in vivo observations to their in situ identification on immunological and enzymological criteria. Demoy, M., J. P. Andreux, et al. (1999). "In vitro evaluation of nanoparticles spleen capture." Life Sciences 64(15): 132937. After intravenous injection, the main part of nanoparticles trapped by the spleen are concentrated in the marginal zone. The first step of this capture is the adhesion of the particles to the marginal zone macrophages. As classical techniques of cell suspension preparation did not allow to isolate without damage these actively capturing cells, tightly bound to a well-developed reticular meshwork, we designed a tissue slice incubation method, in order to study in vitro the interaction of nanoparticles with these particular macrophages, in conditions close to in vivo. In a serum supplemented medium, this in vitro model was able to give similar uptake profile than after intravenous injection of nanoparticles thus proving its validity. Surprisingly, no significant decrease of nanoparticles capture was observed when the medium was depleted from complement, immunoglobulins or proteins affine for heparin, while substitution of serum by purified albumin allowed a near optimal uptake. Addition of competitive ligands for lectin-like receptors did not show any clear inhibition of spleen capture. On the other hand, the scavenger receptor blocking agents, such as maleylated albumin or polyinosinic acid, induced a strong reduction of the spleen nanoparticles uptake. Thus, this paper proposes an in vitro binding assay as a reliable method to investigate the spleen capture of a large variety of nanoparticulate drug carriers. It is also a useful methodology to highlight the interactions between spleen cells and nanoparticles. The data obtained suggest that capture of nanoparticles depends on a multifactorial and complex phenomenon involvi ng for a part albumin and the scavenger receptor. Demoy, M., J. P. Andreux, et al. (1999). "Spleen capture of nanoparticles: influence of animal species and surface characteristics." Pharmacetical Research 16(1): 37-41. PURPOSE: To investigate the influence of animal species and nanoparticle surface characteristics on the intrasplenic distribution of polystyrene nanoparticles. METHODS: Two types of fluorescent polystyrene nanoparticles (Estapor and Fluoresbrite), plain or coated, were used in mice and rats. First, a fluorimetric method was developed for nanoparticle tissue quantification. Then, intrasplenic distribution of plain or coated nanoparticles was studied using histological examination and image analysis. Finally, the role of direct interactions between nanoparticles and spleen capturing cells was assessed by in vitro binding assays, using incubation of thick spleen slices with polystyrene nanoparticles. RESULTS: The two types of polystyrene nanoparticles showed different levels of trapping: Fluoresbrite nanoparticles were more efficiently trapped by the spleen than Estapor nanoparticles, both in mice and rats. In mice, most of the injected nanoparticles were localized in the marginal zone of the spleen, involving a special population of capturing cells, while in rats, the predominant capture occured in the red pulp. In mice, coated nanoparticles were localized both in the marginal zone and in the red pulp, whereas the coating did not seem to change the intrasplenic distribution of the nanoparticles in rats. CONCLUSIONS: These complementary approaches showed different uptake pathways of nanoparticles, according to their surface characteristics and the rodent species used. Deniau, M., R. Durand, et al. (1993). "[In vitro study of leishmanicidal agents with drug carriers]." Annales de Parasitologie Humaine et Comparee 68(1): 34-7. Antileishmanial chemotherapy is hampered by the location of parasites within lysosomal vacuoles of the macrophages which restricts the bioavailability of many potential antileishmanial compounds. In this study, the effectiveness of pentamidine targeted to the infected cells by a linkage to a colloidal drug carrier, methacrylate polymer nanoparticles was explored. In the same way, polyisoalkylcyanoacrylate nanospheres which have, in vitro, trypanolytic properties were also tested. The study was performed in an in vitro model using Leishmania major amastigote stages within the U 937 human monohistiocytic cell line. The antileishmanial activities of unloaded or pentamidine-loaded nanoparticles were compared to those of the free drugs. The 50% effective concentration of targeted pentamidine was 0.10 microgram/ml, while it was up to 2.7 micrograms/ml with the free drug after a 24-hour incubation time. The pentamidine-bound nanoparticles proved to be 25 times more active than the free drug. Unloaded polyisoalkylcyanoacrylate nanoparticles destroyed intracellular amastigote stages (50% EC = 15 micrograms/ml) but at a level close to the cytotoxic concentration. Denisov, S. I., V. F. Nefedchenko, et al. (2000). "Dipolar ferromagnetism in ensembles of ellipsoidal nanoparticles." Journal of Physics Condensed Matter 12(31): 7111-15. The phase diagram and mean local field theory for ensembles of dipolar interacting ellipsoidal nanoparticles

randomly distributed over the sites of a tetragonal lattice are constructed. Dipolar ferromagnetism in the ensembles arises from a competition between the ferro- and antiferromagnetic interactions of the nanoparticle magnetic moments. A critical temperature is defined for these systems with magnitude depending on the shape of the nanoparticles. (14 References). Derose, J. A. and J. Revel (1999). "A comparative study of colloidal particles as imaging standards for microscopy." Journal of Microscopy 195(Pt 1): 64-78. Colloidal particles have long been used as imaging standards for electron microscopy and, more recently, for scanning probe microscopy. We have analysed gold, polystyrene and silica colloidal particles by both transmission electron microscopy and atomic/scanning force microscopy in an attempt to determine if any can be truly used as 'standards' of shape and/or size. From the transmission electron micrographs, we have obtained precise information of the particle circumference and mean diameter. By comparing the ratio of these to the value for pi, we obtained a measure of the sphericity of the particles. We have also shadowed the particles with metal at a known angle and have analysed the shadow length to determine the particles' heights and shapes. The height information obtained from the shadow length data collected from the transmission electron micrographs was then compared with that obtained by atomic/scanning force microscopy. Our results show that cleaned (washed) silica or polystyrene particles closely approach true spheres. In the case of gold particles, height data obtained from shadow lengths analysed in transmission electron micrographs show good agreement with that obtained from the atomic/scanning force microscopy images even without washing. However, the gold particles often deviate from sphericity. Based upon both the shape and the physical properties of the colloidal particles, silica would be the best choice as a standard. We also have noticed that metal shadowing of colloidal particle samples used for atomic/scanning force microscopy offers an advantage which we call a 'nanoscale metric' visible in the image directly at each particle site. This information can be important if one wishes to use samples prepared from colloidal particles simply and reliably to determine the probe shape for scanning probe microscopy from image deconvolution/restoration methods or as a calibration sample. Deterding, L. J., M. A. Moseley, et al. (1991). "Nanoscale separations combined with tandem mass spectrometry." Journal of Chromatography 554(1-2): 73-82. High-efficiency separations of peptide mixtures, tryptic digest and other biological compounds have been achieved using nanoscale packed capillaries and capillary zone electrophoresis (CZE). The coaxial continuousflow fast atom bombardment design is an excellent interface for coupling these separation techniques with mass spectrometry (MS). In addition, this interface is very useful for the acquisition of MS-MS data from compounds separated by nanoscale packed capillary liquid chromatography and CZE. Structurally informative daughter-ion spectra can be obtained at the low picomole to femtomole level. Di Fonzo, F., A. Gidwani, et al. (2000). "Focused nanoparticle-beam deposition of patterned microstructures." Applied Physics Letters 77(6): 910-12. A method was developed for fabricating nanocrystalline microstructures. This method involves synthesizing nanoparticles in a thermal plasma expanded through a nozzle, and then focusing the nanoparticles to a collimated beam by means of aerodynamic lenses. High-aspect-ratio structures of silicon carbide and titanium were deposited on stationary substrates, and lines and two-dimensional patterns were deposited on translated substrates. Linewidths equalled approximately 50 mu m. This approach allows the use of much larger nozzles than in previously developed micronozzle methods, and also allows size selection of the particles that are deposited. (13 References). Dick, W. D., P. H. McMurry, et al. (2000). "White-light detection for nanoparticle sizing with the TSI ultrafine condensation particle counter." Journal of Nanoparticle Research 2(1): 85-90. Several of the most common methods for measuring nanoparticle size distributions employ the ultrafine condensation particle counter (UCPC) for detection purposes. Among these methods, the pulse height analysis (PHA) technique, in which the optical response of the UCPC detector is related to initial particle diameter in the 310 nm range, prevails in applications where fast sampling is required or for which concentrations of nanoparticles are frequently very low. With the PHA technique, white light is required for particle illumination in order to obtain a monotonic relationship between initial particle diameter and optical response (pulse height). However, the popular, commercially available TSI model 3025A UCPC employs a laser for particle detection. Here, we report on a novel white-light detection system developed for the 3025A UCPC that involves minimal alteration to the instrument and preserves normal counting operation. Performance is illustrated with pulse height spectra produced by differential mobility analyzer (DMA)-generated calibration aerosols in the 3-50 nm range. (15 References). Diederichs, J. E. (1996). "Plasma protein adsorption patterns on liposomes: establishment of analytical procedure." Electrophoresis 17(3): 607-11. After intravenous (i.v.) injection, colloidal drug carriers such as liposomes, emulsions, polymeric or solid lipid

nanoparticles immediately interact with plasma proteins. The adsorbed plasma protein patterns depend on physico-chemical characteristics of the carriers' surface and are regarded as a key factor for the in vivo behavior of the carriers. The comprehension of the correlation between protein adsorption and in vivo organ distribution can be utilized to obtain drug targeting to different tissues. Carriers with different protein adsorption patterns will interact with different tissue-specific receptors or will be recognized by different macrophage subpopulations. Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) was applied to determine the protein adsorption patterns on polystyrene particles as model carriers. To transfer this analytical method to i.v. injectable colloidal carriers such as liposomes, a new sample preparation method was developed. The separation of liposomes from plasma after incubation was achieved by gel filtration using a Sepharose 2B column. This technique allowed a mild separation independent from eluent composition and only according to size differences. Possible protein desorption from the liposomes and adsorption onto the gel were minimized by using an eluent with a sufficiently high ionic strength. To estimate the efficiency of separation, the content of liposomes and plasma in each fraction being eluted was determined by ultraviolet (UV) spectroscopy. With this new separation method plasma protein adsorption patterns on liposomes could be analyzed for the first time. The sample preparation by gel filtration seemed to have no influence on liposome stability as far as size distribution is concerned. Diepold, R., J. Kreuter, et al. (1989). "Comparison of different models for the testing of pilocarpine eyedrops using conventional eyedrops and a novel depot formulation (nanoparticles)." Graefes Archives for Clinical and Experimental Ophthalmology 227(2): 188-93. An objective in the development of ophthalmic formulations is the use of in vitro or animal models that closely resemble the clinical situation. For this reason, experiments with conventional pilocarpine nitrate eyedrops and a depot formulation of pilocarpine nitrate sorbed to poly (butylcyanoacrylate) nanoparticles were carried out. In vitro, the diffusion of pilocarpine through bovine cornea was measured using Edelhauser cells. In vivo, the rabbit aqueous humor concentration of pilocarpine and miosis were determined after application of the above formulations. In addition, intraocular pressure was measured. Since pilocarpine has little influence on intraocular pressure in healthy rabbits, the pressure had to be increased artificially. Three models were employed that are described in the literature, namely, the betamethasone model, the alpha-chymotrypsin model, and the waterloading model. Pilocarpine could be loaded onto nanoparticles by 15% but was rapidly released from the nanoparticles based on the bovine corneal experiment. Nanoparticles only enhanced the aqueous humor concentration at 30 min; this increase, however, led to a considerably extended period of miosis as well as a reduction in intraocular pressure. The duration of the action and the intensity of the response were different among the three models tested. According to the present results, the betamethasone model seems to represent the best correlation to the clinical situation. Dingler, A., R. P. Blum, et al. (1999). "Solid lipid nanoparticles (SLN/Lipopearls)--a pharmaceutical and cosmetic carrier for the application of vitamin E in dermal products." Journal of Microencapsulation 16(6): 751-67. Solid lipid nanoparticles (SLN, Lipopearls) are nanoparticles made from solid lipids by high pressure homogenization. Incorporation of chemically labile active ingredients into the solid lipid matrix protects against chemical degradation, which is shown for vitamin E. The SLN are physically stable in aqueous dispersions and also after incorporation into a dermal cream as proven by photon correlation spectroscopy and differential scanning calorimetry. Electron microscopy and atomic force microscopy data reveal the spherical shape of the SLN and the detailed structure of the particle surface. Ultrafine particles form an adhesive film leading to an occlusive effect on the skin. The occlusion promotes the penetration of vitamin E into the skin, as shown by the stripping test. In addition to chemical stabilization of active ingredients, occlusive effects on the skin and subsequent enhanced penetration of compounds, the SLN also possess a pigment effect covering undesired colours leading to an increased aesthetic acceptance by the customer. Dixon, R. A. and R. G. Egdell (2000). "A study of the growth and mobility of Pd nanoclusters on WO 3(001) by scanning tunnelling microscopy." Surface Science 452: 1-3. The growth of Pd on WO/sub 3/(001) at room temperature has been studied by scanning tunnelling microscopy. Thermally evaporated Pd grows on WO/sub 3/(001) c(2*2) as truncated hemispherical nanoparticles whose mean diameter and height increase with increasing Pd coverage. There is some indication of preferential nucleation of clusters at step edges and at boundaries between c(2*2) and p(1*1) rafts on the (001) surface. Thermal annealing of nanoparticle covered surfaces at 873 K leads to agglomeration of the Pd clusters into large clumps with dimensions in excess of 10 nm, leaving bare terrace areas on the WO/sub 3/(001) substrate with an increased proportion of reduced p(1*1) areas. The Pd nanoparticles are susceptible to tip induced movement, which can be used to sweep clusters out of a chosen area or to selectively remove individual clusters from a surface. (45 References). Douglas, S. J., S. S. Davis, et al. (1987). "Nanoparticles in drug delivery." Critical Reviews in Therapeutic Drug Carrier Systems 3(3): 233-61. Alkylcyanoacrylates can be polymerized in acidified aqueous media by a process of anionic polymerization. The

small particles produced tend to be monodisperse and have sizes in the range of 20 to 3000 nm depending upon the polymerization conditions and the presence of additives in the form of surfactants and other stabilizers. The polyalkylcyanoacrylate nanoparticles so produced have been studied in recent years as a possible means of targeting drugs to specific sites in the body, with particular emphasis in cancer chemotherapy. The small colloidal carriers are biodegradable and drug substances can be incorporated normally by a process of surface adsorption. The review by Davis and others considers the formulation of nanoparticles, the important physicochemical variables such as pH, monomer concentration, added stabilizers, ionic strengths, etc., as well as the characteristics of the particle so created in terms of surface charge, particle size, and molecular weight. Monodisperse particles in the range of 20 to 3000 nm can be obtained. In addition, by the use of stabilizers such as dextran and its derivatives, which can be incorporated into the nanoparticle surface by a process of polymer grafting, it is possible to make nanoparticles with interesting surface characteristics and different surface charges (sign). The stability of nanoparticles in vitro and their biodegradation in vivo are examined, and the possible formation of toxic products such as formaldehyde is highlighted. Alternative biodegradable acrylates are mentioned. Drugs can be incorporated into nanoparticles by either direct incorporation during the polymerization process or adsorption to preformed nanoparticles. The efficiency of the incorporation and the release characteristics of model compounds as well as anticancer drugs are discussed. Methods for examining these processes, including the determination of adsorption and desorption, kinetics, and isotherms, are mentioned. Selectivity in drug targeting can, in theory, be achieved by the attachment of some form of homing device, normally a monoclonal antibody or a lectin. Work in vitro and in vivo, where nanoparticles have been coated with monoclonal antibodies, is described. Finally, methods for the labeling of nanoparticles with gamma-emitting radionuclides are presented, and results obtained in animal species are given. Duchene, D., D. Wouessidjewe, et al. (1999). "Cyclodextrins and carrier systems." Journal of Controlled Release 62(1-2): 263-8. This paper describes two new possibilities of using cyclodextrins to increase water solubility and bioavailability of poorly water-soluble drugs intended for targeting delivery by the oral or the parenteral route. They use either amphiphilic cyclodextrin nanoparticles or polymeric nanoparticles containing cyclodextrins. Amphiphilic skirtshaped cyclodextrins, resulting from the esterification of primary hydroxyl groups by hydrocarbon chains varying from C6 to C14, are capable of forming spontaneously nanoparticles which have been loaded with a series of steroid drugs. The drug in the amphiphilic cyclodextrin nanoparticles is molecularly dispersed and can be released very rapidly. Poly(isobutylcyanoacrylate) nanoparticles can be loaded with natural or hydroxypropyl cyclodextrins. This technique results in a significant increase in the loading capacity of nanoparticles with a series of steroids and in a very rapid release of the drug. Both methods are described as well as their potential interest for water-insoluble drugs. Duchene, D., G. Ponchel, et al. (1999). "Cyclodextrins in targeting. Application to nanoparticles." Advanced Drug Delivery Reviews 36(1): 29-40. For some years cyclodextrins and their hydrophilic derivatives have been described in the literature as solubilizers capable of enhancing the loading capacity of liposomes and microparticles. We present here two new possibilities of using cyclodextrins in the design of colloidal carriers. The first possibility consists in increasing the loading capacity of poly(isobutyl cyanoacrylate) nanospheres prepared by anionic polymerization, by employing hydroxypropyl cyclodextrins. The second possibility consists in the spontaneous formation of either nanocapsules or nanospheres by the nanoprecipitation of amphiphilic cyclodextrin diesters. These two new techniques are very promising because of the great interest presented by nanoparticles for drug administration by the oral or parenteral routes. Duguid, J. G., C. Li, et al. (1998). "A physicochemical approach for predicting the effectiveness of peptide-based gene delivery systems for use in plasmid-based gene therapy." Biophys J 74(6): 2802-14. Novel synthetic peptides, based on carrier peptide analogs (YKAKnWK) and an amphipathic peptide (GLFEALLELLESLWELLLEA), have been formulated with DNA plasmids to create peptide-based gene delivery systems. The carrier peptides are used to condense plasmids into nanoparticles with a hydrodynamic diameter (DH) ranging from 40 to 200 nm, which are sterically stable for over 100 h. Size and morphology of the carrier peptide/plasmid complex have been determined by photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM), respectively. The amphipathic peptide is used as a pH-sensitive lytic agent to facilitate release of the plasmid from endosomes after endocytosis of the peptide/plasmid complex. Hemolysis assays have shown that the amphipathic peptide destabilizes lipid bilayers at low pH, mimicking the properties of viral fusogenic peptides. However, circular dichroism studies show that unlike the viral fusion peptides, this amphipathic peptide loses some of its alpha-helical structure at low pH in the presence of liposomes. The peptidebased gene delivery systems were tested for transfection efficiency in a variety of cell lines, including 14-day C2C12 mouse myotubes, using gene expression systems containing the beta-galactosidase reporter gene. Transfection data demonstrate a correlation between in vitro transfection efficiency and the combination of several physical properties of the peptide/plasmid complexes, including 1) DNA dose, 2) the zeta potential of the

particle, 3) the requirement of both lytic and carrier peptides, and 4) the number of lysine residues associated with the carrier peptide. Transfection data on 14-day C2C12 myotubes utilizing the therapeutic human growth hormone gene formulated in an optimal peptide gene delivery system show an increase in gene expression over time, with a maximum in protein levels at 96 h (approximately 18 ng/ml). Durand, R., M. Paul, et al. (1997). "Activity of pentamidine-loaded poly (D,L-lactide) nanoparticles against Leishmania infantum in a murine model." Parasite 4(4): 331-6. The activity of pentamidine-loaded poly(D,L-lactide) nanoparticles was compared, by determination of median effective doses (ED50), to that of free pentamidine in a murine model of visceral leishmaniasis induced by Leishmania infantum. BALB/c mice were infected intravenously on day O with promastigotes and then treated on days 14, 16, and 18. Groups of 5 mice received either 0.57, 1.14 and 2.28 mg/kg of free pentamidine (expressed in pentamidine base) or 0.055, 0.11, 0.22 and 0.44 mg/kg of pentamidine-loaded nanoparticles. In the control group, 12 mice received normal saline. The liver parasite burden was evaluated using the Stauber method 72 h after the last injection and drug levels in livers and spleens were determined. Bound pentamidine was 3.3 times more active than free drug (ED50 value = 0.32 mg/kg versus 1.05 mg/kg for free drug). Drug levels showed a weak accumulation in hepatic and splenic tissues following bound pentamidine administration. A lack of acute toxicity was noted in all groups treated by bound pentamidine. Results obtained with this biodegradable carrier may be of particular interest as no new major antileishmanial compound is today available. Durand, R., M. Paul, et al. (1997). "Activity of pentamidine-loaded methacrylate nanoparticles against Leishmania infantum in a mouse model." International Journal of Parasitology 27(11): 1361-7. The use of drug delivery systems may reduce the toxicity and improve the activity of antileishmanial compounds. In view of such a strategy, we loaded the antileishmanial agent pentamidine on polymethacrylate nanoparticles. The activity of pentamidine-loaded nanoparticles was compared with that of free pentamidine in a BALB/c mice model of visceral leishmaniasis induced by Leishmania infantum. On day 0, mice were infected intravenously with 10(7) promastigotes and then treated via the tail vein on days 14, 16 and 18 with bound pentamidine, free drug or isotonic saline (control group). On day 21, liver parasite burdens were evaluated using the Stauber method. Livers and spleens were removed and weighed. Effective doses (ED) were determined using the Michaelis-Menten representation relating the percentage of parasite suppression to the dose. The ED50 of bound pentamidine was six times lower than that of free pentamidine (0.17 mg kg-1 vs 1.06 mg kg-1). The ED90 value calculated for bound pentamidine was 1 mg kg-1. It was not possible to obtain the ED90 for free pentamidine because the doseresponse curve reached a plateau near 60% of parasite suppression. A significant decrease in liver and spleen weights, probably reflecting the leishmanicidal activity, was observed for treated mice with bound pentamidine. These results showed that bound pentamidine was more potent than the free drug against L. infantum in our BALB/c mice model. Duvanov, S. M. and A. G. Balogh (2000). "Two-stage diffusion and nanoparticle formation in heavily implanted polycrystalline Al 2O 3." Nuclear Instruments and Methods in Physics Research Section B Beam Interactions with Materials and Atoms 171(4): 475-80. Two-stage diffusion was experimentally observed for the first time in polycrystalline alumina. Samples were heavily implanted by Ti ions and the concentration depth profiles were determined by Rutherford backscattering spectrometry (RBS) with 2 MeV He/sup +/ ions. The Arrhenius-plot, derived from the RBS spectra, shows two different diffusion mechanisms for the implanted Ti ions between RT and 900 degrees C: (i) radiation enhanced diffusion (RED) up to 730 degrees C; (ii) transient thermal-like diffusion between 730 degrees C and 900 degrees C. The extrapolation to zero-value at 710 degrees C agrees well with the temperature, reported in (G.P. Pells, J. Am. Ceram. Soc. 77 (2) (1994) 368). At this temperature the annealing of F-centres is already completed. High resolution scanning electron microscopy (HSEM) with energy dispersive X-ray analysis (EDX) showed Ti-enriched nanoparticles with a typical diameter of about 10-15 nm on samples, implanted at RT. The nanoparticles agglomerate into larger particles at an implantation temperature of about 830 degrees C. Combining RBS, HSEM, X-ray photoelectron spectroscopy (XPS) measurements with TRIM simulations (J.F. Ziegler, J.P. Biersack, U. Littmark, 1985), more detailed information on depth and lateral distribution of Ti atoms was obtained. (15 References). Duvivier, C. Grandfils, et al. (1997). "[The size of nanoparticles after incorporation into gastroresistant spheroids]." Journal de Pharmacie Belgique 52(3): 123. Nanoparticles can be used as an attractive carrier for the controlled delivery of drugs by the oral route. This nanoparticular delivery system can protect an active ingredient from enzymatic degradations and enhance its absorption from the intestinal mucosa. We studied the development of a gastroresistant dosage form for the oral administration of nanoparticles. Fast disintegrating pellets were used for the administration of nanoparticles and for their transit to the site of absorption. A gastroresistant film was applied onto the pellets to protect the nanoparticles and/ or the active substance from the acid gastric environment. The integrity of the nanoparticle size was assessed after two critical manufacturing steps: the extrusion/spheronisation process and the coating

process. The determination of the nanoparticles size distribution was performed by photon correlation spectroscopy (PCS). The comparison of the PCS results between the original nanoparticles and the nanoparticles incorporated in the pellets shows a very low aggregation. Moreover the coating process was not a critical step since it was not responsible for an additional agglomeration of the nanoparticles. In conclusion, our manufacturing process allows the redispersion of the nanoparticles with a little change of the size distribution. In a next study we well try to quantify the release of the nanoparticles from the pellets. Duxin, N., M. P. Pileni, et al. (2000). "Magnetic properties of an individual Fe-Cu-B nanoparticle." Langmuir 16(1): 11-14. Superparamagnetic elongated Fe-Cu-B alloys were prepared in aqueous solution via sodium borohydride reduction of copper and iron dodecyl sulfate, Cu(DS)/sub 2/ and Fe(DS)/sub 2/. The magnetization reversal of an individual Fe-Cu-B nanoparticle can be described by uniform rotation of magnetization and by thermal activation over a single-energy barrier as originally proposed by Neel and Brown. (18 References). Ebihara, T., Y. Yanagida, et al. (1999). "In vitro selective RNA synthesis with L-A virus nanoparticles." Biochemical and Biophysical Research Communications 263(1): 23-7. New in vitro RNA synthesis has been performed with an L-A virus nanoparticles, in which the gene and polymerase are integrated. The specific recognition sequence (packaging site) of L-A virus was inserted within a gene of interest. Based on the intrinsic replication cycle, the exogenous RNA with the packaging site was encapsulated by an empty L-A virus nanoparticle. The packaging site worked as a recognition site even for exogenous RNAs. The recognized RNA was replicated to dsRNA, and was then transcribed by empty L-A virus nanoparticles. These results indicate that empty L-A virus nanoparticles recognize an exogenous RNA with the packaging site and synthesize RNA in vitro. Egea, M. A., F. Gamisans, et al. (1994). "Entrapment of cisplatin into biodegradable polyalkylcyanoacrylate nanoparticles." Farmaco 49(3): 211-7. The entrapment of cisplatin into biodegradable colloidal systems (polyalkylcyanoacrylates) was studied. Nanoparticles were characterized in terms of relevant parameters for organ distribution in vivo, such as particle diameter and particle size distribution, determined by correlation photon spectroscopy and transmission electron microscopy. Association efficiency was also evaluated by Plasma Emission Spectrophotometry. The ability of surfactants (sodium lauryl sulphate and poloxamer 188), and dextrans of various molecular weights, to improve the binding of the drug to polyalkylcyanoacrylates was also studied. The dextran content in nanoparticles, as determined by polarimetry, increases with the molecular weight of the polysaccharide. The highest value of association efficiency of cisplatin to nanoparticles was obtained in the presence of dextran 70 with sodium lauryl sulphate (0.08%) as stabiliser. Egelhof, T., N. Delbeck, et al. (1998). "[Can superparamagnetic contrast media improve MRI-tomographic images of experimental gliomas?]." Radiologe 38(11): 943-7. PURPOSE: To investigate whether the margins of microscopic tumors can be delineated better with monocrystalline iron oxide nanoparticles (MION), a superparamagnetic contrast medium, than with Gd-DTPA by magnetic resonance imaging (MRI). METHODS: MRI and histological examinations were conducted in 28 Wistar rats with sterotactically implanted gliomas (C6 gliomas). Of the 28 animals, 14 were examined after intravenous administration of MION [nine animals received 179 mmol Fe/kg body weight (dose 1), and five, 893 mmol Fe/kg (dose 2)]. The other 14 animals were examined first after i.v. administration of Gd-DTPA (0.2 mmol/kg) and then after i.v. administration of MION. The extent of the tumors as seen on MRI and at histological study were compared. RESULTS: Iron particles were identified microscopically in tumor cells and in the tumoral interstitium. After administration of MION at dose 1, the contrast-enhanced area of tumor was 1.55-fold greater than the extent of tumor identified by histological study, at dose 2,2.15-fold. Compared with Gd-DTPA the area of contrast enhancement was greater by a factor of 1.38 with MION administration at dose 1 and by a factor of 1.91 at dose 2. CONCLUSION: MION provides intra- and extracellular contrast enhancement. The area of the contrastenhanced tumor is dose-dependently greater with MION than with Gd-DTPA and also greater than the extent of tumor seen at histological study. El-Jaick, L. J., D. Acosta-Avalos, et al. (2001). "Electron paramagnetic resonance study of honeybee Apis mellifera abdomens." European Biophysic Journal 29(8): 579-86. Although ferromagnetic material has been detected in Apis mellfera abdomens and identified as suitable for magnetic reception, physical and magnetic properties of these particles are still lacking. Electron paramagnetic resonance is used to study different magnetic materials in these abdomens. At least four iron structures are identified: isolated Fe3+ ions, amorphous FeOOH, isolated magnetite nanoparticles of about 3 x 10(2) nm3 and 10(3) nm3 volumes, depending on the hydration degree of the sample, and aggregates of these particles. A lowtemperature transition (52-91 K) was observed and the temperature dependence of the magnetic anisotropy constant of those particles was determined. These results imply that biomineralized magnetites are distinct from inorganic particles and the parameters presented are relevant for the refinement of magnetoreception models in

honeybees. El-Kouedi, M. and C. A. Foss, Jr. (2000). "Optical properties of gold-silver iodide nanoparticle pair structures." Journal of Physical Chemistry B 104(17): 4031-7. Nanoparticle pair structures composed of metal (Au) and semiconductor (AgI) segments with radii ca. 16 nm have been prepared in porous anodic aluminum oxide via electrochemical template synthesis. The metal and semiconductor members can be prepared such that they are in contact or separated in the porous host. UV/ visible spectra of composites in which the Au and AgI segments are in contact show a red-shifted and broadened Au particle plasmon resonance band and the absence of the AgI exciton peak normally observed at lambda =425 nm. A blue shift in the Au particle plasmon band and the reappearance of the AgI exciton peak occur as the average interparticle spacing is increased. The changes in plasmon resonance peak position are consistent with an increased probability of Au and AgI intermixing as the spacing parameter d/sub 12/ is decreased. The absence of the AgI exciton peak in the case of contacting Au and AgI particles is consistent with a large increase in the effective static dielectric constant upon phase intermixing and/or field effects associated with the contact potential at the Au/AgI interface. (34 References). El-Samaligy, M. and P. Rohdewald (1982). "Triamcinolone diacetate nanoparticles, a sustained release drug delivery system suitable for parenteral administration." Pharmaceutica Acta Helvetiae 57(7): 201-4. El-Samaligy, M. S. and P. Rohdewald (1983). "Reconstituted collagen nanoparticles, a novel drug carrier delivery system." Journal of Pharmacy and Pharmacology 35(8): 537-9. Elghanian, R., J. J. Storhoff, et al. (1997). "Selective colorimetric detection of polynucleotides based on the distancedependent optical properties of gold nanoparticles." Science 277(5329): 1078-81. A highly selective, colorimetric polynucleotide detection method based on mercaptoalkyloligonucleotide-modified gold nanoparticle probes is reported. Introduction of a single-stranded target oligonucleotide (30 bases) into a solution containing the appropriate probes resulted in the formation of a polymeric network of nanoparticles with a concomitant red-to-pinkish/purple color change. Hybridization was facilitated by freezing and thawing of the solutions, and the denaturation of these hybrid materials showed transition temperatures over a narrow range that allowed differentiation of a variety of imperfect targets. Transfer of the hybridization mixture to a reverse-phase silica plate resulted in a blue color upon drying that could be detected visually. The unoptimized system can detect about 10 femtomoles of an oligonucleotide. Encinosa, M. (2000). "W-Ni-Fe nanostructure materials synthesized by high energy ball milling." Transactions of Nonferrous Metals Society of China 10(1): 57-9. Investigations were made on the phase evolution and thermal stability of the 90 W-7Ni-3 Fe(mass fraction, %) milled powders by means of XRD and DTA. The results showed that ball milling produced an ultrafine composite powder consisting of supersolidus solution W(Ni,Fe) and amorphous phase, owing to the fast diffusion rate induced by high density of lattice defects and nanograin boundaries. The amorphous phase results from the extension of the solubility of W in gamma -(Ni,Fe) phase which forms during the first 3 h of ball milling. (14 References). Ezpeleta, I., M. A. Arangoa, et al. (1999). "Preparation of Ulex europaeus lectin-gliadin nanoparticle conjugates and their interaction with gastrointestinal mucus." International Journal of Pharmacy 191(1): 25-32. One approach to improve the bioavailability and efficiency of drugs consists of the association of a ligand (i.e. lectins), showing affinity for biological structures located on the mucosa surfaces, to nanoparticulate drug delivery systems. In this context, Ulex europaeus lectin-gliadin nanoparticle conjugates (UE-GNP) were prepared with the aim of evaluating their in vitro bioadhesive properties. The lectin was fixed by a covalent procedure to gliadin nanoparticles by a two-stage carbodiimide method. Typically, the amount of bound lectin was calculated to be approximately 15 microg lectin/mg nanoparticle, which represented a coupling efficiency of approximately 16% of the initial lectin concentration. In addition, the activity of these conjugates was tested with bovine submaxillary gland mucin (BSM) and the level of binding to this mucin was always much greater with UE-GNP than with controls (gliadin nanoparticles). However, the presence of 50 micromol fucose, which is the reported specific sugar for U. europaeus lectin, specifically inhibited the activity of these conjugates and, therefore, the UE-GNP binding to BSM was attenuated by 70%. These results clearly showed that the activity and specificity of U. europaeus lectin was preserved after covalent coupling to these biodegradable carriers. Falvo, M. R. and R. Superfine (2000). "Mechanics and friction at the nanometer scale." Journal of Nanoparticle Research 2: 237-248. Fanyao, Q. and P. C. Morais (2000). "An oxide semiconductor nanoparticle in an aqueous medium: a surface charge density investigation." Journal of Physical Chemistry B 104(22): 5232-6.

The surface charge density in semiconductor metal oxide quantum dots dispersed in alkaline aqueous colloids was obtained by solving the three-dimensional Schrodinger and Poisson's equations. The calculation was carried out self-consistently within the frame of the finite difference method. Surface charge density, in the range of 0.10.3 C/m/sup 2/, was obtained for spherical ZnO nanoparticles in an aqueous medium at pH around 11. The calculated surface charge density, in very good agreement with the average value reported in the literature (0.2 C/m/sup 2/), is obtained as long as a proton-transfer mechanism through the semiconductor-electrolyte interface takes place. The calculated band energy profile for water-based semiconductor colloidal quantum dots, is very much similar to the band energy profile found in symmetric modulation-doped semiconductor quantum wells. (22 References). Farrugia, C. A. and M. J. Groves (1999). "The activity of unloaded gelatin nanoparticles on murine melanoma B16-F0 growth in vivo." Anticancer Resesearch 19(2A): 1027-31. BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccine is a non-specific immunostimulant which has been used clinically in the treatment of melanoma. In this communication, the antimelanoma activity of BCG was related to its fibronectin-binding properties and mimicked using gelatin nanoparticles. MATERIALS AND METHODS: The fibronectin-binding properties of aqueous gelatin solutions, gelatin nanoparticles, BCG vaccine, and PS1 (a glucan extracted from Tice BCG) were compared by an enzyme-linked immunosorbent assay and their ability to suppress murine B16-F0 melanoma in vivo investigated. RESULTS: Aqueous gelatin solutions, gelatin nanoparticles and BCG all bound to fibronectin in vitro. The immunostimulant PS1 did not. In vivo, BCG and gelatin nanoparticles suppressed melanoma growth while PS1 and aqueous gelatin solutions had no effect. CONCLUSIONS: The antimelanoma activity of BCG is not due to the associated immunostimulatory glucan but can be correlated to its fibronectin-binding properties. Since solutions of gelatin have no effect whereas nanoparticles produce total suppression, this suggests a relationship between the volume of the fibronectinbinding entities and their antitumour activity. Thus, gelatin nanoparticles may represent an attractive alternative to the use of BCG vaccine in melanoma treatment. Farrugia, C. A. and M. J. Groves (1999). "Gelatin behaviour in dilute aqueous solution: designing a nanoparticulate formulation." Journal of Pharmacy and Pharmacology 51(6): 643-9. Although it has been claimed that nanoparticles can be produced from gelatin, a naturally occurring polypeptide, the commercial conversion of animal collagen to gelatin results in a heterogeneous product with a wide molecular-weight range. This is probably responsible for the widely observed variation in the experimental conditions required for nanoparticle formation. In this study, 0.2% w/v aqueous B225 gelatin solutions were incubated under various conditions of time, temperature, pH and ethanol concentration and characterized by both size-exclusion high-performance liquid chromatography (HPLC) and dynamic light scattering. Gelatin was shown to be denatured when the temperature was increased to 37 degrees C (approx.) and the rate of renaturation was optimized over the temperature range 7-20 degrees C at pH 5.0, equivalent to the isoelectric point (IEP). The molecular-weight profile remained unchanged at 37 degrees C (approx.) in the pH range 5-7. When the gelatin solutions were mixed with ethanol, higher-molecular-weight fractions (microgel, delta and zeta fractions, all with molecular weights &gt; 700 kDa) precipitated at ethanol concentrations lower than those required to precipitate the lower molecular weight material ( &lt; 700 kDa), with maximum precipitation occurring close to the isoelectric point (pH 5.0). The molecular weight profile of gelatin in solution is evidently critically affected in a time-dependent manner by both pH and temperature. These two factors influence the noncovalent interactions responsible for the molecular structure of gelatin. The molecular weight profiles, in turn, affect the phase behaviour of gelatin in hydroalcoholic solutions. Systematically investigating the effect of time, temperature, pH and ethanol concentration on the molecular-weight-distribution profile of a gelatin solution enabled a robust method to be developed for the preparation of colloidal dispersions of non-aggregated gelatin nanoparticles 220-250 nm in diameter. This contrasts with the multiparticulate aggregates produced by earlier literature methods. Fattah, G. A. (2000). "Light emission due to carrier confinement in nanoparticles of DC discharge processed silicon." Physics of Low Dimensional Structures, no. Direct Current (DC) discharge has been applied to produce nanocrystalline silicon. The formed layer characteristics have been measured using the photoluminescence (PL) measurement technique with the two excitation wavelengths of 326 nm and 488 nm. There are two observable PL bands centered at 688 nm and 704 nm for UV and visible excitation wavelengths, respectively. The estimated increase of the band gap energy due to the formation of nanocrystals is calculated using the effective mass approximation, hence the particle size can be calculated. The calculated crystal diameters equal 6 nm and 7 nm for the PL peaks at 688 nm and 704 nm, respectively. Also scanning electron microscope (SEM) has been used to examine the formation of the dots on the silicon surface. (6 References). Fattal, E., M. Youssef, et al. (1989). "Treatment of experimental salmonellosis in mice with ampicillin-bound nanoparticles." Antimicrobial Agents and Chemotherapy 33(9): 1540-3. We tested the effectiveness of ampicillin bound to nanoparticles of polyisohexylcyanoacrylate (PIHCA) in treating

C57BL/6 mice experimentally infected with Salmonella typhimurium C5. The diameter of the nanoparticles was 187 +/- 13 nm, and the ampicillin/PIHCA ratio was 0.2/1. The proportion of ampicillin bound was 90 +/- 3%. All control mice and all those treated with nonloaded nanoparticles died within 10 days of infection. By contrast, all mice treated with a single injection of 0.8 mg of nanoparticle-bound ampicillin survived. With free ampicillin, a similar curative effect required three doses of 32 mg each. Lower doses delayed but did not reduce mortality. The sharp increase in the therapeutic index of ampicillin after linkage to PIHCA nanoparticles was explained by studies of the distribution of ampicillin, which showed that when bound to nanoparticles, the ampicillin was concentrated mainly in the liver and spleen, the primary foci of infection in the experimental model that we used. These findings warrant further development of intracellular targeting of antibiotics on biodegradable polymeric carriers such as PIHCA. Fattal, E., J. Rojas, et al. (1991). "Liposome-entrapped ampicillin in the treatment of experimental murine listeriosis and salmonellosis." Antimicrobial Agents and Chemotherapy 35(4): 770-2. The tissue distribution of ampicillin entrapped in liposomes was studied in normal noninfected mice and showed that ampicillin concentrated mostly in the liver and spleen. Liposomate ampicillin was significantly more effective than free ampicillin in reducing splenic and hepatic bacterial counts in C57BL/Ka nude mice chronically infected with Listeria monocytogenes EGD. It was also significantly more effective than free ampicillin in reducing mortality in C57BL/6 mice acutely infected with Salmonella typhimurium C5. Comparison of the results with those previously obtained in the same experimental models with the same amounts of ampicillin bound to polyisohexylcyanoacrylate nanoparticles showed that liposomes were more effective than nanoparticles (M. Youssef, E. Fattal, M. J. Alonso, L. Roblot-Treupel, J. Sauzieres, C. Tancrede, A. Omnes, P. Couvreur, and A. Andremont, Antimicrob. Agents Chemother. 32:1204-1207, 1988) in targeting ampicillin to the spleen but were less effective than nanoparticles in targeting ampicillin to the liver and reducing mortality in acute salmonellosis. Fattal, E., J. Rojas, et al. (1991). "Ampicillin-loaded liposomes and nanoparticles: comparison of drug loading, drug release and in vitro antimicrobial activity." Journal of Microencapsulation 8(1): 29-36. In this paper, we report the physico-chemical properties of negatively charged liposomes and of polyisohexylcyanoacrylate nanoparticles loaded with ampicillin. Although the carriers were of the same size (200 nm), drug-loading capacity was 20 times higher for nanoparticles than for liposomes. After freeze-drying or storage at +4 degrees C, no drug escaped from polymeric nanoparticles. On the other hand, in the same conditions, ampicillin leaked rapidly from liposomes. Drug release in foetal calf serum was gradual (of zero order) with nanoparticles, whereas it was rapid with liposomes. Finally, the antimicrobial activity of ampicillin-entrapped liposomes or nanoparticles was studied in vitro. Fattal, E., C. Vauthier, et al. (1998). "Biodegradable polyalkylcyanoacrylate nanoparticles for the delivery of oligonucleotides." Journal of Controlled Release 53(1-3): 137-43. Antisense oligonucleotides with base sequences complementary to a specific RNA can, after binding to intracellular mRNA, selectively modulate the expression of a gene. However, these molecules are poorly stable in biological fluids and are characterized by a low intracellular penetration. In view of using oligonucleotides as active molecules, the development of polymeric particulate carriers was considered. Oligonucleotides were associated with biodegradable polyalkylcyanoacrylate nanoparticles through the formation of ion pairs between the negatively charged oligonucleotides and hydrophobic cations. Oligonucleotides bound to these nanoparticles were found to be protected from nuclease attack in cell culture media and their cellular uptake was increased as the result of the capture of nanoparticles by an endocytotic/phagocytotic pathway. The in vivo pharmacokinetic profile of oligonucleotides free or associated with nanoparticles has been investigated after intravenous administration to mice and the stability of these molecules has been evaluated by original methodology based on the use of polyacrylamide gel electrophoresis (PAGE) followed by multichannel radioactivity counting. Stability in vivo in the plasma and in the liver was shown to be improved when the oligonucleotides were adsorbed onto the nanoparticles. These results obtained both in vitro and in vivo open exciting perspectives for the specific delivery of oligonucleotides to the liver, thus considering this approach for the treatment of liver diseases (e.g. liver metastasis or hepatitis). Fenart, L., A. Casanova, et al. (1999). "Evaluation of effect of charge and lipid coating on ability of 60-nm nanoparticles to cross an in vitro model of the blood-brain barrier." Journal of Pharmacology and Experimental Therapeutics 291(3): 101722. A cell culture model of the blood-brain barrier (BBB) consisting of a coculture of bovine brain capillary endothelial cells and rat astrocytes has been used to examine the ability of 60-nm nanoparticles with different physicochemical characteristics to cross the BBB. Neutral, anionic, and cationic nanoparticles were made from crosslinked malto-dextrins derivatized or not (neutral) with phosphates (anionic), quaternary ammoniums (cationic) ligands. Then, these particles were coated or not with a lipid bilayer made of dipalmitoyl phosphatidyl choline and cholesterol. Lipid coating of ionically charged nanoparticles was able to increase BBB crossing 3- or 4-fold compared with uncoated particles, whereas coating of neutral particles did not significantly alter their

permeation characteristics across the endothelial cell monolayer. Lipid-coated nanoparticles were nontoxic toward BBB integrity, and crossed the BBB by transcytosis without any degradation. Furthermore, a 27-fold increase in albumin transport was observed when albumin had previously been loaded in the cationic lipid-coated nanoparticles. The influence of red blood cells was studied; a marked inhibition of the transport was observed, probably due to strong interaction between nanoparticles and red blood cells. Ferdous, A. J., N. Y. Stembridge, et al. (1998). "Role of monensin PLGA polymer nanoparticles and liposomes as potentiator of ricin A immunotoxins in vitro." Journal of Controlled Release 50(1-3): 71-8. Monensin is a carboxylic ionophore which can potentiate the activity of ricin based immunotoxins (IT) in vitro and in vivo against a variety of human tumours. Monensin was encapsulated into nanoparticles (NP) by using biodegradable poly(DL-lactide-co-glycolide) (PLGA, 50:50). The NP were prepared by modified emulsificationsolvent evaporation method. High shear homogenization followed by simultaneous stirring and bath sonication were used for preparing NP. The size of NP was determined by photon correlation spectroscopy using a BI 90 particle sizer (Brookhaven Instruments). The average size of NP could be decreased from 567 nm to 163 nm by increasing the concentration of polyvinyl alcohol from 10% to 100% of PLGA. The NP were spherical in shape as observed by Atomic Force Microscopy. The concentration of monensin in the NP was analyzed by HPLC and the entrapment efficiency was found to be more than 12%. The zeta potential of NP was -25.8 (+/- 1.3) mv, which did not change significantly after resuspension of the freeze dried sample. The NP were tested against HL-60 and HT-29 human tumour cell lines in vitro. Monensin NP potentiated the activity of IT by 40 to 50 times against these cell lines. There was however, no difference between the NP and liposomes for their potentiating affect of IT against the two tumour cell lines. Fernandez, A., J. C. Sanchez-Lopez, et al. (1998). "Characterization of nanophase Al-oxide/Al powders by electron energy-loss spectroscopy." Journal of Microscopy 191(2): 212-220. Al nanoparticles were prepared by the inert gas condensation method. After passivation with oxygen and air exposure we obtained a powdered sample of an Al-oxide/Al nanocomposite material. In the present paper we describe the use of the electron energy-loss spectroscopy (EELS) technique in a transmission electron microscope to characterize such nanostructured powders compared with a microcrystalline commercial aluminium foil. Energy-filtered images showed the presence of an alumina overlayer of approximately 4 nm covering the aluminium nanoparticles (23 nm in diameter). EELS analysis enabled us to determine the total amount of Al2O3 and metallic Al and the structure of the alumina passivation overlayer in the sample. In particular, the extended energy-loss fine structure analysis of the data showed a major presence of Al tetrahedrally coordinated with oxygen in the alumina passivation layer of Al nanoparticles instead of the octahedral coordination found for a conventional Al foil. This surprising effect has been attributed to the nanoscopic character of the grains. The analysis of the electron-loss near-edge structure also determines the presence of a certain degree of aggregation in this kind of powdered sample as result of the coalescence of the nanocrystalline grains. The procedure presented here may have the potential to solve other problems during characterization of nanostructured materials. Fernandez-Urrusuno, R., E. Fattal, et al. (1995). "Influence of surface properties on the inflammatory response to polymeric nanoparticles." Pharmacetical Research 12(9): 1385-7. Fernandez-Urrusuno, R., E. Fattal, et al. (1995). "Evaluation of liver toxicological effects induced by polyalkylcyanoacrylate nanoparticles." Toxicology and Applied Pharmacology 130(2): 272-9. Intravenous administration of drug-loaded polyalkylcyanoacrylate (PACA) nanoparticles is followed by a rapid uptake by the tissues of the reticuloendothelial system, mainly the liver. Nevertheless, it is so far unknown whether chronic administration of nanoparticles can lead to damage to the liver cells. We have studied the subacute toxicological effects of these drug carriers in a rat in vivo/ex vivo model. Nanoparticles were administered intravenously at a total dose of 200 mg/kg for 14 days (10 individual doses of 20 mg/kg). Hepatocytes were then isolated. Levels of alpha 1-acid glycoprotein secretion increased while albumin secretion decreased in hepatocytes from rats treated with PACA nanoparticles. In addition, glucose production due to the fructose metabolism was lowered. Treated rats induced a temporary increase and hyposialyation of serum alpha 1-acid glycoprotein. These effects were reversible 15 days after the treatment was concluded. Finally, the involvement of Kupffer cells and polymer degradation products was studied in vitro. Modifications of hepatocyte protein synthesis related to the treatments were only observed when direct contact between nanoparticles and hepatocytes existed. Kupffer cells and polymer degradation products did not mediate the hepatocyte response to nanoparticles in vitro. In conclusion, modifications in hepatic function after chronic administration of PACA nanoparticles have been detected by the use of very sensitive models for detecting hepatoxicity. These effects were, however, found to be reversible when the treatment was stopped. Fernandez-Urrusuno, R., E. Fattal, et al. (1996). "Effect of polymeric nanoparticle administration on the clearance activity of the mononuclear phagocyte system in mice." Journal of Biomedical Materials Research 31(3): 401-8.

We investigated the consequences of acute and subacute administration of mice with polyisobutylcyanoacrylate (PIBCA), polyisohexylcyanoacrylate (PIHCA), poly(D,L-lactic) acid (PLA), and polystyrene (PS) nanoparticles on the mononuclear phagocyte system phagocytic function. This was done by measuring the clearance rate of colloidal carbon. Single administration of PIBCA and PIHCA (but not PLA and PS) nanoparticles reduced carbon clearance in both a time- and dose-dependent fashion. Since clearance of preopsonized carbon was normal, it was assumed that PIBCA and PIHCA nanoparticles deplete opsonins specific for carbon recognition. A decrease in plasma fibronectin levels resulting from nanoparticle administration suggested its implication in their removal from blood. However, fibronectin does not seem to be responsible for PIBCA and PIHCA blockade. Phagocytic function was preserved after repeated treatment with nanoparticles, probably as a result of increased Kupffer cell phagocytic activity and the contribution of spleen macrophages. Neither toxicity nor effects due to nanoparticle hepatic accumulation were observed. Fernandez-Urrusuno, R., E. Fattal, et al. (1997). "Evaluation of hepatic antioxidant systems after intravenous administration of polymeric nanoparticles." Biomaterials 18(6): 511-7. We have investigated the modifications of the levels of intracellular markers of the oxidative stress in hepatocytes, after single or repeated injections of poly(isobutyl cyanoacrylate) (PIBCA) and polystyrene (PS) nanoparticles. Nanoparticles were administered intravenously at single doses of 20 and 100 mg kg 1 for 14 days. Levels of reduced (GSH) and oxidized (GSSG) glutathione, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CT) and the peroxidation of membrane lipids were measured. Single and repeated administration of PIBCA and PS nanoparticles induced a transient depletion of GSH and GSSG levels, a transient inhibition of SOD activity and a slight increase in CT activity. However, GPx activity was not modified and lipid peroxidation was not observed, suggesting that hepatocytes are not strongly affected by these modifications. Since nanoparticles do not distribute in hepatocytes, oxidative species could proceed from hepatic macrophages, activated after nanoparticle phagocytosis. It is unlikely that poly(alkyl cyanoacrylate) degradation products might be responsible for the oxidative attack because non-biodegradable PS nanoparticles induced the same effect. Uptake of polymeric nanoparticles by Kupffer cells in the liver induce modifications in hepatocyte antioxidant systems, probably due to the production of radical oxygen species. However, the depletion in glutathione was not great enough to initiate hepatocyte damage, since no changes in lipid peroxidation and reversible alterations were observed. This is an important factor to be considered in the use of polymeric nanoparticles as drug carriers. Fernandez-Urrusuno, R., P. Calvo, et al. (1999). "Enhancement of nasal absorption of insulin using chitosan nanoparticles." Pharmacetical Research 16(10): 1576-81. PURPOSE: To investigate the potential of chitosan nanoparticles as a system for improving the systemic absorption of insulin following nasal instillation. METHODS: Insulin-loaded chitosan nanoparticles were prepared by ionotropic gelation of chitosan with tripolyphosphate anions. They were characterized for their size and zeta potential by photon correlation spectroscopy and laser Doppler anemometry, respectively. Insulin loading and release was determined by the microBCA protein assay. The ability of chitosan nanoparticles to enhance the nasal absorption of insulin was investigated in a conscious rabbit model by monitoring the plasma glucose levels. RESULTS: Chitosan nanoparticles had a size in the range of 300-400 nm, a positive surface charge and their insulin loading can be modulated reaching values up to 55% [insulin/nanoparticles (w/w): 55/100]. Insulin association was found to be highly mediated by an ionic interaction mechanism and its release in vitro occurred rapidly in sink conditions. Chitosan nanoparticles enhanced the nasal absorption of insulin to a greater extent than an aqueous solution of chitosan. The amount and molecular weight of chitosan did not have a significant effect on insulin response. CONCLUSIONS: Chitosan nanoparticles are efficient vehicles for the transport of insulin through the nasal mucosa. Fishbein, I., M. Chorny, et al. (2000). "Nanoparticulate delivery system of a tyrphostin for the treatment of restenosis." Journal of Controlled Release 65(1-2): 221-9. Restenosis, the principal complication of percutaneous transluminal coronary angioplasty is responsible for the 35-40% long-term failure rate following coronary revascularization. The neointimal formation, a morphological substrate of restenosis, is dependent on smooth muscle cells (SMC) proliferation and migration. Signal transduction through the platelet-derived growth factor (PDGF)/PDGF receptors system is involved in the process of post-angioplasty restenosis. The unsuccessful attempts to control restenosis by systemic pharmacological interventions have prompted many researchers to look for more promising therapeutic approaches such as local drug delivery. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases. We assessed the release kinetics and in vivo effects of nanoparticles containing PDGF-Receptor beta (PDGFRbeta) tyrphostin inhibitor, AG-1295. AG-1295-loaded poly(DL-lactide) (PLA) nanoparticles were prepared by spontaneous emulsification/solvent displacement technique. In vitro release rate and the impact of drug/polymer ratio on the nanoparticle size were determined. The degree of tyrosine phosphorylation was assessed by Western blot with phosphotyrosine-specific antibody in rat SMC extracts. Several bands characteristic of PDGF BB-stimulated SMC disappeared or weakened following tyrphostin treatment. Local intraluminal delivery of AG-1295-loaded PLA nanoparticles to the injured rat carotid artery had no effect on proliferative activity in medial and neointimal

compartments of angioplastisized arteries, indicating a primary antimigration effect of AG-1295 on medial SMC. Fisker, R., J. M. Carstensen, et al. (2000). "Estimation of nanoparticle size distributions by image analysis." Journal of Nanoparticle Research 2: 267-277. Fiurasek, J., B. M. Chernobrod, et al. (2000). "Coherent light scattering and resonant energy transfer in apertureless nearfield optical microscope." Quantum Electronics and Laser Science Conference 40(IEEE Cat. No.00CH37089). Summary form only given. We consider two resonant molecules (or nano-particles) located near the tip of an apertureless near-field scanning optical microscope (NSOM). The tip serves as a probe that allows us to observe the molecules and control the coupling between them. Various models are considered for the nanosized probe tip: a point-like dipole, a small dielectric sphere, and an elongated spheroidal metallic nanoparticle. In all the cases, the molecules are modeled as classical point-like dipoles. (6 References). Florence, A. T., A. M. Hillery, et al. (1995). "Factors affecting the oral uptake and translocation of polystyrene nanoparticles: histological and analytical evidence." Journal of Drug Targeting 3(1): 65-70. Quantitative and qualitative evidence from our laboratories on the absorption and translocation of polystyrene latex nanoparticles both by histological (qualitative) and analytical measurement of levels of polystyrene (quantitative) is briefly reviewed in this paper. We have previously compared the uptake of nonionized polystyrene latex ranging in size from 50nm to 3 microns, and made some comparisons of uptake between carboxylated microspheres and nonionic systems, showing the lower uptake of the former through the lymphoid tissue of the gastrointestinal tract. Size is a key parameter, uptake increasing with decreasing particle diameter. Early evidence suggested that uptake is by way of the Peyer's patches and other elements of the gut associated lymphoid tissue (GALT). Adsorption of hydrophilic block-copolymers onto polystyrene markedly reduces the uptake by intestinal GALT. Modification of the surface with specific ligands such as by covalent attachment of tomato lectin molecules has indicated widespread uptake by non-GALT tissues, following their binding to and internalisation by enterocytes. The ability to decrease and increase uptake is clear evidence of a phenomenon which has the potential for further control to allow it to be exploited fully for drug or vaccine delivery. The evidence to date with nanoparticles as carriers systems for labile drugs such as proteins by the oral route remains to be substantiated. Fonseca, L. F., O. Resto, et al. (2000). "Fabrication and nanostructure of oriented FePt particles." Journal of Applied Physics 87(9): 1-3. Thin films of oriented tetragonal FePt particles separated by amorphous alumina have been fabricated by electron beam evaporation. The ordering of the FePt particles without coarsening can be tailored by annealing conditions. The value of coercivity of the annealed film reached as high as 4.4 kOe. The perpendicular magnetic coercivity of the annealed film was slightly larger than in-plane coercivity. Some of the tetragonal FePt particles were found to have {111} twins and stacking faults. From our high-resolution electron microscopy observations, it was determined that central region of the ordered FePt particles tended to have c-axis perpendicular to the film plane. (10 References). Fontana, G., G. Pitarresi, et al. (1998). "Preparation, characterization and in vitro antimicrobial activity of ampicillin-loaded polyethylcyanoacrylate nanoparticles." Biomaterials 19(11-12): 1009-17. In this paper, the experimental conditions for preparing ampicillin-loaded polyethylcyanoacrylate (PECA) nanoparticles are described. The effects of drug concentration and surfactant type in the polymerization medium on the particle size distribution and loading capacity were studied. The results of these studies show that only the type of surfactant has an impact on the nanoparticle dimensions. The release rate of ampicillin from PECA nanoparticles at pH 7.4 (extracellular value pH) performed either with and without esterases, show that the drug release is considerably increased in the presence of these exzymes. The results of drug release study at pH 1.1 (simulated gastric juice) are very interesting. This study has evidenced that the 70% of ampicillin is released quickly, while the remaining fraction is firmly incorporated in nanoparticles. The released ampicillin is quickly degraded in acid medium while the entrapped fraction is protected from acid degradation and afterwards, when nanoparticles reach the small intestine, can be readily released in the presence of esterases. This result could be exploited for the oral administration of the ampicillin-PECA system. Finally, studies of antimicrobial activity of prepared systems evidenced that ampicillin-loaded PECA nanoparticles exhibit an activity equal or higher than the free drug. Ford, J. V., B. G. Sumpter, et al. (2000). "Domain-size effects in optical diffraction from polymer/composite microparticles." Journal of Physical Chemistry B 104(3): 495-502. Poly(ethylene glycol) PEG microparticles were doped with ceramic or latex nanoparticles in order to examine domain-size and refractive index effects of nanometer-sized guest inclusions on two-dimensional diffraction patterns. Composite microparticles were examined for different inclusion sizes and polymer/nanoparticle weight ratios in order to determine the size and number-density threshold of detection for guest nanoparticles within the polymer host as indicated by fringe distortion in 2-D angular scattering. PEG host particles having a 10 mu m

(nominal) diameter were formed with three different guest nanoparticles (Al/sub 2/O/sub 3/, TiO/sub 2/, and latex nanospheres with respective sizes of 46, 29, and 14 nm). For the ceramic nanoparticle inclusions, distortion was observed at relative guest-host weight fractions of 5-10%. For the 14 nm latex inclusions, no distortion was observed at any weight fraction. A perturbation method was used to simulate the effect of nanometer-size inclusions on 2-D optical diffraction from polymer host microparticles and to suggest how the distortions should vary with inclusion size, refractive index, and number. (30 References). Forestier, F., P. Gerrier, et al. (1992). "Effect of nanoparticle-bound ampicillin on the survival of Listeria monocytogenes in mouse peritoneal macrophages." Journal of Antimicrobial Chemotherapy 30(2): 173-9. The efficacy of ampicillin bound to polyisohexylcyanoacrylate nanoparticles was studied in vitro in mouse peritoneal macrophages infected with Listeria monocytogenes. Nanoparticles containing ampicillin 1 mg/L were more effective after 30 h than free ampicillin at the same concentration, with viable counts of 3.68 and 5.43 log10 cfu/mL, respectively. The nanoparticles acted on the intracellular bacteria after a lag period of 6-9 h; this time was apparently required for the degradation of the polymer. At the doses used in these experiments, empty nanoparticles had neither an anti-listeria nor a cytotoxic effect. Fouarge, M., M. Dewulf, et al. (1989). "Development of dehydroemetine nanoparticles for the treatment of visceral leishmaniasis." Journal of Microencapsulation 6(1): 29-34. The preparation and physico-chemical characterization of lyophilized polyisohexylcyanoacrylate nanoparticles loaded with dehydroemetine (DHE) for the treatment of visceral leishmaniasis disease is described. The resulting formulation was found to efficiently absorb DHE and gave very reproducible preparations with regard to the size and drug adsorption rate. Stability has been confirmed for at least 24 months. The acute toxicity of DHE was reduced in intravenous administration by its association with nanoparticles. Data concerning tissue distribution in mice showed that DHE nanoparticles were rapidly cleared from the blood stream and that they mainly concentrated in the reticuloendothelial system. Furthermore, DHE linkage to the carrier reduced the cardiac concentrations of the drug. Freitas, C. and R. H. Mullera (1998). "Spray-drying of solid lipid nanoparticles (SLN )." European Journal of Pharmaceutics and Biopharmaceutics 46(2): 145-51. Aqueous dispersions of solid lipid nanoparticles (SLNTM) were converted by spray-drying into dry, reconstitutable powders which could be stored over a long period. After redispersion, the resulting granulates were still acceptable for i.v. administration with respect to the particle size distribution and toxicity. Therefore only physiologically-acceptable excipients such as carbohydrates and alcohols (ethanol and methanol) were added to the SLN dispersions before spraying. The particle size was influenced by the applied spraying parameters and by the chemical nature of the lipid phase, the type of carbohydrate and the spraying, and the redispersion medium. An identical size distribution before and after the spraying process, followed by subsequent redispersion was achieved by: reducing the temperature by spraying alcoholic dispersions, reducing the lipid concentration while increasing the sugar concentration, and by redispersion in a poloxamer 188 solution. Freitas, C. and R. H. Muller (1999). "Stability determination of solid lipid nanoparticles (SLN) in aqueous dispersion after addition of electrolyte." Journal of Microencapsulation 16(1): 59-71. The contribution of mono-, di- and trivalent ions to the destabilization of solid lipid nanoparticle (SLN) dispersions was investigated, i.e. particle growth and subsequent formation of semi-solid gels. Sodium, calcium and aluminium chloride were added in varying concentrations to a Compritol formulation which had proved to be highly sensitive towards destabilizing effects. Dispersions containing up to 10(-3) M sodium chloride remained stable for 14 days. The same concentrations of calcium or aluminium induced slight and rapid particle growth, respectively. Generally, a pronounced destabilizing effect was observed with increasing electrolyte concentration and increasing valence. Higher concentrations of electrolyte (10(-2), 10(-1) M) induced gelation of the systems. The extent of solidification was highly dependent on the crystallinity of the lipid phase. The recrystalization indices of the gels were distinctly higher compared to the liquid systems. Additionally, unstable modifications, being present in liquid dispersions, were transformed into stable ones with increasing solidification. The mechanisms of the destabilizing effect of the electrolytes are reduced electrostatic repulsion and transformation of the lipid Compritol to the beta' modification promoting gel formation. Freitas, C. and R. H. Muller (1999). "Correlation between long-term stability of solid lipid nanoparticles (SLN) and crystallinity of the lipid phase." European Journal of Pharmaceutics and Biopharmaceutics 47(2): 125-32. Aqueous dispersions of solid lipid nanoparticles (SLN) are usually physically stable for more than 3 years. However, in some systems gelation occurred leading to solid gels due to an unknown mechanism. To elucidate this mechanism, Compritol SLN were stored at different temperatures, varying light exposure, in different packing materials and stressed by shear forces in short-term tests and a long-term study of 3 years. The SLN were analyzed by differential scanning calorimetry and sizing techniques. After production by hot homogenization of the melted lipid, the Compritol SLN crystallize in a mixture of stable beta' with unstable polymorphs (alpha, sub
TM

alpha). The destabilizing factors light, temperature and shear forces cause a distinct increase in the recrystallization index by transformation of the lipid to the beta' modification being accompanied by gel formation. Physically stable SLN remain as a mixture of modifications, increase in crystallinity index during storage is slow and crystallization occurs mainly in unstable modifications. From this, stabilization of physically critical SLN dispersions seems possible by inhibition of the transformation of the lipid to the stable modification. Fresta, M., G. Puglisi, et al. (1995). "Pefloxacine mesilate- and ofloxacin-loaded polyethylcyanoacrylate nanoparticles: characterization of the colloidal drug carrier formulation." Journal of Pharmaceutical Sciences 84(7): 895-902. The entrapment of fluoroquinolones, perfloxacine mesilate (PFX) and ofloxacin (OFX), in polyalkylcyanoacrylate (PECA) nanoparticles could offer some advantages for their biological application; for examples, increasing their bioavailability, controlling the drug time-release in blood, and reducing the formation of bacterial resistance. To load these two drugs in PECA polymeric bulk, the incorporation or adsorption method was performed. These two methods were capable of influencing nanoparticle size, molecular weight, release profile, and drug-polymer association. The incorporation method, particularly for the OFX system, achieved PECA nanoparticle suspensions with a mean size value three times higher than that obtained in the absence of the drug. In contrast, negligible changes were observed for PFX systems. This preparation process also influenced the nanoparticle storage stability. The molecular weight values of the various nanoparticle preparations were also influenced; that is, the PFX-loaded systems showed an enhancement in the average molecular weight values, whereas a reduction was observed for OFX-loaded systems. The adsorption method showed no particular difference in particle size, molecular weight, and storage stability compared with nanoparticles prepared without the drugs. The nanoparticle loading capacity was higher for the colloidal systems obtained following the incorporation preparation procedure. The release of drug from the nanoparticles was biphasic for both preparation processes. The fluoro-quinoloneloaded nanoparticles showed an enhancement of the antimicrobial activity against standard bacteria strains from 2- to 50-fold compared with the free drugs. Fresta, M., G. Cavallaro, et al. (1996). "Preparation and characterization of polyethyl-2-cyanoacrylate nanocapsules containing antiepileptic drugs." Biomaterials 17(8): 751-8. Biocompatible and biodegradable colloidal drug delivery systems can be obtained by means of in situ polymerization of alkylcyanoacrylate. In particular, nanocapsules of polyethylcyanoacrylate (PECA) were prepared by adding the monomer to an organic phase, consisting of Miglyol 812 and an organic solvent (ethanol, acetone or acetonitrile), and subsequently mixing the organic phase with an aqueous phase containing Pluronic F68 at different concentrations. The possible mechanism of formation and the influence of preparation conditions on the quality of nanocapsule formulations were investigated by freeze-fracture electron microscopy and laser light scattering using both the inverse Laplace transform and the standard cumulant analysis for data fitting. Highquality nanocapsule systems were obtained using an aprotic fully water-miscible organic solvent such as acetone. The presence of ethanol led to the formation of both nanospheres and nanocapsules. The concentrations of nonionic surfactant in the aqueous phase of monomer in the organic phase did not influence the kind of colloidal suspension obtained. The oil simply plays the role of monomer support. The diameter of PECA nanoparticles (nanospheres and nanocapsules) ranged from 100 to 400 nm. Three antiepileptic drugs (Ethosuximide, 5,5diphenyl hydantoin and carbamazepine) were entrapped in PECA nanocapsules. The loading capacity of PECA nanocapsules, prepared using acetone as organic solvent, varied from 1% to 11% (drug/dried material) as a function of the solubility (affinity) of the different drugs with the oil core. This parameter also influenced the release from PECA nanocapsules, which was slower for drugs with a higher affinity for Miglyol 812. By encapsulating the three antiepileptic drugs in the PECA nanocapsules, it was possible to achieve controlled drug release. The mechanism of drug release from PECA nanocapsules was mainly diffusion from the oil core through the intact polymer barrier. Frey, A., M. R. Neutra, et al. (1997). "Peptomer aluminum oxide nanoparticle conjugates as systemic and mucosal vaccine candidates: synthesis and characterization of a conjugate derived from the C4 domain of HIV-1MN gp120." Bioconjugate Chemistry 8(3): 424-33. Peptomers are polymers composed of peptides that are specifically cross-linked in a head-to-tail fashion. Recently, a peptomer composed of an amphipathic peptide from the C4 domain of HIV-1MN gp120 was shown to display a prominent alpha-helical conformation that, as an immunogen, elicited rabbit antibodies recognizing native and recombinant gp120 [Robey et al. (1995) J. Biol. Chem. 270, 23918-23921]. For the present study, we synthesized a conjugate composed of the C4 peptomer covalently linked to calcinated aluminum oxide nanoparticles. The nanoparticles were first reacted with (3-aminopropy])-triethoxysilane to provide an amine load of 15.9 mmol of R-NH2/g of solid. The amine-modified aluminum oxide nanoparticles then were reacted with Nacetylhomocysteine thiolactone at pH 10 to place a reactive thiol on the nanoparticles. A bromoacetylated C4 peptomer, modified at the epsilon-amines of lysine residues, then was reacted with the thiolated nanoparticles to give the peptomer covalently linked to aluminum oxide via a thioether bond. The peptomer load was determined to be 16 mg of peptomer/g of particles, a 55% theoretical yield. Particle shape and size of the peptomerconjugated alumina were analyzed by electron microscopy and displayed a mean maximum diameter of 355 nm

and a mean minimum diameter of 113 nm, well within the desired size range of 300 nm believed to be optimal for mucosal immunization purposes. Experimentally determined values of mean particle diameters, specific surface area, and specific peptomer load provided the information necessary to calculate the mean antigen load, which was determined to be 53000 +/- 42000 peptomer epitopes per particle. Peptomer-alumina conjugates, such as that described here, could form the basis of a new class of biomaterial that combines a chemically defined organic immunogen with a nontoxic chemically defined inorganic adjuvant. Frey, A., N. Mantis, et al. (1999). "Immunization of mice with peptomers covalently coupled to aluminum oxide nanoparticles." Vaccine 17(23-24): 3007-19. Subunit vaccines generally require adjuvants to elicit immune responses, but adjuvants may alter the conformation of critical epitopes and reduce vaccine efficacy. We therefore tested an immunization strategy in which antigen is covalently coupled to aluminum oxide nanoparticles using a method that favors preservation of the native conformation. The test antigen consisted of &quot;peptomers&quot; (head-to-tail-linked peptide homopolymers) derived from the 4th conserved region (C4) of HIV-1 gp120 which is believed to be in an alphahelical conformation prior to binding to CD4. Immune responses in mice to peptomer-nanoparticle conjugates were compared to responses elicited by free C4 peptide and C4 peptomers, with and without the hydrophilic adjuvant muramyl dipeptide (MDP). Highest peptomer-specific serum antibody responses were induced by peptomer-particles without MDP. Serum antibodies induced by peptomer-particles also showed highest reactivity towards recombinant, glycosylated gp120 and HIV-1 infected T cells. The results suggest that this novel vaccine approach could be useful for induction of immune responses against conformation-sensitive viral antigens without the need for additional adjuvants. Friedlander, S. (1999). "Polymer-like behavior of inorganic nanoparticle chain aggregates." Journal of Nanoparticle Research 1: 9-15. Friedlander, S. K. (1999). "Nanoparticles and their structures: The next generation." Journal of Nanoparticle Research 1: 159-160. Friedlander, S. K., K. Ogawa, et al. (2000). "Elastic behavior of nanoparticle chain aggregates: a hypothesis for polymerfiller behavior." Journal of Polymer Science Part B Polymer Physics 38(20): 2658-65. Electron microscopy studies in our laboratory have shown that nanoparticle chain aggregates (NCAs) of inorganic oxides have elastic properties. Measurements were made with titania, alumina, and iron oxide NCAs generated by laser ablation. Primary particles were 5-10 nm in diameter, and the mobility diameters of the NCAs studied were about 0.5 mu m NCA stretching appeared to begin with the rotation and/or sliding of adjacent nanocrystals. This led to a small change in the NCA. Length but allowed for chain straightening. Most of the NCA lengthening resulted from the separation of kinked chain segments held together by weak, probably van der Waals (vdw), forces. NCA strains up to 90% were observed. Calculated values for NCA deformation energies per unit volume were compared with those for conventional polymers; under certain conditions, the two deformation energies were of the same order of magnitude. These results may help explain the remarkable effects that nanoparticle reinforcing fillers such as carbon black and silica have on commercial rubber. It may be possible to improve the properties of composites of molecular polymers and NCAs through the use of NCAs with prescribed primary particle sizes, vdw-bond numbers, chain lengths, and morphological properties. Synthesizing such NCAs will require the use of modern concepts of aerosol aggregate formation. (19 References). Friedlander, S. K., K. Ogawa, et al. (2000). "Vacancies in SiC nanopowders." Materials Science and Engineering B Solid State Materials for Advanced Technology(2): 147-58. Origin of vacancies in the large-sized SiC nanocrystals (higher than 10 nm) has been investigated using theoretical band structure calculations and experimental electronic paramagnetic resonance (EPR) measurements. Influence of geometry sizes on appearance of concrete vacancy has been studied. The theoretical approach includes self-consistent norm-conserving pseudopotential band energy calculations and geometry structure optimisation. The performed calculations show that the presence of the vacancies is a necessary attribute of the SiC nanocrystallites. Moreover, the type and concentration of the vacancies are dependent on the nanoparticle geometry. We have revealed that spin-polarised states of intracrystallite vacancies differ essentially from vacancies in the bulk crystals. A comparison between the performed theoretical simulations and obtained EPR experimental data shows the possibility of using the proposed methods for prediction of vacancy appearance in the binary nanocrystallites and possibility for their operation. (48 References). Friese, A., E. Seiller, et al. (2000). "Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system." European Journal of Pharmaceutics and Biopharmaceutics 49(2): 103-9. A novel non-competitive NMDA receptor antagonist MRZ 2/576 is a potent but rather short-acting (5-15 min) anticonvulsant following intravenous administration to mice as estimated by the prevention of maximal

electroshock induced convulsions. This is most probably due to a rapid elimination of the drug from the central nervous system by transport processes that are sensitive to probenecid. Intravenous administration of the drug bound to poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 prolongs the duration of the anticonvulsive activity in mice up to 210 min and after probenecid pre-treatment up to 270 min compared to 150 min with probenecid and MRZ 2/576 alone. The results of this study demonstrate that polysorbate 80 coated poly(butylcyanoacrylate) nanoparticles used so far as a delivery system to the brain for drugs that do not freely penetrate the blood brain barrier can also be used as a parenteral controlled release system to prolong the CNS availability of drugs that have a short duration of action. Friggeri, A., H. J. van Manen, et al. (2001). "Chemistry on surface-confined molecules: an approach to anchor isolated functional units to surfaces." Journal of the American Chemical Society 123(26): 6388-95. The synthesis of surface-confined, nanometer-sized dendrimers and Au nanoparticles was performed starting from single Pd(II) pincer adsorbate molecules (10) embedded as isolated species into 11-mercapto-1-undecanol and decanethiol self-assembled monolayers (SAMs) on gold. The coordination of monolayer-protected Au nanoclusters (MPCs) bearing phosphine moieties at the periphery (13), or dendritic wedges (8) having a phosphine group at the focal point, to SAMs containing individual Pd(II) pincer molecules was monitored by tapping mode atomic force microscopy (TM AFM). The individual Pd(II) pincer molecules embedded in the decanethiol SAM were visualized by their coordination to phosphine MPCs 13; isolated objects with a height of 3.5 +/- 0.7 nm were observed by TM AFM. Reaction of these embedded Pd(II) pincer molecules with the dendritic wedge 8 yielded individual molecules with a height of 4.3 +/- 0.2 nm. Fuller, S. and J. Jacobson (2000). "Ink jet fabricated nanoparticle MEMS." Proceedings IEEE Thirteenth Annual International Conference on Micro Electro Mechanical Systems. This paper presents a novel three-step process utilizing an ink jet print head to fabricate active MEMS devices. Both an in-plane and vertical thermal actuator with 100 mu m lines are demonstrated, as well as a printed electrostatic linear drive motor. Fabrication of the devices is achieved by selective ink jet deposition of nanoparticles onto a surface of either glass or plastic. The ink jet printing of nanoparticles is shown to be a viable technology for building MEMS structures which consist of a large number of layers (>100), a diverse material set (metals, semiconductors, and insulators) and which have the ability to cover large areas. Such an approach represents a potential route to a complete desktop semiconductor fab. (5 References). Fundaro, A., R. Cavalli, et al. (2000). "Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats." Pharmacol Res 42(4): 337-43. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin were prepared as drug delivery systems. The pharmacokinetics and tissue distribution of doxorubicin in these SLN were studied after i.v. administration to conscious rats and were compared to the commercial solution of doxorubicin. The same dose of each formulation (6 mg kg(-1)of body weight) of doxorubicin was injected in the rat jugular vein. Blood samples were collected after 1, 15, 30, 45, 60 min and 2, 3, 6, 12, and 24 h after the injection. Rats were sacrificed after intervals of 30 min, 4 h, and 24 h and samples of liver, spleen, heart, lung, kidney, and brain were collected. In all samples, the concentration of doxorubicin and of the metabolite, doxorubicinol, were determined. Doxorubicin and doxorubicinol were still present in the blood 24 h after injection of stealth and non-stealth SLN, while they were not detectable after the injection of the commercial solution. The results confirmed the prolonged circulation time of the SLN compared to the doxorubicin solution. In all rat tissues, except the brain, the amount of doxorubicin was always lower after the injection of the two types of SLN than after the injection of the commercial solution. In particular, SLN significantly decreased the heart concentration of doxorubicin. Fung, K. K., B. Qin, et al. (2000). "Passivation of alpha -Fe nanoparticle by epitaxial gamma -Fe 2O 3 shell." Materials Science and Engineering A Structural Materials Properties Microstructure and Processing(1): 135-8. Nanoparticles of iron prepared by inert gas condensation of plasma evaporated vapour exhibit remarkable resistance to oxidation. They remain rust free in air and in water for years. We have found by transmission electron microscopy and X-ray photoelectron spectroscopy, that all the passivated nanoparticles of iron are covered by an epitaxial shell of gamma -Fe/sub 2/O/sub 3/ about 4 nm thick. The epitaxial relationship between the gamma -Fe/sub 2/O/sub 3/ shell and the iron core is (001)/sub gamma -Fe2O3///(001)/sub alpha -Fe/, and 110/sub gamma -Fe2O3///100/sub alpha -Fe/, 110/sub gamma -Fe2O3///010/sub alpha -Fe/. The passivation of the nanoparticles of iron by an epitaxial oxide can be accounted for by the Caberra-Mott theory of oxidation of metal. The oxide layer grows rapidly at 420 K but slows down dramatically when the layer thickens. When the oxide layer thickens to 4 nm in a few hours, growth virtually stops. The 4-nm epitaxial oxide shell protects the iron core from further oxidation at room temperature. (12 References). Furman, B., H. R. Rawls, et al. (2000). "Metal-oxide nanoparticles for the reinforcement of dental restorative resins." Critical Reviews in Biomedical Engineering 28(3): 439-43. Metal oxide nanoparticles were synthesized from tantalum ethoxide and zirconium isopropoxide and subsequently

surface grafted with vinyl silane and silyl methacrylate coupling agents. The nanoparticles were then dispersed into a commercial dental resin, and the composite was photocured into rigid three-point bend and fracture toughness specimens. The optically transparent/translucent cured composites demonstrated strength, toughness, and elastic modulus inferior to the unfilled material. Therefore, modifications in surface functionalization are being made to improve coupling and reduce interparticle associations. Fusai, T., M. Deniau, et al. (1994). "Action of pentamidine-bound nanoparticles against Leishmania on an in vivo model." Parasite 1(4): 319-24. The efficiency of antileishmanial agents may be enhanced by improving their bioavailability with a colloidal drug carrier. We have investigated the action of free pentamidine, compared with pentamidine bound to polymethacrylate nanoparticles, in a rodent model. BALB/c mice were infected, via the tail vein, with 4 x 10(7) L. major (MON 74) promastigotes. Twelve days after infection, seven groups of mice were treated respectively with methylglucamine antimoniate (Glucantime) 5.56 mg/kg i.p. x 5 d., pentamidine bound nanoparticles (100 microM), unloaded polymethacrylate nanoparticles, unloaded nanoparticles associated with free pentamidine (100 microM) 0.1 ml i.v. x 3 d and free pentamidine isethionate (2.28 mg/kg and 0.17 mg/kg i.v. x 3 d.). Twenty-one days post infection, the mice were sacrificed and the Leishmania load in the liver calculated from the number of amastigotes/500 liver cells and total liver weight in treated and untreated mice. Results demonstrated a 77% amastigote reduction in the group treated with targeted pentamidine relative to the control group. The ratio free pentamidine/bound-pentamidine was approx. 12. Fusai, T., R. Durand, et al. (1995). "[Importance of drug carriers in the treatment of visceral leishmaniasis]." Med Trop 55(1): 73-8. Visceral leishmaniasis is caused by hemoflagellate protozoa which are obligatory parasites of the mononuclear phagocyte system. Leishmaniasis causes high morbidity and mortality worldwide. The treatment of choice remains pentavalent antimonials, but high toxicity and failures have been reported. An alternative to conventional treatment is delivery anti-leishmania agents using colloidal carrier systems. Carriers improve drug activity against intracellular disease involving the mononuclear phagocyte system. The principle of drug delivery by carrier systems has been applied successfully for anticancer drugs. Recently complete remission of polyresistant visceral leishmaniasis was obtained by injection of liposomal amphotericin B. At present, no colloidal drug carrier for antimony derivatives is available, but pentamidine can be linked experimentally to methacrylate polymer nanoparticles. Drug-loaded nanoparticles have been shown to be effective against amastigote leishmania both in vitro and in vivo. Another colloidal system of major interest for drug delivery, the liposome has already been loaded with amphotericin B and used for human therapy. The concept of particulate drug carriers opens the way for new chemotherapeutic approaches in the field of parasitology. Fusai, T., Y. Boulard, et al. (1997). "Ultrastructural changes in parasites induced by nanoparticle-bound pentamidine in a Leishmania major/mouse model." Parasite 4(2): 133-9. Drug targeting enhances drug efficacy. This principle was tested in the treatment of an experimental visceral leishmaniasis. Using transmission electron microscopy (TEM) we localized pentamidine-loaded polymethocrylate nanoparticles in the liver of mice infected with Leishmania major and compared the ultrastructural changes in the parasites of these mice when they were treated with bound versus free pentamidine. Between days 13 and 17 after infection, loaded nanoparticles treated group were injected i.v. with 3 doses of 0.17 mg/kg bound pentamidine loaded on 2 x 10(11) nanospheres; control groups received 2 x 10(11) unloaded nanospheres. Drug reference control groups received five doses of 200 mg/kg pentavalent antimony (Glucantime) or three doses of free pentamidine (0.17 mg/kg or 2.28 mg/kg). Mice treated with bound pentamidine displayed a 77% reduction in their parasite burden versus the untreated controls. Nanoparticles were located by TEM inside parasitized Kupffer cells, in the phagolysosomes without entering the Leishmania. The low dose of 0.17 mg/kg bound pentamidine damaged the Leishmania to the same extent as 2.28 mg/kg of free pentamidine (the usual dose in human chemotherapy). In the parasites inside the Kupffer cells, TEM showed a swollen mitochondrian with loss of cristae, destruction or fragmentation of the kinetoplast, loss of ribosomes and destruction of parasite structures except for the subpellicular microtubules. This study therefore shows that a dose of bound pentamidine 13 times smaller than the usual dose of free pentamidine has a similar effect on the parasite. Gao, L., W. Li, et al. (1999). "Influence of some parameters on the synthesis of ZrO2 nanoparticles by heating of alcohol aqueous salt solutions." Journal of Nanoparticle Research 1: 349-352. Gao, Y., R. Sun, et al. (2000). "Tribological properties of oleic acid - modified TiO 2 nanoparticle in water." Materials Science and Engineering A Structural Materials Properties Microstructure and Processing(1): 149-51. A cis-9-octadecenoic acid (OA) surface-modified TiO/sub 2/ nanoparticle with average diameter of 30 nm was chemically synthesized. The tribological properties of the prepared OA-TiO/sub 2/ nanoparticle as an additive in water were evaluated with a four-ball tester. The results show that the OA-TiO/sub 2/ nanoparticle exhibits good performance in wear and friction reduction as well as in load-carrying capacity. The maximum nonseizure load

(P/sub B/ value) can be raised about six to ten times when 0.1-1.0% OA-TiO/sub 2/ nanoparticle was added into water. (9 References). Garcia de Abajo, F. J. (2000). "Smith-Purcell radiation emission in aligned nanoparticles." Physical Review E. Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics 61(5B): 5743-52. Smith-Purcell (SP) radiation produced by interaction of fast electron beams running parallel to strings of nanoparticles is investigated. Results for the radiation emission probability and electron energy loss spectra using finite and infinite strings of Al and silica spheres are presented. Both of these quantities are obtained by solving Maxwell's equations exactly using a multipole expansion approach. The response of the spheres is described in terms of their local frequency-dependent dielectric functions. In silica, the emission probability is seen to coincide with the energy loss probability within the gap region, where the solid cannot absorb any energy. Large emission rates are predicted for Al, suggesting its possible application in tunable soft uv light generation. The dependence of the emission on the size of the spheres, the string period, and the electron energy is discussed in detail. Finite size effects are also studied for strings of 1-15 Al spheres. Gardea-Torresdey, J. L., K. J. Tiemann, et al. (1999). " Gold nanoparticles obtained by bio-precipitation from gold(III) solutions." Journal of Nanoparticle Research 1: 397-404. Gasco, M. R., S. Morel, et al. (1988). "Incorporation of doxorubicine in nanoparticles obtained by polymerization from non aqueous micromulsion." Farmaco [Prat] 43(12): 373-80. Gasco, M. R., S. Morel, et al. (1991). "Doxorubicine englobed in polybutylcyanoacrylate nanocapsules: behaviour in vitro and in vivo." Pharmaceutica Acta Helvetiae 66(2): 47-9. Nanocapsules of polybutylcyanoacrylate containing doxorubicine were prepared from w/o microemulsion. A concentration of about 10% of the drug was obtained. After washing, dispersion and lyophilization of the nanocapsules, some experiments were performed in vivo and in vitro. About 1% of doxorubicine was released in vitro in 48 hours; after injection on the hairless back of rabbits, the nanoparticles without the drug gave any inflammatory processes, while the nanocapsules containing doxorubicine gave a deeper and more prolonged ulcer than that of the same amount of doxorubicine in solution, indicating that practically all the drug was inside the nanocapsules. Gaspar, R., V. Preat, et al. (1992). "Macrophage activation by polymeric nanoparticles of polyalkylcyanoacrylates: activity against intracellular Leishmania donovani associated with hydrogen peroxide production." Pharm Res 9(6): 782-7. Nanoparticles of polyalkylcyanoacrylates (PACA) can be useful carrier for the targeting of antileishmanial drugs into macrophages and also possess significant antileishmanial activity by themselves. No significant difference in antileishmanial activity could be detected between nanoparticles of five PACAs with differing alkyl side chains, suggesting that the main degradation products of PACA are not involved in their antileishmanial action. The effect of polyisohexylcyanoacrylate (PIHCA) on the induction of the respiratory burst in a macrophage-like cell line (J774G8) was assessed in non-infected macrophages and in macrophages infected with amastigotes of Leishmania donovani infantum, by measuring nitroblue tetrazolium (NBT) reduction and hydrogen peroxide production. Phagocytosis of PIHCA nanoparticles led to a respiratory burst, which was more pronounced in infected than in uninfected macrophages. The production of reactive oxygen intermediates associated with the respiratory burst was inhibited by addition of superoxide dismutase and catalase to the cell suspensions. The addition of catalase to the culture medium together with PIHCA nanoparticles significantly reduced the antileishmanial activity of PIHCA. Moreover PIHCA nanoparticles did not induce interleukin-1 release by macrophages. It is suggested that the antileishmanial action of PIHCA and other PACA nanoparticles results from the activation of respiratory burst in macrophages. Gaspar, R., F. R. Opperdoes, et al. (1992). "Drug targeting with polyalkylcyanoacrylate nanoparticles: in vitro activity of primaquine-loaded nanoparticles against intracellular Leishmania donovani." Annals of Tropical Medicine and Parasitology 86(1): 41-9. The efficacy of primaquine-loaded polyisohexylcyanoacrylate (PIHCA) nanoparticles was evaluated using J774G8 macrophage-like cells infected with Leishmania donovani: as an in vitro model of visceral leishmaniasis. The in vitro antileishmanial activity of primaquine-loaded nanoparticles showed a 21-fold increase in ED50 compared with free primaquine. Although unloaded PIHCA nanoparticles also exhibited a significant anti-leishmanial effect, the loaded nanoparticles showed a synergistic effect compared with a mixture of unloaded nanoparticles and free primaquine at equivalent concentrations. Primaquine release and isohexanol production were evaluated in a lysosomal fraction; the correlation of both with protein concentration and the rapid drug release indicate the processes are associated with an enzymatic degradation. The results indicate that PIHCA and other polyalkylcyanoacrylates may be useful for targeting drugs at intracellular Leishmania, and that the unloaded carrier itself could be of interest in experimental chemotherapy of leishmaniasis.

Gasper, M. M., D. Blanco, et al. (1998). "Formulation of L-asparaginase-loaded poly(lactide-co-glycolide) nanoparticles: influence of polymer properties on enzyme loading, activity and in vitro release." Journal of Controlled Release 52(1-2): 53-62. This paper describes the preparation and characterisation of poly(lactide-co-glycolide) (PLG) nanoparticles containing the enzyme L-asparaginase. L-Asparaginase was encapsulated in PLG nanospheres using a water-inoil-in-water solvent evaporation technique. The effect of the copolymer molecular weight and the presence of carboxyl-end groups in the copolymer chain on the physicochemical and in vitro release properties of the nanoparticles was investigated. Results indicated that size, encapsulation efficiency and in vitro release properties (enzymatic activity retention and protein quantification) of the nanoparticles were affected by the PLG molecular weight. As expected, nanoparticles made of high-molecular-weight PLG had a larger size, a higher loading and la slower release rate than those made od a low-molecular-weight PLG. Nevertheless, the most relevant factor affecting the entrapment and release of L-asparaginase from PLG nanoparticles was the presence of free carboxyl-end groups in the PLG chain. The nanoparticles made of PLG with free carboxyl-end groups had a high protein loading (4.86%, w/w) and provided a continuous delivery of the active enzyme for 20 days. However, the enzyme loading was lower (2.65%, w/v) and no active enzyme was detected in the release medium after a 14-day incubation period when nanoparticles were made of PLG with carboxyl-end groups esterified. These results give evidence of the potential of PLG nanospheres for the continuous delivery of L-asparaginase for extended periods of time and show the effect of the PLG chain end-groups in the amount and activity of the enzyme loaded into the nanospheres. Gaumet, J. J. and G. F. Strouse (2000). "Electrospray mass spectrometry of semiconductor nanoclusters: comparative analysis of positive and negative ion mode." Journal of the American Society for Mass Spectrometry 11(4): 338-44. There has been a substantial growth in the application of mass spectrometry (MS) methods for the analysis of inorganic materials, due to the inherent sensitivity of mass spectrometry ionization to the specific composition and structure of the analyzed materials. To date, few mass spectrometry studies have focused on metal-chalcogenide materials, an important class of semiconductor materials at the nanoscale, that exhibit interesting optical and electronic properties as a function of size. In this study, we report the application of a correlated electrospray mass spectrometry (ESMS) study between negative-ion and positive-ion mode under low-cone voltage to probe size, composition, and stability of metal-chalcogenide materials at the <1 nm scale. This correlation approach provides insight into the ionization behavior and thermodynamic stability of clusters in the <1.0 nm size domain of the form [Zn4(SPh)10][Me4N]2, [Cd4(SPh)10][Me4N]2, [E4Zn10(SPh)16][Me4N]4, [E4Cd10(SPh)16][Me4N]4 (E = S, Se). It is demonstrated that application of low-cone voltage ESMS can be a useful technique for the rapid analysis of intact solid state nanomaterials when both negative and positive ionic modes are analyzed, with a potential for extrapolation to other classes of nanoscale materials. Gaur, U., S. K. Sahoo, et al. (2000). "Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system." International Journal of Pharmacy 202(1-2): 1-10. The rapid clearance of circulating nanoparticles from the blood stream coupled with their high uptake by liver and spleen has thus far been overcome by reducing the particle size, and by making the particle surface hydrophilic with poloxamers and poloxamines. We have prepared hydrogel nanoparticles of polyvinylpyrrolidone of a size less than 100 nm diameter with precise size distribution. Since the inner cores of these particles are also hydrophilic, these particles are capable of encapsulating water-soluble compounds. Biodistribution of these particles shows practically negligible (&lt;1%) uptake by the macrophages in liver and spleen, and approximately 5-10% of these particles remain in circulation even 8 h after i.v. injection. Increasing the surface hydrophobicity as well as particle size can increase the RES uptake of these particles. Because of longer residence in blood, the hydrogel nanoparticles have potential therapeutic applications particularly in cancer: the water-soluble cytotoxic agents encapsulated in these particles can be targeted to tumors while minimizing the likelihood of toxicity to reticuloendothelial system (RES). Gautier, S., N. Grudzielski, et al. (2001). "Preparation of poly(D,L-lactide) nanoparticles assisted by amphiphilic poly(methyl methacrylate-co-methacrylic acid) copolymers." Journal of Biomaterial Science Polymer Edition 12(4): 429-50. When co-precipitated with amphiphilic copolymers from DMSO, poly(D,L-lactide) (PLA) can be readily converted into stable sub-200 nm nanoparticles by addition of an aqueous phase, free of any polymeric stabilizers such as poly(vinyl alcohol) or Poloxamer. In this work, the ability of random poly(methyl methacrylate-co-methacrylic acid) copolymers (PMMA-co-MA) to stabilize PLA nanoparticles was demonstrated, and the properties of PLA/PMMAco-MA nanoparticles were investigated. When co-precipitated with PMMA-co-MA, PLA was totally converted into nanoparticles using a polymer concentration in DMSO (Cp) below 17.6 mg ml(-1), and a PMMA-co-MA proportion above a critical value depending on the content of MA repeating units (X). For instance, the lowest PMMA-co-MA proportion required was 0.9 mg mg(-1) PLA for X = 12%, and 0.5 mg mg(-1) PLA for X = 25% (for C(PLA) = 16 mg ml(-1) DMSO). The nanoparticle diameter was essentially independent of X, the proportion of PMMA-co-MA, and the PLA molecular weight, except for oligomers for which the nanoparticle diameter was smaller. It decreased when the organic phase was diluted (126 +/- 13 nm for Cp = 17.6 mg ml(-1), and 81 +/- 5 nm for C(P) = 5.6 mg

ml(-1)). The time-dependence of the stability and the degradation of PLA/PMMA-co-MA nanoparticles was discussed. One of the main advantages of this technique is the ability to control surface properties and to bring functional groups to otherwise non-functionalized PLA nanoparticles. To illustrate this, a conjugate of PMMA-coMA25 and biotin was synthesized, and used to prepare biotinylated nanoparticles that could be detected by fluorescence and transmission electron microscopy after infiltration into ligatured rat small intestine. Gayral, P. and W. Peters (1991). "[Innovation in antiparasitic agents]." Annals of Parasitology and Human Comp 66(Suppl 1(4)): 61-3. The emergence of new parasitic diseases has encouraged studies on the elucidation of the mode of action of new and old antiparasitic drugs, and has led to the development of new chemical series. Resistance occurs rapidly when a single drug is used massively in human and animals. A better knowledge of the mode of action allow synergistic combination of compounds, slow-release devices proposed for cattle. Another alternative is to improve bioavailability of antiparasitic drugs by targetting at the parasite molecular level with prodrugs, drug-carriers as liposomes, nanoparticles. The use of new compounds should be expected with relative optimism. Gazelle, G. S., G. L. Wolf, et al. (1994). "Nanoparticulate computed tomography contrast agents for blood pool and liverspleen imaging." Academic Radiology 1(4): 373-6. RATIONALE AND OBJECTIVES: We investigated the properties of a group of iodine-containing, insoluble compounds formulated as nanoparticles for use as potential blood pool and liver-spleen contrast agents. METHODS: High-resolution, quantitative computed tomography (CT) was performed prior to and at intervals following the intravenous administration of the contrast agents to rabbits. Time-density characteristics for three organs were evaluated. RESULTS: Excellent enhancement of blood (&lt; or = 232 Hounsfield units [HU]), liver (&lt; or = 263 HU), and spleen (&lt; or = 350 HU) was achieved at the administered dose of 3.0 ml/kg. The composition of the agents influenced the biodistribution, as well as the residence time in blood, and time to peak enhancement in liver. CONCLUSION: Iodinated nanoparticulate compounds are promising CT contrast agents. Development of agents with desirable pharmacokinetic and biodistribution profiles may permit application-specific contrast enhancement. Gazelle, G. S., G. L. Wolf, et al. (1995). "Hepatic imaging with iodinated nanoparticles: a comparison with iohexol in rabbits." Academic Radiology 2(8): 700-4. RATIONALE AND OBJECTIVES: We evaluated the efficacy of a particulate computed tomography (CT) contrast agent in an animal model of focal liver disease. METHODS: Ethyl ester of diatrizoic acid (EEDA) is an iodinated (89 mg I/ml) nanoparticulate (200 nm) contrast agent intended for intravenous use that is currently undergoing preclinical testing in our laboratory. Focal liver abscesses were created in 11 New Zealand White rabbits. Iohexol and EEDA were administered to each animal on different days. CT scanning was performed at intervals following contrast agent administration. Liver and abscess enhancement were measured and compared. Dynamic imaging experiments in normal animals were also performed using both agents. RESULTS: EEDA resulted in significantly greater enhancement of the liver and liver-to-abscess contrast than did iohexol at all time points beyond 5 min at approximately 25% of the total iodine load. During dynamic imaging, liver and aortic enhancement were greater with EEDA than with iohexol, except during a 20- to 40-sec period immediately following contrast agent administration. CONCLUSION: EEDA is superior to iohexol for imaging liver abscesses. Our results suggest that liver-directed agents such as EEDA may prove to be more efficacious than currently available extracellular agents designed for liver CT scanning. Gearheart, L., K. K. Caswell, et al. (2001). "Recognition of hypermethylated triplet repeats in vitro by cationic nanoparticles." Journal of Biomedical Optics 6(2): 111-5. Genomic DNA contains many higher-order structural deviations from the Watson-Crick global average. The massive expansion and hypermethylation of the duplex triplet repeat (CCG)(n)(CGG)(n) has characteristic higherorder structures that are associated with the fragile X syndrome. We have used luminescent mineral nanoparticles of protein-sized cadmium sulfide in optical assays to detect anomalous DNA structures. The photoluminescence of these particles is sensitive to the presence and nature of adsorbates. We previously found that our nanoparticles bind the fragile X repeat well but do not bind to normal double-helical DNA. In this study, we have determined that these particles are also able to detect the hypermethylated forms of these triplet repeats. Therefore, these nanoparticles may form the basis for future optical assays of higher-order DNA structures, especially those associated with human disease. Geldwerth, D., D. Helley, et al. (1999). "Detection of phosphatidylserine surface exposure on human erythrocytes using annexin V-ferrofluid." Biochemical and Biophysical Research Communications 258(1): 199-203. The asymmetric transbilayer distribution of phospholipids in the plasma membrane and the regulation of phosphatidylserine (PS) exposure at the cell surface of animal cells are of high physiological significance. It has been shown previously that annexin V is one of the most sensitive tools with which the presence of small amounts of PS on the outer surface of eukaryotic cells can be detected. We present here the covalent coupling of annexin

V molecules to magnetic nanoparticles of maghemite. The resulting annexin V-ferrofluid is used in the magnetic separation of PS exposing cells, as illustrated for human erythrocytes modified in their phospholipid transbilayer asymmetry by the use of a calcium ionophore. Results on stored human erythrocytes and comparison with results obtained using iodinated and fluorescein-labeled annexin V are also presented. Gelperina, S. E., S. E. Severin, et al. (2000). "Nanoparticulate doxorubicin for systemic chemotherapy of intracranial glioblastoma." Tumor Biology 21(Supplement 1): 138. Georgantas, R. W., K. W. Leong, et al. (2000). "Antigen-specific induction of peripheral T cell tolerance in vivo by codelivery of DNA vectors encoding antigen and Fas ligand." Human Gene Therapy 11(6): 851-8. Fas ligand (FasL, CD95L) induces apoptosis in activated T cells with upregulated Fas (CD95) expression through the process termed activation-induced cell death (AICD). We postulated that coexpression of antigen and FasL within individual antigen-presenting cells would lead to antigen-specific activation of T cells and to their consequent deletion by FasL-mediated AICD. A DNA-gelatin coacervate containing transferrin cell ligand, calcium, and the lysosomatropic agent chloroquine, a formulation previously shown to achieve high-level transfection of immune and muscle cells in vivo, was used to codeliver plasmids encoding FasL and antigen. Mice developed a strong cytolytic T cell response to beta-Gal when injected with DNA encoding beta-galactosidase (LacZ) model antigen, either as naked DNA or DNA nanoparticles, but failed to respond when there was concomitant injection of nanoparticles containing both the LacZ and murine FasL DNA vectors. This loss of T cell response was systemic, specific for beta-Gal, complete when nanoparticles were administered before antigen challenge, and decreased the T cell response from prior immunization with LacZ DNA. In effect, this &quot;tolerization&quot; injection induced antigen-specific peripheral tolerance in study mice, and represents a possible approach to the treatment of autoimmune diseases and transplantation rejection. Gerlovin, I. Y., V. V. Ovsyankin, et al. (2000). "The role of rare earth dopants in nanophase zirconia catalysts for automotive emission control." Journal of Alloys and Compounds 303(304): 60-5. Rare earth (RE) modification of automotive catalysts (e.g., ZrO/sub 2/) for exhaust gas treatment results in outstanding improvement of the structural stability, catalytic functions and resistance to sintering at high temperatures. Owing to the low redox potential of nonstoichiometric CeO/sub 2/, oxygen release and intake associated with the conversion between the 3+and 4+oxidation states of the Ce ions in Ce-doped ZrO/sub 2/ provide the oxygen storage capacity that is essentially to effective catalytic functions under dynamic air-to-fuel ratio cycling. Doping tripositive RE ions such as La and Nd in ZrO/sub 2/, on the other hand, introduces oxygen vacancies that affect the electronic and ionic conductivity. These effects, in conjunction with the nanostructure and surface reactivity of the fine powders, present a challenging problem in the development of better ZrO/sub 2/containing three-way catalysts. We have carried out in situ small- to wide-angle neutron diffraction at high temperatures and under controlled atmospheres to study the structural phase transitions, sintering behavior, and Ce/sup 3+/ to or from Ce/sup 4+/ redox process. We found substantial effects due to RE doping on the nature of aggregation of nanoparticles, defect formation, crystal phase transformation, and metal-support interaction in ZrO/sub 2/ catalysts for automotive emission control. (33 References). Gerster, M., J. Schewitz, et al. (1998). "Quantitative analysis of modified antisense oligonucleotides in biological fluids using cationic nanoparticles for solid-phase extraction." Analytical Biochemistry 262(2): 177-84. Based on a novel method for solid-phase extraction using cationic polystyrene nanoparticles, the suitability of the extraction procedure for quantitation of terminally and backbone-modified antisense oligonucleotides was investigated. Extractions were carried out from both human plasma and urine. Quantitative analysis of the extracted samples was performed with capillary gel electrophoresis. In accordance with previous results obtained with phosphorothioate oligonucleotides in human plasma, high linearity and accuracy of the assay was demonstrated for an oligodeoxyribonucleotide-palmityl conjugate as well as for a modified oligoribonucleotide. Optimized extraction conditions allow the isolation of oligonucleotides in high yields and purity even for concentrations in the low nanomolar range, down to 5 nM. Comparing the results obtained from human plasma and urine, no significant differences in the absolute recovery rates which reach values up to 95% were observed. However, when the loading capacity of the nanoparticles was exceeded, selective recovery was observed for the coisolation of phosphodiester and phosphorothioate oligonucleotides. This effect can be explained by differences in the attractive forces between PO- and PS-oligonucleotides and the particle surface and appears to be valuable for a modification-dependent enrichment of oligonucleotides out of complex mixtures. Gesenhues, U. (1999). "Substructure of titanium dioxide agglomerates from dry ball-milling experiments." Journal of Nanoparticle Research 1: 223-234. Gessner, A., R. Waicz, et al. (2000). "Nanoparticles with decreasing surface hydrophobicities: Influence on plasma protein adsorption." International Journal of Pharmaceutics 196(2): 245-249. The rapid uptake of i.v. injected nanoparticles by cells of the mononuclear phagocytic system (MPS) is a major

obstacle for a long blood circulation time and a drug targeting to sites other than the MPS. The adsorption of proteins on the particles surface after i.v. administration depends on their surface characteristics and is regarded as key factor for the in vivo organ distribution. The objective of this study is to investigate changes in the plasma protein adsorption patterns in the course of surface hydrophobicity variation. Latex particles with decreasing surface hydrophobicity were synthesized as model colloidal carriers. Physicochemical characterization had been performed and considerable differences in the protein adsorption patterns on the particles could be detected by using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Correlations between physicochemical characteristics and the protein adsorption patterns have been found and are discussed. Gessner, A., C. Olbrich, et al. (2001). "The role of plasma proteins in brain targeting: species dependent protein adsorption patterns on brain-specific lipid drug conjugate (LDC) nanoparticles." International Journal of Pharmacology 214(1-2): 87-91. The in vivo organ distribution of particulate drug carriers is decisively influenced by the interaction with plasma proteins after i.v. administration. Serum protein adsorption on lipid drug conjugate nanoparticles, a new carrier system for i.v. application, was investigated by 2-dimensional electrophoresis (2-DE). The particles were surfacemodified to target them to the brain. To assess the protein adsorption pattern after i.v. injection in mice prior to in vivo studies, the particles were incubated in mouse serum. Incubation in human serum was carried out in parallel to investigate similarities or differences in the protein patterns obtained from men and mice. Distinct differences were found. Particles incubated in human serum showed preferential adsorption of apolipoproteins A-I, A-IV and E. Previously, preferential adsorption of ApoE was reported as one important factor for targeting of Tween(R)80 modified polybutylcyanoacrylate nanoparticles to the brain. Preferential adsorption of ApoA-I and A-IV took place after incubation in mouse serum, adsorption of ApoE could not be clearly confirmed. In vivo localization of the LDC nanoparticles at the blood-brain barrier and diffusion of the marker Nile Red into the brain could be shown by confocal laser-scanning microscopy. Differences of the obtained adsorption patterns are discussed with regard to their relevance for correlations of in vitro and in vivo data obtained from different species. Ghanem, G. E., C. Joubran, et al. (1993). "Labelled polycyanoacrylate nanoparticles for human in vivo use." Applied Radiatiation and Isotopes 44(9): 1219-24. Isobutyl and isohexyl cyanoacrylate nanoparticles are used as drug carriers, particularly for some anti-cancer drugs. Body distribution as well as pharmacokinetics have been well studied in animal and partially in man. Labelling of the monomer itself or of the carried drug with beta-emitters allowed such studies. In man, however, organ distribution and uptake could easily be done and followed by means of scintigraphy (imaging) techniques if one could achieve nanoparticle labelling with gamma-emitting isotopes. We have developed labelling methods able to supply such carriers using gamma-emitters like radioactive iodine (125I or 131I), indium or technetium. We used DTPA as a spacer in order to fix the last two isotopes. This would mean that any other gamma-emitting cation can theoretically be tried pending on its ability to be chelated by DTPA. The preparations were obtained with high labelling yields, usually &gt; 80% and were relatively stable in human plasma over the whole period of investigation. 111In and 99mTc labelled forms have been administered to rabbit and then to man with 60-75% accumulation in the reticulo-endothelial system. Ghirardelli, R., F. Bonasoro, et al. (1999). "Identification of particular epithelial areas and cells that transport polypeptidecoated nanoparticles in the nasal respiratory mucosa of the rabbit." Biochimica et Biophysica Acta 1416(1-2): 39-47. The active transcytosis of many different polypeptides (either presented free or adsorbed on latex nanoparticles), found in the respiratory mucosa of the upper nasal concha, has previously been shown to be proportional to the total volume of the lymphoid aggregates present in the tissue. By combining the use of fluorescent nanoparticles, flux measurements, confocal and scanning electron microscopy and conventional histology, it is shown in this paper that: (i) the areas of epithelium overlying lymphoid aggregates are the only transporting polypeptides; (ii) the respiratory epithelium in these areas consists mainly of non-ciliated microvillar cells, with numerous ciliated cells and rare mucous goblet cells at the periphery of the area only; (iii) non-ciliated microvillar cells are distinguishable in cells with well developed finger-like microvilli and cells with an irregularly pleated apical membrane, similar to that of intestinal and bronchial antigen-sampling M-cells; (iv) groups of polypeptide-coated nanospheres are found bound to this latter type of cells, demonstrating that these are the transporting cells, detected at the first stage of the transcytotic cycle. Gibaud, S., J. P. Andreux, et al. (1994). "Increased bone marrow toxicity of doxorubicin bound to nanoparticles." European Journal of Cancer 6: 820-6. The in vivo myelosuppressive effects of free and polyalkylcyanoacrylate-bound doxorubicin were compared in a mouse model. After intravenous administration of 11 mg/kg body weight of doxorubicin either free or bound to polyisobutyl (doxo-PIBCA) or polyisohexylcyanoacrylate (doxo-PIHCA) nanoparticles, we studied the total and differential counts of blood, bone marrow and spleen cells; the number of granulocyte progenitors (CFU-GM) was determined by culture. Doxorubicin concentrations were measured with an HPLC method in the bone marrow and the spleen. Doxo-PIHCA nanoparticles showed the highest and longest myelosuppressive effects which

correlated well with a high concentration of the drug in the bone marrow and the spleen. Moreover, it was found that PIHCA nanoparticles induced the release of colony stimulating factors, which might account for the observed increase of toxic effects of doxorubicin on bone marrow progenitors. These data also indicate that a more precise evaluation of the myelosuppressive effects of targeted formulations of anticancer drugs is needed, which may be attained by studies on bone marrow progenitors. Gibaud, S., M. Demoy, et al. (1996). "Cells involved in the capture of nanoparticles in hematopoietic organs." Journal of Pharmaceutical Sciences 85(9): 944-50. The affinity of nanoparticles for hematopoietic organs could be valuable for the targeting of certain stimulating factors to those tissues, but this affinity should also be taken into account in the toxicological evaluation of those carriers, especially when they are loaded with antimitotic compounds such as doxorubicin. However, the cells responsible for the capture of the nanoparticles and their localization in these organs is an important point to know before trying to modulate the nanoparticle's tissue distribution. Thus, we have studied, in this paper, the capture, the localization, and the retention in the bone marrow and in the spleen of biodegradable poly(isohexyl cyanoacrylate) nanoparticles as well as of nonbiodegradable polystyrene nanoparticles. The histological localization of these nanoparticles has been completed by cytological localization with a method used in cytochemistry for the evaluation of intracellular accumulation of various substances, such as iron deposits in bone marrow sideroblasts. These data indicate that, in the bone marrow, after a quick passage through the endothelium, nanoparticles were dispersed throughout in the tissue and captured by all types of phagocytizing cells. In the spleen, nanoparticles were mainly localized in large angular capturing cells in the marginal zone of the lymphoid follicles. Gibaud, S., C. Rousseau, et al. (1998). "Polyalkylcyanoacrylate nanoparticles as carriers for granulocyte-colony stimulating factor (G-CSF)." Journal of Controlled Release 52(1-2): 131-9. The human recombinant granulocyte colony-stimulating factor (rhG-CSF) is largely used in the treatment of neutropenia occurring during chemotherapy. After injection, this glycoprotein distributes through the whole body. Thus, to obtain high and durable bone marrow concentrations, targeting with polyalkylcyanoacrylate nanoparticles was considered. Two methods of preparation were investigated: anionic polymerization and precipitation of the preformed polymer. By anionic polymerization, it was possible to associate more than 66% of rhG-CSF with nanoparticles (polyisobutyl- or polyisohexylcyanoacrylate nanoparticles) when the glycoprotein was added at the end of the polymerization process. It has been shown that the rhG-CSF was mainly adsorbed on the surface of the nanoparticles and most of the colony stimulating activity was conserved. Using precipitation of performed polyisohexylcyanoacrylate, 90% of rhG-CSF was associated with nanoparticles, the protein being mainly adsorbed onto the nanoparticle surface. In this case, a decrease of the colony stimulating activity was however observed. Whatever the method used, the in vitro release of rhG-CSF from the polyisohexylcyanoacrylate nanoparticles, was progressive during 8 h in seric conditions. Nevertheless, using mice as an animal model, it has been shown that the short-term effects of intravenously injected rhG-CSF were not increased by its association with polyisohexylcyanoacrylate nanoparticles. Gibaud, S., C. Weingarten, et al. (1999). "[Targeting bone marrow with the help of polyalkylcyanoacrylate nanoparticles]." Annales Pharmaceutiques Francaises 57(4): 324-31. Using a mouse model, we examine drug targeting towards bone marrow. One cytotoxic (doxorubicin) and one stimulating (rhG-CSF), bound to polyalkylcyanoacrylate nanoparticles, were studied. Histological studies, using a fluorescence microscope, showed rapid capture of nanoparticles by bone marrow macrophages and granulocytes as soon as 15 minutes after injection into the blood stream. Doxorubicin nanoparticles, administered at a dose of 11 mg/kg were more toxic than free doxorubicin on all blood and marrow cell lines. Moreover, the choice of the nature of the polymer had an influence on toxicity: doxorubicin polyisohexylcyanoacrylate nanoparticles were more toxic than polyisobutylcyanoacrylate particles. Quantification of doxorubicin in bone marrow has confirmed these results. The bone marrow concentrations observed demonstrated that there was a high level of targeting towards the bone marrow that would be very interesting to use for a stimulating drug. Nevertheless, rhG-CSF nanoparticles did not show better efficacy than free rhG-CSF. Gipps, E. M., R. Arshady, et al. (1986). "Distribution of polyhexyl cyanoacrylate nanoparticles in nude mice bearing human osteosarcoma." Journal of Pharmaceutical Sciences 75(3): 256-8. [14C]Polyhexyl cyanoacrylate nanoparticles (PHCA), with diameters between 200 and 300 nm, were injected intravenously into nude mice bearing a human osteosarcoma. The distribution in liver, spleen, lung, heart, kidney, GI tract, gonads, brain, muscle, as well as in serum and transplanted tumor fragments was investigated by liquid scintillation counting. The peak levels in all organs with the exception of tumor and spleen were reached within 24 h. The highest levels were found in the organs of the reticuloendothelial system, liver, spleen, and lungs. The radioactivity in the other organs was found to be low, approximately 2%. In the tumor and the spleen the highest levels of radioactivity were found at approximately 7 d. At this stage the level of radioactivity in the tumor was 40 times higher than that in muscle. However, the amount of isotope detected in the tumor was still generally less

than 1% of the injected dose. The concentration of radioactivity in the tumor was found to be quite variable. Higher levels of radioactivity were correlated with a low amount of tumor necrosis indicating the importance of viable tumor tissue for the accumulation of the radiolabel in this particular animal model. Glinka, Y. D., L. Sheng-Hsien, et al. (2000). "Two-photon-excited luminescence and defect formation in SiO2 nanoparticles induced by 6.4-eV ArF laser light." Physical Review B Condensed Matter 62(7): 4733-43. The photoluminescence (PL) from 7- and 15-nm silica (SiO/sub 2/) nanoparticles induced both by ArF laser light lambda /sub exc/=193 nm (6.4 eV), tau /sub L/=15 ns and by Nd:YAG (yttrium-aluminum-garnet) laser light lambda /sub exc/=266 nm (4.66 eV), tau /sub L/=8 ns was studied. The laser light intensity dependencies of the PL yields reveal the two-photon (TP) process of the PL excitation in the case of ArF laser light. The PL results from the radiative relaxation of self-trapped excitons (STE- the blue band), also from the surface hydrogen-related species (the green band), and the bulk nonbridging oxygen hole centers (NBOHC's- the red band) excited by a radiationless relaxation of TP-produced free excitons (FE's). The main point is focused on the effect of the nanoparticle surface condition on the FE dynamics. The dynamics includes either an elastic scattering or quenching by the nanoparticle boundary, the laser heating of FE's up to energies in excess of the STE barrier, the FE energy transfer to the surface and bulk NBOHC's and hydrogen-related centers, the saturation of the FE density, and the biexciton process in the formation of Frenkel defects with their subsequent transformation into NBOHC's. (54 References). Godard, G., A. S. Boutorine, et al. (1995). "Antisense effects of cholesterol-oligodeoxynucleotide conjugates associated with poly(alkylcyanoacrylate) nanoparticles." European Journal of Biochemistry 232(2): 404-10. Oligonucleotides covalently attached to a cholesteryl moiety are more stable in biological media and better taken up by eukaryotic cells. However, their anchoring in hydrophobic cellular membranes and endosomes after endocytosis restricts their access to cellular nucleic acids. New methods of cellular delivery and the biological activity of the conjugates were studied. The cholesteryl residue was conjugated via disulfide bond to the 5' or 3' terminal phosphate group of two oligodeoxyribonucleotide dodecamers complementary to the mutated region of Ha-ras oncogene mRNA. The conjugates were able to form complementary duplexes with the mutated 27-b target fragment of mRNA but not with the wild-type sequence. Efficient sequence-specific RNase H cleavage of complementary mRNA was induced with low (&lt; or = 500 nM) concentrations of the conjugates. At higher concentrations, this cleavage was progressively inhibited, probably due to an interaction between RNase H and the cholesterol residue. The hydrophobic conjugates could be adsorbed onto poly(isohexylcyanoacrylate) nanoparticles via their cholesteryl moieties and delivered to eukaryotic cells. Cholesterol-conjugated oligonucleotides were able to sequence-specifically inhibit the proliferation of T24 human bladder carcinoma cells in culture. Godovsky Yu, K. and S. N. Magonov (2000). "Comparative analysis of the 1.54 mu m emission of Er-doped Si/SiO2 films and the size distribution of the nanostructure." Materials Science and Engineering B Solid State Materials for Advanced Technology: 2-3. Er/sup 3+/-doped nanocrystalline-Si/SiO/sub 2/ composite films were synthesized by RF co-sputtering of bulk-Si, SiO/sub 2/, and Er/sub 2/O/sub 3/ targets. The visible and 1.54 mu m emission bands of the samples were measured, as well as their optical transmission. We varied the relative concentrations of Si, Er, and the annealing temperature. The nanoparticles size distributions of the samples were obtained from their optical transmission spectra. We analyzed the dependence of the characteristic 1.54 mu m Er-emission intensity on the size and concentration of the nanocrystalline particles and the dependence of the emission on the preparation conditions. (7 References). Gohla, S. H. and A. Dingler (2001). "Scaling up feasibility of the production of solid lipid nanoparticles (SLN)." Pharmazie 56(1): 61-3. Solid lipid nanoparticles (SLN/Lipopearls) are widely discussed as colloidal drug carrier system. In contrast to polymeric systems, such as polylactic copolyol capsules, these systems show up with a good biocompatibility, if applied parenterally. The solid lipid matrices can be comprised of fats or waxes and allow protection of incorporated active ingredients against chemical and physical degradation. The SLN can either be produced by "hot homogenisation" of melted lipids at elevated temperatures or a "cold homogenization" process. This paper deals with production technologies for SLN formulations, based on non-ethoxylated fat components for topical application and high pressure homogenization (APV Deutschland GmbH, D-Lubeck). Based on the chosen fat components, a novel and easy manufacturing and scaling up method was developed to maintain chemical and physical integrity of encapsulated active and carrier. Golan, Y., C. Drummond, et al. (2000). "Gas sensitivity of composite Langmuir-Blodgett films of Fe 2O 3 nanoparticlecopper phthalocyanine." Sensors and Actuators B Chemical: 1-2. The Langmuir-Blodgett (LB) composite films, ferric oxide nanoparticle composite with tris-(2,4-di-t-amylphenoxy)(8-quinolinoly) copper phthalocyanine (CuPcA/sub 2/), were obtained by capped type and alternated type and

characterized by X-ray photoelectron spectroscopy (XPS) and visible spectra. The gas sensitivity of the composite films and the pure ferric oxide and pure CuPcA/sub 2/ LB films to ammonia and ethanol were measured at room temperature. The composite films could be used as the C/sub 2/H/sub 5/OH sensors in the range of 2-8 or 100-200 ppm. The XPS data suggested that the adduct complex NH/sub 3/-CuPcA/sub 2/ was formed after the capped film was exposed to the detected gas of ammonia. (15 References). Golightly, L., J. E. Brown, et al. (1988). "Trypanocidal activity of free and carrier bound daunorubicin." Cell Biology International Report 12(2): 77-83. Activities of a range of macromolecular conjugates of daunorubicin against Trypanosoma brucei rhodesiense in vitro and in vivo are described and compared to those of free daunorubicin. Conjugates tested were daunorubicin attached to bovine serum albumin by (i) a labile 'glutaraldehyde' linkage (D-BSAG), and (ii) a stable succinyl linkage (D-BSAS), daunorubicin covalently linked to agarose beads (D-AG), and daunorubicin adsorbed onto polyisobutylcyanoacrylate nanoparticles (D-PICA). Trypanocidal activity in vitro was retained in all except DBSAS, whereas in vivo only D-BSAG had any activity. The results indicate that daunorubicin must be released from the conjugate before it can exert its activity. Golosovsky, I. V., I. Mirebeau, et al. (2001). "Magnetic ordering and phase transition in mno embedded in a porous glass." Physical Review Letters 86(25): 5783-6. We present the results of a neutron diffraction study of the antiferromagnet MnO embedded in a porous glass. The type of magnetic ordering and the structural distortion are similar to those of the bulk, but the ordered magnetic moment of 3.84(4)&mgr;(B)/ion is strongly reduced and the Neel temperature is enhanced. The magnetic transition is second order, in contrast to the first order transition of the bulk. The size of the magnetic region is smaller than the average size of the nanoparticles. The reasons for this behavior are discussed. Gonella, F. (2000). "Nanoparticle formation in silicate glasses by ion-beam-based methods." Nuclear Instruments and Methods in Physics Research Section B Beam Interactions with Materials and Atoms 166(167): 831-9. Ion implantation (single or sequential) and ion irradiation of metal-doped matrices can be used to prepare metal nanocluster composite glasses. Some experiments are reviewed pointing out the effectiveness of these methods for controlled nanoparticle formation in silicate glasses. (36 References). Gonzalez-Martin, G., I. Merino, et al. (1998). "Characterization and trypanocidal activity of nifurtimox-containing and empty nanoparticles of polyethylcyanoacrylates." Journal of Pharmacy and Pharmacology 50(1): 29-35. The aim of this study was to evaluate the utility of nanoparticles of polyalkylcyanoacrylate as a targeted delivery system for nifurtimox against Trypanosoma cruzi, responsible for Chagas' disease. Ethylcyanoacrylate nanoparticles were prepared by an emulsion polymerization process and formulations containing different concentrations of nifurtimox, polyethylcyanoacrylates and surfactants were investigated and analysed for size and drug content. The nanoparticles obtained were less than 200 nm in size, as measured by electron microscopy and cytometry. The peak percentage of nifurtimox uptake into the nanoparticles was 33.4% for use of 500 microL polyethylcyanoacrylate, 200 microL surfactant (Tween 20) and 10 mg nifurtimox in 50 mL polymerization medium. The highest release of nifurtimox from the nanoparticles was 65.4% after 6-h incubation at pH 7.4. In-vitro studies using cultures of T. cruzi epimastigotes revealed considerably increased trypanocidal activity compared with a standard solution of nifurtimox. Studies of cell cultures previously infected with metacyclic forms of the parasite showed that only 2-h treatment with solutions of 0.001% of the nanoparticle suspension reduced parasitism by 87-94% both when the nanoparticles were loaded with nifurtimox and when unloaded. Electron-microscopic examination revealed processes of degeneration and lysis, suggesting apoptotic processes, in intracellular amastigotes and free amastigotes treated with the nanoparticles. It was demonstrated that unloaded nanoparticles, by mechanisms not completely elucidated, have trypanocide activity similar to that of a standard solution of nifurtimox. It is concluded that the nanoparticles loaded with nifurtimox constitutes a good carrier of the drug against T. cruzi. The loaded-nanoparticles significantly increase trypanocidal activity. Gonzalez-Martin, G., C. Figueroa, et al. (2000). "Allopurinol encapsulated in polycyanoacrylate nanoparticles as potential lysosomatropic carrier: Preparation and trypanocidal activity." European Journal of Pharmaceutics and Biopharmaceutics 49(2): 137-142. The activity of allopurinol-loaded polyethylcyanoacrylate nanoparticles against Trypanosoma cruzi was compared to that of free allopurinol using in vitro cultures of epimastigotes. Ethylcyanoacrylate nanoparticles were prepared by an emulsion polymerization process, and formulations containing different concentrations of allopurinol, polyethylcyanoacrylate and surfactants were investigated and analyzed in size and amount of drug entrapped. The nanoparticles obtained were less than 200 nm in size, as measured by electron microscopy and cytometry. The peak amount of allopurinol entrapped in the nanoparticles was 62.8 +- 1.9 mug mg-1 of nanoparticles using 400 mul of polyethylcyanoacrylate, 200 mul of surfactant (Tween 20) and 20 mg of allopurinol in 50 ml of polymerization medium and the association efficiency was 100.7%. After 6 h of incubation at pH 7.4 the release of allopurinol from the nanoparticles was 7.4%, while at pH 1.2 only 3.1% was released after 4-6 h (t = 42.8, P <

0.0001). The in vitro studies, using cultures of T. cruzi epimastigotes, demonstrated considerable increases in the trypanocidal activity of the allopurinol-loaded nanoparticles in comparison with a standard solution of allopurinol (91.5 vs. 45.9%) at an allopurinol concentration of 16.7 mug ml-1. In addition, it was shown that the unloaded nanoparticles, by mechanisms not completely elucidated, had a trypanocidal activity similar to that of standard solutions of allopurinol. To study cytotoxicity, increasing concentrations of unloaded nanoparticles were incubated on vero-line cell cultures. The concentration that killed 50% cells was 200 mug ml-1, four times higher than that necessary to kill 50% of T. cruzi. It is concluded that the polyethylcyanoacrylate nanoparticles constitute a good carrier of drugs against the T. cruzi. The allopurinol loaded-nanoparticles significantly increased the trypanocidal activity in comparison to the free drug. Gonzalez-Varona, O., A. Perez-Rodriguez, et al. (2000). "Ion beam synthesis of semiconductor nanoparticles for Si based optoelectronic devices." Nuclear Instruments and Methods in Physics Research Section B Beam Interactions with Materials and Atoms 161(163): 904-8. Intense white (to the eye) luminescence has been obtained by multiple implantation of Si/sup +/ and C/sup +/ ions into thermal SiO/sub 2/ and a post-implantation annealing process. This white emission is a consequence of the convolution of three luminescence peaks centred at about 1.45 eV (infrared with a long tail in the red), 2.1 eV (yellow) and 2.8 eV (blue). These emissions have been correlated to the synthesis of nanocrystals of Si and SiC, and the existence of C-rich precipitates. Cross section TEM shows a buried layer with dark contrast, which correlates with the maximum of the C implanted profile, and likely with a high density of C-rich amorphous domains. Besides, two kinds of nanocrystalline precipitates are found, which have been identified as Si and hexagonal 6H-SiC by electron diffraction experiments. To our knowledge, these data provide the first experimental evidence on the ion beam synthesis of nanocrystalline 6H-SiC embedded in SiO/sub 2/. Correlation with previous data gives support to the assignment of the infrared, yellow and blue peaks with the Si, C-rich and SiC precipitate phases and/or its interfaces with SiO/sub 2/. (12 References). Goto, H., T. Isobe, et al. (1999). "Controlled dissolution of phenytoin by hybridizing with silica nanoparticles." Journal of Nanoparticle Research 1: 205-213. Govender, T., S. Stolnik, et al. (1999). "PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug." Journal of Controlled Release 57(2): 171-85. The nanoprecipitation technique for preparation of nanoparticles suffers the drawback of poor incorporation of water soluble drugs. The aim of this study was therefore to assess various formulation parameters to enhance the incorporation of a water soluble drug (procaine hydrochloride) into poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared by this technique. Approaches investigated for drug incorporation efficiency enhancement included the influence of aqueous phase pH, replacement of procaine hydrochloride with procaine dihydrate and the inclusion of excipients: poly(dl-lactide) (PLA) oligomers, poly(methyl methacrylate-co-methacrylic acid) (PMMA-MA) or fatty acids into the formulation. The nanoparticles produced were submicron size (&lt;210 nm) and of low polydispersity. It was found that an aqueous phase pH of 9.3, replacement of procaine hydrochloride with procaine dihydrate and the incorporation of PMMA-MA, lauric and caprylic acid into the formulation could enhance drug incorporation efficiency without the size, morphology and nanoparticle recovery being adversely influenced. For instance changing the aqueous phase pH from 5.8 to 9.3 increased nanoparticle recovery from 65.1 to 93.4%, drug content from 0.3 to 1.3% w/w and drug entrapment from 11.0 to 58.2%. However, the presence of high ratios of lauric acid and procaine dihydrate in the formulation adversely affected the morphology and size of the nanoparticles. Also, PLA oligomers were not considered a feasible approach since it decreased drug entrapment from 11.0 to 8.4% and nanoparticle recovery from 65.1 to 19.6%. Drug release from nanoparticles appears to consist of two components with an initial rapid release followed by a slower exponential stage. This study has demonstrated that formulation variables can be exploited in order to enhance the incorporation of a water soluble drug into PLGA nanoparticles by the nanoprecipitation technique. Govender, T., T. Riley, et al. (2000). "Defining the drug incorporation properties of PLA-PEG nanoparticles." International Journal of Pharmacy 199(1): 95-110. The drug incorporation and physicochemical properties of PLA-PEG micellar like nanoparticles were examined in this study using a model water soluble drug, procaine hydrochloride. Procaine hydrochloride was incorporated into nanoparticles made from a series of PLA-PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3-110 kDa). The diameter of the PLA-nanoparticles increased from 27.7 to 174.6 nm, with an increase in the PLA molecular weight. However, drug incorporation efficiency remained similar throughout the series. Incorporation of drug into the smaller PLA-PEG nanoparticles made from 3:5, 15:5 and 30:5 copolymers did not influence the particle size, while an increase was observed for the larger systems comprising 75:5 and 110:5 copolymers. An increase in drug content for PLA-PEG 30:5 nanoparticles was achieved by increasing the theoretical loading (quantity of initially present drug). The size of these nanoparticles remained unchanged with the increasing drug content, supporting the proposed micellar type structure of the PLA-PEG 30:5 nanoparticles. The morphology of these systems remained unchanged both at low and high theoretical drug loadings.

Formulation variables, such as an increase in the aqueous phase pH, replacement with the base form of the drug and inclusion of lauric acid in the formulation did not improve the incorporation efficiency of drug into PLA-PEG 30:5 nanoparticles. While poly(aspartic acid) as a complexation agent did not improve the drug incorporation efficiency of procaine hydrochloride, it did so for another water soluble drug diminazene aceturate. This may be attributed to a stronger interaction of diminazene aceturate with poly(aspartic acid) relative to procaine hydrochloride, as confirmed by thermodynamic analysis of isothermal titration calorimetric data. The drug incorporation and physicochemical characterisation data obtained in this study may be relevant in optimising the drug incorporation and delivery properties of these potential drug targeting carriers. Gradon, L., D. Orlicki, et al. (2000). "Deposition and retention of ultrafine aerosol particles in the human respiratory system. Normal and pathological cases." International Journal of Occupational Safety and Ergonomics 6(2): 189-207. The particle number concentration in ambient air is dominated by nanometer-sized particles. Recent epidemiological studies report an association between the presence of nanoparticles in inhaled air at the workplace and acute morbidity and even mortality in the elderly. A theoretical model of deposition of 20 nm particles in the human alveolus was formulated. Gas flow structure and deposition rate were calculated for alveoli with different elastic properties of lung tissue. Data obtained in the paper show increased convective effects and diffusional rate of deposition of nanoparticles for alveoli with higher stiffness of the alveolar wall. The retention of deposited particles is also higher in these pathological alveoli. Results of our calculations indicate a possibility of existence of a positive loop of coupling in deposition and retention of nanoparticles in the lung with pathological changes. Green, M. and P. O'Brien (2000). "Synthesis of passivated metal nanoparticles." Nanophase and Nanocomposite Materials III. Symposium 581: 47-52. Here we report the synthesis of organically passivated nanoparticles of gold, chromium and nickel. The routes involve the reduction of a metal precursor in various Lewis base solvents, which appear to affect the final nanoparticle morphology. The preparation of highly monodispersed samples can lead to the potential for further manipulation of dots into ordered 2D and 3D arrays. These colloidal thin films and crystals have potential application in magnetic data storage devices. (17 References). Gref, R., M. Luck, et al. (2000). "'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption." Colloids Surf B Biointerfaces 18(3-4): 301-313. Nanoparticles possessing poly(ethylene glycol) (PEG) chains on their surface have been described as blood persistent drug delivery system with potential applications for intravenous drug administration. Considering the importance of protein interactions with injected colloidal dug carriers with regard to their in vivo fate, we analysed plasma protein adsorption onto biodegradable PEG-coated poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(varepsilon-caprolactone) (PCL) nanoparticles employing two-dimensional gel electrophoresis (2D PAGE). A series of corona/core nanoparticles of sizes 160-270 nm were prepared from diblock PEG-PLA, PEG-PLGA and PEG-PCL and from PEG-PLA:PLA blends. The PEG Mw was varied from 2000-20000 g/mole and the particles were prepared using different PEG contents. It was thus possible to study the influence of the PEG corona thickness and density, as well as the influence of the nature of the core (PLA, PLGA or PCL), on the competitive plasma protein adsorption, zeta potential and particle uptake by polymorphonuclear (PMN) cells. 2-D PAGE studies showed that plasma protein adsorption on PEG-coated PLA nanospheres strongly depends on the PEG molecular weight (Mw) (i.e. PEG chain length at the particle surface) as well as on the PEG content in the particles (i.e. PEG chain density at the surface of the particles). Whatever the thickness or the density of the corona, the qualitative composition of the plasma protein adsorption patterns was very similar, showing that adsorption was governed by interaction with a PLA surface protected more or less by PEG chains. The main spots on the gels were albumin, fibrinogen, IgG, Ig light chains, and the apolipoproteins apoA-I and apoE. For particles made of PEG-PLA45K with different PEG Mw, a maximal reduction in protein adsorption was found for a PEG Mw of 5000 g/mole. For nanospheres differing in their PEG content from 0.5 to 20 wt %, a PEG content between 2 and 5 wt % was determined as a threshold value for optimal protein resistance. When increasing the PEG content in the nanoparticles above 5 wt % no further reduction in protein adsorption was achieved. Phagocytosis by PMN studied using chemiluminescence and zeta potential data agreed well with these findings: the same PEG surface density threshold was found to ensure simultaneously efficient steric stabilization and to avoid the uptake by PMN cells. Supposing all the PEG chains migrate to the surface, this would correspond to a distance of about 1.5 nm between two terminally attached PEG chains in the covering 'brush'. Particles from PEG5K-PLA45K, PEG5K-PLGA45K and PEG5K-PCL45K copolymers enabled to study the influence of the core on plasma protein adsorption, all other parameters (corona thickness and density) being kept constant. Adsorption patterns were in good qualitative agreement with each other. Only a few protein species were exclusively present just on one type of nanoparticle. However, the extent of proteins adsorbed differed in a large extent from one particle to another. In vivo studies could help elucidating the role of the type and amount of proteins adsorbed on the fate of the nanoparticles after intraveinous administration, as a function of the nature of

their core. These results could be useful in the design of long circulating intravenously injectable biodegradable drug carriers endowed with protein resistant properties and low phagocytic uptake. Gref, R., P. Quellec, et al. (2001). "Development and characterization of CyA-loaded poly(lactic acid)-poly(ethylene glycol)PEG micro- and nanoparticles. Comparison with conventional PLA particulate carriers." European Journal of Pharmacology and Biopharmacology 51(2): 111-8. Cyclosporin A (CyA) loaded poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) micro- and nanoparticles have been developed using an emulsion-solvent evaporation method. Physico-chemical properties, peptide loading content and in vitro release profiles of these novel CyA carriers were compared with those corresponding to conventional PLA micro- and nanoparticles. Results obtained confirm the previously described disposition of PEG chains on the surface of the PLA-PEG formulations. In addition, they revealed the presence of CyA molecules on the surface of both PLA and PLA-PEG systems. Further determination of the surface chemical composition by electron spectroscopy for chemical analysis (ESCA) allowed us to quantify the amount of CyA in the nanospheres' top layers, this amount being higher for nanoparticles than for microparticles, and higher for the PLA systems than for those based on PLA-PEG. In vitro release experiments revealed that PLA-PEG particles provided a more adequate control of CyA release than conventional PLA micro- and nanoparticles. Physico-chemical characterization of the systems during the release studies showed that the developed PLA and PLA-PEG microand nanoparticles were not degraded, which suggest a diffusion-mediated release mechanism. Furthermore, we have hypothesized that the hydrophilic outer shell of PEG provides a stationary layer for the diffusion of CyA. Gu, X. G., M. Schmitt, et al. (1998). "A novel hydrophobized polysaccharide/oncoprotein complex vaccine induces in vitro and in vivo cellular and humoral immune responses against HER2-expressing murine sarcomas." Cancer Research 58(15): 3385-90. To elicit specific cellular immune responses against cancer, the development of efficient devices to deliver tumor antigen peptides to the MHC class I pathway constitutes a central issue. We report here a novel formula of hydrophobized polysaccharide nanoparticles, which can deliver a HER2 oncoprotein containing an epitope peptide to the MHC class I pathway. A protein consisting of the 147 amino-terminal amino acids of oncogene erbB-2/neu/HER2 (HER2) was complexed with two kinds of hydrophobized polysaccharides, cholesteryl groupbearing mannan (CHM) and cholesteryl group-bearing pullulan (CHP), to form nanoparticles (CHM-HER2 and CHP-HER2). CHM-HER2 and CHP-HER2 were able to induce CD3+/CD8+ CTLs against HER2-transfected syngeneic fibrosarcoma cell lines. In contrast, the oncoprotein alone failed to do so. These CTLs were Kdrestricted and specifically recognized a peptide (position 63-71) that was a part of a truncated HER2 protein used as an immunogen. In addition, vaccination by CHM-HER2 complexes led to a strongly enhanced production of IgG antibodies against HER2, whereas vaccination with HER2 proteins alone resulted in a production of antibodies at a marginal level. Mice immunized with CHM-HER2 or CHP-HER2 before tumor challenge successfully rejected HER2-transfected tumors. The complete rejection of tumors also occurred when CHMHER2 was applied not later than 3 days after tumor implantation. In the effector phase of in vivo tumor rejection, CD8+ T cells played a major role. The results suggest that a sort of hydrophobized polysaccharide may help soluble proteins to induce cellular immunity as well enhance humoral immunity; hence, such a novel vaccine may be of potential benefit to cancer prevention and cancer therapy. Guimaraes, R., O. Clement, et al. (1994). "MR lymphography with superparamagnetic iron nanoparticles in rats: pathologic basis for contrast enhancement." American Journal of Roentgenology 162(1): 201-7. OBJECTIVE. The purpose of this study in rodents was to determine the pathologic basis for enhancement patterns of hyperplastic and tumours lymph nodes shown by MR lymphography after IV injection of superparamagnetic iron oxide nanoparticles (AMI-227). MATERIALS AND METHODS. Hyperplastic and tumorous lymph nodes were imaged in vivo at 1.5 T 1 day after IV administration of AMI-227 (40-200 mumol Fe/kg) to rats. Inguinal and axillary lymph nodes were surgically resected, and in vitro imaging was done by using the same magnet with a prototype coil that allowed a pixel size of 70 x 230 microns. Imaging findings were correlated with histologic findings and iron staining of the nodes. RESULTS. With all sequences, at doses of 80 mumol Fe/kg or higher, the signal intensity of hyperplastic nodes was lower than on unenhanced images. The same pattern was seen in the remaining normal tissue of tumourous lymph nodes. This T2* effect was a result of clustered particles inside macrophages in the lymphatic sinuses. At doses of 200 mumol/kg, the tumor itself consistently showed an increase in signal intensity on T1-weighted images. This T1 effect probably resulted from particles leaking into the interstitial spaces of the tumor. CONCLUSION. After IV injection of superparamagnetic nanoparticles, a decrease in signal intensity indicates active uptake of particles into macrophages, whereas an increase in signal intensity indicates altered capillary permeability in tumor. These findings in rats may prove to be clinically useful in the future for differentiating benign from malignant enlarged lymph nodes. Guiot, P. and P. Couvreur (1983). "Quantitative study of the interaction between polybutylcyanoacrylate nanoparticles and mouse peritoneal macrophages in culture." Journal de Pharmacie de Belgique 38(3): 130-4.

Guise, V., P. Jaffray, et al. (1987). "Comparative cell uptake of propidium iodide associated with liposomes or nanoparticles." Cell Mol Biol 33(3): 397-405. Guise, V., J. Y. Drouin, et al. (1990). "Vidarabine-loaded nanoparticles: a physicochemical study." Pharm Res 7(7): 73641. The chemical reaction of vidarabine (VIDA) with isohexyl cyanoacrylate nanoparticles in a pH-dependent fashion occurs only in the presence of dioctylsulfosuccinate (DOSS). The formation of an ion pair with DOSS allows a better contact of VIDA with the monomer during the polymerization process taking place in micelles. On the basis of molecular weight profiles of the polymer, determined by gel permeation chromatography (GPC), it is proposed that VIDA induces the polymerization of cyanoacrylic monomers through a zwitterionic pathway. This mechanism allows the covalent linkage of the drug with the polymer, which is consistent with NMR experiments. The present study illustrates the need for physicochemical studies in the design of new colloidal drug delivery formulations. Gulyaev, A. E., S. E. Gelperina, et al. (1999). "Significant transport of doxorubicin into the brain with polysorbate 80coated nanoparticles." Pharm Res 16(10): 1564-9. PURPOSE: To investigate the possibility of delivering of anticancer drugs into the brain using colloidal carriers (nanoparticles). METHODS: Rats obtained 5 mg/kg of doxorubicin by i.v. injection in form of 4 preparations: 1. a simple solution in saline, 2. a simple solution in polysorbate 80 1% in saline, 3. bound to poly(butyl cyanoacrylate) nanoparticles, and 4. bound to poly(butyl cyanoacrylate) nanoparticles overcoated with 1% polysorbate 80 (Tween 80). After sacrifice of the animals after 10 min, 1, 2, 4, 6, and 8 hours, the doxorubicin concentrations in plasma, liver, spleen, lungs, kidneys, heart and brain were determined after extraction by HPLC. RESULTS: No significant difference in the body distribution was observed between the two solution formulations. The two nanoparticle formulations very significantly decreased the heart concentrations. High brain concentrations of doxorubicin (&gt;6 microg/g) were achieved with the nanoparticles overcoated with polysorbate 80 between 2 and 4 hours. The brain concentrations observed with the other three preparations were always below the detection limit (&lt; 0.1 microg/g). CONCLUSIONS: The present study demonstrates that the brain concentration of systemically administered doxorubicin can be enhanced over 60-fold by binding to biodegradable poly(butyl cyanoacrylate) nanoparticles, overcoated with the nonionic surfactant polysorbate 80. It is highly probable that coated particles reached the brain intact and released the drug after endocytosis by the brain blood vessel endothelial cells. Guo, L., Z. Wu, et al. (2000). "The effect of surface modification on the microstructure and properties of gamma -Fe2O3 nanoparticles." Physica A 8(2): 199-203. The gamma -Fe/sub 2/O/sub 3/ nanoparticles coated with DBS and CTAB were prepared by the microemulsion method. The microstructure was researched using synchrotron radiation. The XPS results reveal the chemical bonds between gamma -Fe/sub 2/O/sub 3/ nanoparticles and surfactant groups. The Mossbauer spectra at room temperature were measured for the coated samples. The EXAFS results show substantial effect of the surface modification on the local atomic structures. The coated samples exhibit an enhanced nonlinear optical response. The coated layers were found to have a significant influence on the electron structures of the nanoparticle surface. (12 References). Gupta, A. K., S. Madan, et al. (2000). "Ketorolac entrapped in polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies." International Journal of Pharmacy 209(1-2): 1-14. Polymeric micelles made of copolymer of N-isopropylacrylamide (NIPAAM), vinyl pyrrolidone (VP) and acrylic acid (AA) having cross-linkage with N,N'-methylene bis-acrylamide (MBA) were used as host carrier in which up to 30%w/w ketorolac (free acid) was entrapped to make the formulation. The lyophilised powder was used for physical characterisation. The drug entrapment was found to be about 80% and the formulation was stable for 810 days at room temperature. The smaller the amount of ketorolac dissolved into the micelles, the longer was the formulation shelf life. The size of the particles as measured by dynamic light scattering was found to be around 35 nm diameter at 25 degrees C. TEM picture showed spherical particles. The structure of the polymer and its morphology were characterised by FTIR, NMR and XRD measurements. IR data indicated weak interaction between polymer and ketorolac in the encapsulated system. NMR spectra indicated rigid polymer backbone with intermittent iso-propyl group in the chain. XRD spectra showed significant loss of crystallinity of the drug while being entrapped in the polymeric micelles. The release of drug in aqueous buffer (pH 7.2) from the polymeric micelles at 25 degrees C were 20 and 60% after 2 and 8 h respectively and is temperature and pH dependent. In vitro corneal permeation studies through excised rabbit cornea indicated two fold increase in ocular availability with no corneal damage compared to an aqueous suspension containing same amount of drug as in nanoparticles. The formulation showed significant inhibition of lid closure up to 3 h and PMN migration up to 5 h compared to the suspension containing non-entrapped drug, which did not show any significant effect. Gurkan, H., H. S. Yalabik-Kas, et al. (1987). "Streptomycin sulphate microspheres: dissolution rate studies and release kinetics. I." Journal of Microencapsulation 4(1): 39-46.

Targeting of drugs by microspheres, nanoparticles and liposomes is intended to increase the selective targeting to specific organs and to reduce their side effects. Streptomycin sulphate, a tuberculostatic antibiotic, is used as the active principle in this study. The aim is to accumulate the loaded microspheres in the lungs. The release of drugs associated with microsphere carriers has been found to be dependent on a number of factors. The aim of the investigation was to study the influence of the extent and nature of cross-linking, the type and the amount of the matrix material on the release characteristics of streptomycin sulphate microspheres. Human serum albumin and gelatin (Type B) were used as two different matrix materials. The crosslinking agents used were 2,3-butanedione and formaldehyde at different concentrations, and variable duration times. The in vitro release of streptomycin sulphate from microspheres is characteristically biphasic, with an initial fast release (the 'burst effect'), followed by a much slower release. Alteration in the characteristics of drug-loaded microspheres result in significant changes in the second (slow) phase of release. The release profiles of the different formulations has been studied and evaluated kinetically. Guzman, M., J. Molpeceres, et al. (1993). "Formation and characterization of cyclosporine-loaded nanoparticles." Journal of Pharmaceutical Sciences 82(5): 498-502. The commercially available formulations of cyclosporine (cyclosporin A, CyA) are associated with acute hemodynamic changes that result in high nephrotoxicity. Among colloidal vectors, nanoparticles (NPs) are receiving much attention as potential drug carriers that would avoid the therapeutic risks of conventional formulations. Two different mechanisms for obtaining polymeric NPs loaded with CyA were studied with regard to their preparation and physicochemical characterization. Isobutyl-2-cyanoacrylate monomer (IBCA) was polymerized, whereas poly-E-caprolactone (PCL, a preformed polymer) was precipitated; both reactions took place in an aqueous medium containing Pluronic F-68 (polyoxypropylene polyoxyethylene block copolymer) as a surface active agent. The encapsulation efficiencies were 78.49 +/- 5.87 and 84.85 +/- 5.02%, respectively, and they remained stable over a wide range of drug concentrations. The polymeric NP had average sizes of 81 +/- 25 and 95 +/- 25 nm for poly-IBCA and PCL, respectively, as confirmed by photon correlation spectroscopy. PolyIBCA NPs were built from oligomers with molecular weights of 157 to 2644 that joined to form a polymeric nanomatrix. In vitro activity of the drug and the carrier was tested by inhibition of lymphocyte proliferation induced by Concanavalin A. Drug-loaded PCL NPs and free CyA inhibited lymphocyte proliferation by 91.40 and 86.19%, respectively. However, drug-free NPs also exhibited statistically significant (p &lt; 0.05) immunosuppressive activity. Guzman, L. A., V. Labhasetwar, et al. (1996). "Local intraluminal infusion of biodegradable polymeric nanoparticles. A novel approach for prolonged drug delivery after balloon angioplasty." Circulation 94(6): 1441-8. BACKGROUND: Several perfusion balloon catheters are under investigation for local drug delivery; however, sustained tissue drug levels are difficult to achieve with these techniques. To overcome this problem, sustainedrelease, biodegradable nanoparticles represent a potential alternative for prolonged local delivery. METHODS AND RESULTS: A biodegradable polylactic-polyglycolic acid (PLGA) copolymer was used to formulate nanoparticles. Fluorescent-labeled nanoparticles were intraluminally administered in a single, 180-second infusion after balloon injury in the rat carotid model. Localization and retention at different time points and biocompatibility of nanoparticles were evaluated. To evaluate the potential of the system in the prevention of neointimal formation, dexamethasone was incorporated into the particles and delivered locally as above. Nanoparticles were seen in the three layers of the artery at 3 hours and 24 hours. At 3 days, they were mainly present in the adventitial layer, decreasing at 7 days, with no fluorescent activity at 14 days. The PLGA nanoparticles appeared to be fully biocompatible. In the dexamethasone nanoparticle study, a significant amount of dexamethasone was present in the treated segment for up to 14 days after a single infusion, with no plasma levels detected after the first 3 hours. There was a 31% reduction in intima-media ratio in animals treated with local dexamethasone nanoparticles compared with control. CONCLUSIONS: Nanoparticles successfully penetrated into the vessel wall and persisted for up to 14 days after a short, single intraluminal infusion. Local administration of nanoparticles with incorporated dexamethasone significantly decreased neointimal formation. This methodology appears to have important potential for clinical applications in local drug delivery. Guzman, M., M. R. Aberturas, et al. (2000). "Effect of nanoparticles on digitoxin uptake and pharmacologic activity in rat glomerular mesangial cell cultures." Drug Delivery 7(4): 215-22. Our experiments analyzed the uptake of free and nanoparticles (NP)-associated digitoxin (DGT) by rat glomerular mesangial cells. NP were prepared by the nanoprecipitation method using the biodegradable polyester, polycaprolactone (PCL). Prior to in vitro experiments, the systems were characterized by means of spectrofluorimetry, dynamic light scattering, and size exclusion chromatography (SEC). The loading efficiency was 80.30 +/- 1.03% of the initial DGT amount in the preparation, and the average particle size was 176 +/- 8 and 161 +/- 6 nm for DGT-NP and &quot;empty&quot; NP, respectively. SEC studies revealed noncovalent interactions among the different chemical compounds in the formulation. In vitro experiments were conducted at 37 degrees C and pH 7.5 by incubating &quot;empty&quot; NP, free DGT or DGT-NP (10 microg PCL/mL; 100 ng DGT/mL) with glomerular mesangial cells for 30 and 60 min. Uptake of DGT by the cells was favored by its

incorporation into PCL-NP and showed time dependency. After 30 min of incubation, no significant differences of drug uptake were seen between free DGT (13.1 +/- 2.8%) or DGT-NP (17.4 +/- 4.9%); however, the uptake of DGT, when it was associated to the polymeric carrier, increased by approximately 2-fold (37.8 +/- 5.7%) at 60 min, whereas no significant changes were observed for free drug (20.0 +/- 6.8%). The pharmacologic activity of the drug was evaluated by measuring the planar cell surface area (PCSA). &quot;Empty&quot; NP, free drug, or DGT-NP did not produce significant variations on the PCSA as compared with control cells after a 30-min incubation. Nonetheless, DGT-NP reduced the PCSA to 82.51 +/- 8.42% of control values when the incubation lasted 60 min. The ability of cells to exclude the trypan blue dye and the leakage of lactate dehydrogenase into the medium revealed no signs of increased toxicity from incorporation of DGT into PCL-NP. Therefore, PCL-NP improved drug uptake by the cells without altering the pharmacologic activity and toxicity of the drug. Thus, they can be a useful approach to target drugs to the kidneys or the heart. Haase, M., K. Riwotzki, et al. (2000). "Synthesis of fullerenic nanocapsules from bio-molecule carbonisation." Chemical Physics Letters 322(6): 553-60. There has been great interest in the incorporation of foreign materials into fullerene structures (C/sub 60/, nanotubes, nanoparticles, onions). This interest has been driven by the potential applications of the filled fullerenes, which lie in areas as diverse as optical, electronic, magnetic recording materials and nuclear medicine. In particular, the onion structures of extreme strength may offer excellent protection to their encapsulated nanomaterials for applications. We describe controlled carbonisation of an iron-containing biomolecule, ferritin, at elevated temperatures. This simple technique produces macroscopic quantities of quasi-spherical fullerenic shells (onions) that encapsulate iron nanoparticles of a very narrow range of particle diameters. (22 References). Hai-Ping, W., A. Okano, et al. (2000). "Visible photoluminescence from size-dispersed Si nanoparticle films." Review of Laser Engineering 28(6): 354-8. We produced silicon nanoparticles with diameters from 1 to 20 nm by laser ablation of Si in He ambient gas and extracted them into a vacuum as a cluster beam. Using a technique of crossing an Ar molecular beam perpendicularly to the silicon cluster beam before deposition on a substrate, we synthesized size-dispersed Si nanoparticle films. These size-dispersed nanoparticle films exhibited visible photoluminescence (PL) after exposure to air. The peak PL energy was shifted from 1.42 to 1.72 eV when the average diameter of the surfaceoxidized nanoparticles deposited in the film changed from 10 to 3 or 4 nm. At positions that we expected to have particles smaller than 3 or 4 nm, however we observed no further blue shift of the peak PL energy. In this paper, we discuss mechanisms of the size-dependent PL of the surface-oxidized Si nanoparticles. (30 References). Hainfeld, J. F., F. R. Furuya, et al. (1999). "Metallosomes." Journal of Structural Biology 127(2): 152-60. Structures and ordered arrays containing organometallic particles have potential application in nanofabrication, smaller computer components, optical devices, sensors, and membrane probes and as detection agents. Here, we describe construction of gold clusters covalently attached to lipids and their use in forming typical lipid structures: micelles, liposomes (&quot;metallosomes&quot;), and sheets on an air-water interface. Two sizes of gold clusters were used, undecagold, with an 11-gold atom core 0.8 nm in diameter, and the larger Nanogold, with a 1.4-nm gold core. The morphology of the structures formed was determined by electron microscopy at a resolution at which single gold-lipid molecules were visualized. Further modification by additional catalytic metal deposition enhanced detectability. The approach is flexible and permits a wide variety of metal particle structures to be created using known lipid structures as templates. Additionally, these gold-lipids may serve as useful membrane labels. Hall, M., P. A. McCarron, et al. (2000). "Evaluation of nanoparticulate loading of a water-soluble drug (ranitidine) using solid-phase extraction." Journal of Pharmacy and Pharmacology 52(Supplement): 149. Hall, B. D., A. D. Zanchet, et al. (2000). "Estimating nanoparticle size from diffraction measurements." Journal of Applied Crystallography 33(6): 1335-41. Nanometre-sized particles are of considerable current interest because of their special size-dependent physical properties. Debye-Scherrer diffraction patterns are often used to characterize samples, as well as to probe the structure of nanoparticles. Unfortunately, the well known `Scherrer formula' is unreliable at estimating particle size, because the assumption of an underlying crystal structure (translational symmetry) is often invalid. A simple approach is presented which takes the Fourier transform of a Debye-Scherrer diffraction pattern. The method works well on noisy data and when only a narrow range of scattering angles is available. (26 References). Hall Christopher, S., N. Marsh Jon, et al. (2000). "Time evolution of enhanced ultrasonic reflection using a fibrin-targeted nanoparticulate contrast agent." Journal of the Acoustical Society of America 108(6): 3049-3057. Complex molecular signaling heralds the early stages of pathologies such as angiogenesis, inflammation, unstable atherosclerotic plaques, and areas of remote thrombi. In previous studies, acoustic enhancement of blood clot morphology was demonstrated with the use of a nongaseous, fibrin-targeted acoustic nanoparticle

emulsion delivered to areas of thrombosis both in vitro and in vivo. In this study, a system was designed and constructed that allows visualization of the evolution of acoustic contrast enhancement. To evaluate the system, two targets were examined: avidin-complexed nitrocellulose membrane and human plasma clots. The time evolution of enhancement was visualized in 10-min increments for 1 h. A monotonic increase was observed in ultrasonic reflection enhancement from specially treated nitrocellulose membranes for targeted emulsions containing perfluorooctylbromide (1.30+-0.3 dB) and for perfluorooctane (2.64+-0.5 dB) within the first 60 min of imaging. In comparison, the inherently nonechogenic plasma clots showed a substantial increase of 12.0+-0.9 dB when targeted with a perfluoro-octane emulsion. This study demonstrates the concept of molecular imaging and provides the first quantifiable time-evolution report of the binding of a site-targeted ultrasonic contrast agent. Moreover, with the incorporation of specific drug treatments into the nanoparticulate contrast agent, ultrasonic molecular imaging may yield reliable detection and quantification of nascent pathologies and facilitate targeted drug therapy. Han, S., J. Lin, et al. (2000). "Oligonucleotide-capped gold nanoparticles for improved atomic force microscopic imaging and enhanced selectivity in polynucleotide detection." Biochemical and Biophysical Research Communications 279(1): 265-269. A novel assay for selective determination of polynucleotides using atomic force microscopy in conjunction with the formation of the probe/target/DNA-gold nanoparticle sandwich structure at a gold surface is described. A 17-mer probe was attached to the surface for subsequent hybridization with a polynucleotide target. Due to the flat orientation of the probe-target hybrid with respect to the surface and the spatial obstruction of the unhybridized probes near the hybrids, the AFM images are not clear. The hybridization efficiency was estimated to be about 1.1% since certain surface features could not be resolved. The utilization of 30-mer-capped gold nanoparticles not only provides another dimension of selectivity, but also reorients the previously formed probe-target hybrid in such a way that the strands of the target become tethered with respect to the surface. This reorientation improves the resolution in imaging the hybridized target molecules and provides an accurate determination of the hybridization efficiency (16%). Han, H.-S., D.-R. Chen, et al. (2000). "A nanometer aerosol size analyzer (nASA) for rapid measurement of highconcentration size distributions." Journal of Nanoparticle Research 2: 43-52. Hao, E., H. Zhang, et al. (2001). "Preparation of luminescent polyelectrolyte/Cu-doped ZnSe nanoparticle multilayer composite films." Journal of Colloid and Interface Science 238(2): 285-290. ZnSe and Cu-doped ZnSe nanoparticle aqueous suspensions were prepared in the presence of mercaptopropionic acid (MPA). Cu-doped ZnSe nanoparticles exhibited a strong blue emission that was strongly dependent upon the Cu dopant level and the chemical surface passivation produced by zinc-mercaptopropionic acid complexes. These Cu-doped ZnSe nanoparticles were further assembled into ultrathin polymer-supported films using electrostatic interactions and the layer-by-layer assembly method. UV-visible spectroscopy and X-ray photoelectron spectroscopy (XPS) provided evidence for the presence and optical activity of Cu-doped ZnSe nanoparticles within the polymer ultrathin films. Moreover, XPS data supported the presence of zinc mercaptopropionic acid complexes on nanoparticle surfaces and the presence of Cu(+) ions with high luminescent activity in the doped nanoparticles. Copyright 2001 Academic Press. Harma, H., T. Soukka, et al. (2000). "Zeptomole detection sensitivity of prostate-specific antigen in a rapid microtitre plate assay using time-resolved fluorescence." Luminescence 15(6): 351-355. Prostate-specific antigen (PSA) was detected in microtitre wells coated with a PSA-specific antibody using biotinylated antibody and streptavidin-coated, highly fluorescent 107 nm nanoparticles, which contained more than 30000 europium ions entrapped by beta-diketones. PSA was monitored directly on the surface of a well without any additional enhancement step. The sensitivity of the assay was 1.6 ng/L, corresponding to 50 fmol/L or 250 zeptomoles (250 X 10-21 mol/L) of PSA. The high specific activity and low non-specific binding of the streptavidin-coated nanoparticles improved the sensitivity of the PSA assay 100-fold compared to the conventional europium-labelled streptavidin tracer in the same assay format. Additionally, the streptavidin-coated nanoparticle label made very rapid assays possible, due to the high affinity of the streptavidin-biotin complex and a high number of binding sites available for tracing the biotinylated antibody on the surface. Due to the inherent problems of tracing analyte with a complex of biotinylated antibody and streptavidin-coated nanoparticles, the streptavidin-coated nanoparticles reacting with the surface-captured analyte and biotinylated antibody was favoured and factors influencing this are discussed. This universal labelling technology can be applied to detect any biotinylated molecule, either in solution or on a solid phase, in order to improve detection sensitivities in many areas of biochemical analysis, such as cyto- and histochemistry, multianalyte DNA-chip assays and single-particle assays. Harma, H., T. Soukka, et al. (2001). "Europium nanoparticles and time-resolved fluorescence for ultrasensitive detection of prostate-specific antigen." Clinical Chemistry 47(3): 561-8.

Background: Nanoparticle-based detection technologies have the potential to improve detection sensitivity in miniature as well as in conventional biochemical assays. We introduce a detection technology that relies on the use of europium(III) nanoparticles and time-resolved fluorometry to improve the detection limit of biochemical assays and to visualize individual molecules in a microtiter plate format. METHODS: Streptavidin was covalently coated on 107-nm nanoparticles containing >30 000 europium molecules entrapped with beta-diketones. In a model assay system, these nanoparticles were used to trace biotinylated prostate-specific antigen (PSA) in a microtiter plate format. RESULTS: The detection limit (mean + 3 SD of the zero calibrator) of biotinylated PSA was 0.38 ng/L, corresponding to 10 fmol/L or 60 zeptomoles (60 x 10(-21) moles) of PSA. Moreover, single nanoparticles, representing individual PSA molecules, were visualized in the same microtiter wells with a timeresolved fluorescence microscope using a x10 objective. Single nanoparticles, possessing high specific activity, were also detected in solution by a standard time-resolved plate fluorometer. CONCLUSIONS: The universal streptavidin-coated europium(III) nanoparticle label is suitable for detection of any biotinylated molecule either in solution or on a solid phase. The europium(III) nanoparticle labeling technology is applicable to many areas of modern biochemical analysis, such as immunochemical and multianalyte DNA-chip assays as well as histo- and cytochemistry to improve detection sensitivities. Harmia, T., P. Speiser, et al. (1986). "A solid colloidal drug delivery system for the eye: encapsulation of pilocarpin in nanoparticles." Journal of Microencapsulation 3(1): 3-12. The present study was undertaken in order to encapsulate pilocarpin into nanoparticles. Two principally different methods for manufacturing these particles were investigated. Firstly, pilocarpin was dissolved in an aqueous medium in which the polymerization was carried out, and secondly, the polymerizing monomer was kept saturated with the drug solution under acidic conditions resulting in an incorporation into the nanoparticles in an aqueous environment. The amount of pilocarpin that could be incorporated into the nanoparticles was found to be largely influenced by the temperature at which the nanoparticles were produced and by the stabilizers used. At low temperatures, up to 60 per cent of pilocarpin nitrate could be encapsulated into butylcyanoacrylate nanoparticles using emulsion polymerization techniques. Larger amounts of pilocarpin could not be incorporated because of the hydrophilicity of the salts of this drug. The physico-chemical characteristics of the nanoparticles are reported: the particle size and morphology were determined by scanning and transmission electron microscopy and photon correlation spectrometry. The average particle size was about 100 nm. The results obtained in this study show that photon correlation spectrometry is a suitable method for the sizing of nanoparticles. Harmia, T., P. Speiser, et al. (1987). "Nanoparticles as drug carriers in ophthalmology." Pharmaceutica Acta Helvetiae 62(12): 322-31. Harmia-Pulkkinen, T., A. Tuomi, et al. (1989). "Manufacture of polyalkylcyanoacrylate nanoparticles with pilocarpine and timolol by micelle polymerization: factors influencing particle formation." Journal of Microencapsulation 6(1): 87-93. Nanoparticles with pilocarpine and timolol were produced by micelle polymerization. The influence of manufacturing temperature, type of monomer, drug concentration and ethylcyanoacrylate concentration on the particle size were investigated with a Coulter Nano Sizer. The nanoencapsulation succeeded only with the pilocarpine or timolol base, not with the salts of these drugs. Different micelle formation in aqueous medium compared with organic solvents was evidently responsible for this phenomenon. The particle formation was affected both by the manufacturing temperature and the type of monomer. The smallest particles were produced at lower temperatures and with the most lipophilic monomers. The monomer and drug concentration had very little influence on the particle size. The nanoparticles made with pilocarpine were, in general, much bigger than those made with timolol. Harnisch, S. and R. H. Muller (1998). "Plasma protein adsorption patterns on emulsions for parenteral administration: establishment of a protocol for two-dimensional polyacrylamide electrophoresis." Electrophoresis 19(2): 349-54. The two-dimensional polyacrylamide electrophoresis (2-D PAGE) of the plasma protein adsorption pattern previously established for polymeric nanoparticles was modified and transferred to oil in water emulsions for intravenous administration. The emulsions were incubated with citrated plasma, and separation from excess plasma was performed by centrifugation under optimized conditions: 15000 g and three washing steps with 0.05 M phosphate buffer, pH 7.4. With this sample preparation, coalescence of droplets could be avoided and an unchanged surface area maintained, in addition the phosphate buffer minimized artificial IgG adsorption. Critical factors affecting sensitivity were contamination of the sample by oil residues and the use of thiourea in the immobilized pH gradients. Changes in the protein adsorption pattern caused by altered surface properties of the emulsion (i.e. adsorbed Poloxamer 407) were detectable when applying the optimized protocol. Knowledge of the protein adsorption patterns and their correlation to in vivo behavior opens the perspective for the development of intravenous emulsions for controlled drug delivery. Harnisch, J. A., A. D. Pris, et al. (2001). "Attachment of gold nanoparticles to glassy carbon electrodes via a mercaptobenzene film." Journal of the American Chemical Society 123(24): 5829-30.

Harris, P. J. F., R. D. Vis, et al. (2000). "Fullerene-like carbon nanostructures in the Allende meteorite." Earth and Planetary Science Letters 183: 3-4. Transmission electron microscopy has been used to examine carbon isolated from the Allende meteorite. The structure of the carbon is rather disordered, consisting of curved and faceted graphene sheets with little large scale graphitization, and resembles that of a microporous carbon following high temperature heat treatment. Closed carbon nanoparticles, typically ~2-10 nm in diameter are commonly observed. These closed particles, which are probably fullerene-like in structure, are strong candidates to be carriers of planetary gases. (20 References). Haskell, R. J. (1998). "Characterization of submicron systems via optical methods." Journal of Pharmaceutical Sciences 87(2): 125-9. As a means of addressing the issues of drug delivery, submicron colloidal systems have become increasingly used as pharmaceutical formulations. Accurately characterizing physical properties of the constituent particulates present in these systems is an indispensable activity. However, measuring descriptors such as particle size distribution and surface potential presents an experimental challenge. This paper describes the physical basis for a number of optically based techniques that are useful in this task. In addition, the caveats and benefits of these methods are discussed and reference is made to their use in the examination of various multiphase systems such as liposomes, nanoparticles, and emulsions. He, Q. and Z. Zhang (1998). "[Determination of valaciclovir polybutylcyanoacrylate nanoparticles]." Hua Xi Yi Ke Da Xue Xue Bao 29(3): 272-4. The valaciclovir content of polybutylcyanoacrylate nanoparticles was determined by HPLC after dissolving the valaciclovir-poly butylcyanoacrylate nanoparticles in a solvent mixture. ODS-C18 column was used. The mobile phase consisted of CH3OH-0.02 mol/L KH2PO4 (20:80). The linear range was 2.02-20.20 micrograms/ml; the recovery 97.30%, and RSD 4.90%. This method is accurate and can be used for determining the contents of other nanoparticles. He, L. and X. Jiang (2000). "Study on the distribution of aclarubicin A poly lactide nanoparticle lyophilization in mice." Zhongguo Kangshengsu Zazhi 25(3): 214-217. Objective: Comparing the distribution of aclarubicin A lyophilization and aclarubicin A poly lactide nanoparticle (ACRB-A-PLA-NP) lyophilization in mice. Method: HPLC is selected to determine the concentration of aclarubicin A in plasma and in main organisms. Results: The concentratin of ACRB-A-PLA-NP in liver is higher than that of the reference. Conclusion: ACRB-A can be significantly concentrated in liver after prepared in nanoparticle. He, H., J. Zhou, et al. (2000). "Simulation of I-V property of Au nanoparticle self-assembly system using finite well potential." Chinese Journal of Quantum Electronics 17(6): 562-7. The hopping rates of electrons in a nanoparticle self-assembly system are computed using a transfer Hamiltonian based on the finite well potential model of quantum dots. Then the relation between tunneling current and bias voltage is obtained by the solution of the master equation of electron hopping. (16 References). He, H. X., H. Zhang, et al. (2000). "Fabrication of designed architectures of Au nanoparticles on solid substrate with printed self-assembled monolayers as templates." Langmuir 16(8): 3846-51. This paper provides a convenient method for fabricating architectures of Au nanoparticles on solid substrate, with precise position and density control. Our strategy is to modify Au substrate with self-assembled monolayers (SAMs) terminated with different functional groups. They were chosen to be -CH/sub 3//-NH/sub 2/ or -CH/sub 3//SH according to their affinities to Au nanoparticle. Au nanoparticles assemble selectively on -NH/sub 2/ or -SH terminated locations, the -NH/sub 2/ functional group binding electrostatically to the nanoparticles whereas the SH groups bonding chemically. (38 References). He, H., J. Zhou, et al. (2000). "The numerical simulation of Au nanoparticle self-assembly systems." Dianzi Qijian/Journal of Electron Devices 23(1): 7-12. In this letter, the current-voltage characterization of standard tunneling junctions which form room temperature single electron devices is computed by solution of the Schrodinger equation using the WKB method. The currentvoltage characterization of Au nanoparticle self-assembly systems at room temperature is simulated numerically. We find the numerical results are in good agreement with the experimental results. The numerical method has important meaning for the experiments and for realization of nanoscale devices. (9 References). Heiati, H., N. C. Phillips, et al. (1996). "Evidence for phospholipid bilayer formation in solid lipid nanoparticles formulated with phospholipid and triglyceride." Pharmacetical Research 13(9): 1406-10. PURPOSE: Solid lipid nanoparticles (SLN) are comprised of a high-melting point triglyceride (TG) core with a phospholipid (PL) coating. This study has investigated the possible formation of multiple PL bilayers on the TG

core of SLN's as a function of increasing the PL:TG molar ratio. METHODS: Trilaurin (TL) was used as the SLN core. Dipalmitoylphos-phatdylcholine (DPPC) or a mixture of DPPC and dimyristoylphosphatidylglycerol (DMPG) were used to produce neutral and negatively charged SLN's. The volume of aqueous phase associated with the PL was determined using calcein and 6-carboxyfluorescein (6-CF) as hydrophilic markers incorporated during the preparation of the SLN's. RESULTS: The diameter of the SLN's decreased as the molar ratio of PL to TL was increased, until a PL:TL ratio of 0.15 was reached. After this point the diameter was not affected by further increases in the molar ratio. The experimental amount of PL required to prepare SLN's was significantly higher than the theoretical amount required to form a single monolayer on the surface. The aqueous volume associated with the PL was increased with increasing PL:TL molar ratios. CONCLUSIONS: The results obtained suggest that the formation of multiple PL bilayers is probable in SLN's prepared with a high molar ratio of PL to TL. The volume of the aqueous phase between the PL-bilayers, estimated from the amount of the hydrosoluble markers trapped in this phase, provides an indication of the relative number of bilayers at different PL:TL ratios. Heiati, H., R. Tawashi, et al. (1998). "Drug retention and stability of solid lipid nanoparticles containing azidothymidine palmitate after autoclaving, storage and lyophilization." Journal of Microencapsulation 15(2): 173-84. Solid lipid nanoparticles (SLNs) were prepared using trilaurine (TL) as the SLN core and phospholipid (PL) as coating. Neutral and negatively charged PLs were used to produce neutral and negatively charged SLNs. An ester prodrug of 3'-azido-3'-deoxythymidine (Zidovudine, AZT), AZT palmitate (AZT-P), was synthesized and incorporated in the SLNs. The stability of SLN formulations containing AZT-P was studied at different temperatures. Drug retention and mean particle diameter of SLNs were determined after autoclaving, during temperature stability testing, and after lyophilization (with or without cryoprotective sugars) and reconstitution. There were no significant changes in the mean diameter and the zeta potential (zeta) of SLNs after autoclaving (121 degrees C for 20 min). The amount of incorporated AZT-P was, however, slightly reduced due to the formation of hydrosoluble AZT. Autoclaved SLNs were stable for a period of 10 weeks at 20 degrees C but an increase in particle size and loss of AZT-P were observed at 4 and 37 degrees C. Trehalose was an effective cryoprotectant for preventing SLN aggregation during lyophilization and subsequent reconstitution. Thermal gravimetric analysis showed that lyophilized preparations contained approximately 1% water. Using appropriate trehalose to lipid ratios, AZT-P retention in the SLNs was 100% after reconstitution. Our results demonstrate that SLNs containing AZT-P can be autoclaved, lyophilized and reconstituted without significant changes in SLN diameter and zeta potential or in the quantity of incorporated prodrug. Hellmig, R. J., J. F. Castagnet, et al. (2000). "Properties of alumina-zirconia nanocomposites." Materials Science Forum 343(346): 482-7. Alumina-zirconia nanopowder mixtures of different composition were produced by laser ablation from micropowder pellets followed by condensation of the induced vapour in a controlled aggregation gas. The employed laser was a pulsed 1000 W Nd:YAG-laser. The median particle diameter of the produced nanopowder was about 13 nm. Nanopowders of different composition were consolidated and sintered under various temperature conditions. The sintered composites were investigated regarding density and hardness. In order to investigate the coarsening of the nanostructure, the grain sizes of the composites were determined by scanning electron microscopy. (7 References). Helveg, S., J. V. Lauritsen, et al. (2000). "Atomic-scale structure of single-layer MoS2 nanoclusters." Physical Review Letters 84(5): 951-4. We have studied using scanning tunneling microscopy (STM) the atomic-scale realm of molybdenum disulfide ( MoS2) nanoclusters, which are of interest as a model system in hydrodesulfurization catalysis. The STM gives the first real space images of the shape and edge structure of single-layer MoS2 nanoparticles synthesized on Au(111), and establishes a new picture of the active edge sites of the nanoclusters. The results demonstrate a way to get detailed atomic-scale information on catalysts in general. Hinz, M., S. Gura, et al. (2001). "Polymer support for exonucleolytic sequencing." Journal of Biotechnology 86(3): 281-8. Different kinds of particles were investigated for their potential use as supports for exonucleolytic sequence analysis. Composite beads composed of an unreactive polystyrene "core" and a "shell" of functionalized silica nanoparticles were found to best fulfill the various prerequisites. The biotin/streptavidin system was used for attachment of DNA to composite beads of 6 microm diameter. Applying M13 ssDNA in extremely high dilution (approximately 1 molecule versus 100 beads) with internal fluorescent labels, only a small fraction of beads was found to be associated with fluorescent entities, which likely correspond to a very small number of bound DNA molecules per particle. For better selection and transfer of DNA-containing beads into microstructures for exonuclease degradation the loading experiments were repeated with composite beads of 2.3 microm diameter. In this case a covalent bond was formed between carboxylate-functionalized beads and amino-terminated oligonucleotides, which were detected through external labelling with fluorescent nanoparticles interacting with biotinylated segments of the complementary strand.

Hirai, T., H. Okubo, et al. (2001). "Incorporation of CdS nanoparticles formed in reverse micelles into mesoporous silica." Journal of Colloid and Interface Science 235(2): 358-364. The incorporation of CdS nanoparticles, prepared in reverse micellar systems, into thiol-modified mesoporous silica, such as FM41 (functionalized MCM-41) and FM48 (functionalized MCM-48), has been investigated. The nanoparticles were immobilized in the mesopores via the incorporation of water droplets of the reverse micelles. A particle-sieving effect for FM41 having large (L-FM41, 3.8 nm) and medium (M-FM41, 3.6 nm) pore size was observed, in that the incorporation of the CdS nanoparticles was decreased with increasing particle size and with decreasing pore size of the FM41. Chemical vapor deposition treatment employed to narrow the mesopores of the CdS-FM41 enhanced the stability of CdS nanoparticles against heat treatment. The CdS-FM41 composites demonstrated photocatalytic activity for H(2) generation from 2-propanol aqueous solution, the better photocatalytic activity being obtained with the larger pore size for CdS-L-FM41. Copyright 2001 Academic Press. Ho, P. K., D. S. Thomas, et al. (1999). "All-polymer optoelectronic devices." Science 285(5425): 233-6. Composites of nanoparticles and conjugated polymers that exhibit composition-tunable optical constants have been developed for use in semiconducting photonic structures. For example, the 550-nanometer wavelength inplane refractive index of poly(p-phenylenevinylene)-silica composites can be tailored over the range of 1.6 to 2.7, allowing efficient distributed Bragg reflectors and waveguides to be fabricated. Low levels of chemical doping improve electrical conductivity through these structures without detriment to their photonic properties. Exemplifying these concepts, all-polymer microcavities and microcavity light-emitting diodes were demonstrated. Appropriate confinement of photons and electron-hole pairs in these organic semiconductor-based structures can be achieved. Hoffmann, F., J. Cinatl, et al. (1997). "Preparation, characterization and cytotoxicity of methylmethacrylate copolymer nanoparticles with a permanent positive surface charge." International Journal of Pharmacy 157(2): 189-198. Methylmethacrylate copolymer nanoparticles containing different cationic comonomers such as Ntrimethylammoniumethylmethacrylate (TMAEMC), N-dimethylammoniumethylmethacrylate (DMAEMC), Ntrimethylammoniumpropylmethylacrylamide (MAPTAC) or the anionic comonomer sulfopropylmethacrylate (SPM), respectively, were prepared by free radical polymerization. Particle size was determined by photon correlation spectroscopy (PCS), transmission and scanning electron microscopy (TEM, SEM), and surface charge by microelectrophoresis. Pure poly(methylmethacrylate) nanoparticles served as control. Depending on the method, mean diameters of permanently positively-charged nanoparticles MMA-TMAEMC and MMA-MAPTAC were 243 or 207 nm (PCS), 161 or 201 nm (TEM), and 158 or 197 nm (SEM), respectively. Zeta potential examined in demineralized water or NaCl solution was +63.4 or +32.1 mV for MMA-TMAEMC nanoparticles and +49.2 or +32.0 mV for MMA-MAPTAC nanoparticles, respectively. Cytotoxicity of nanoparticles was determined by MTT assay in three different cell cultures including human foreskin fibroblasts (HFF) and two monkey kidney cell lines MA-104 and Vero. Cell viability profiles of TMAEMC and MAPTAC containing nanoparticles were different, showing IC(50) values for MMA-TMAEMC nanoparticles of 189.6+/-11.4 ?g/ml (MA-104), 110.9+/-3.1 ?g/ml (Vero) and 27.2+/-4.0 ?g/ml (HFF). Cell viability at maximum concentration of 500 ?g/ml MMA-MAPTAC nanoparticles was 98.3% (Vero), 85.7% (MA-104), or 94.0% (HFF), respectively. Hogemann, D., L. Josephson, et al. (2000). "Improvement of MRI probes to allow efficient detection of gene expression." Bioconjugate Chemistry 11(6): 941-946. Recently, it has been demonstrated that magnetic resonance imaging (MRI) utilizing monocrystalline iron oxide nanoparticles (MIONs) targeted to an engineered transferrin receptor enables imaging of gene expression. However, the relatively high doses of iron oxides used indicated the need for improved MR imaging probes to monitor changes in gene expression in vivo. Using alternative conjugation chemistries to link targeting ligands and iron oxide nanoparticles, we present the development and characterization as well as improved receptor binding and MRI detection of a novel imaging probe. Iron oxide nanoparticles with a cross-linked dextran coat were conjugated to transferrin (Tf) through the linker molecule N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) to yield Tf-S-S-CLIO. The characteristics of this conjugate were evaluated in comparison to Tf-MION and Tf-CLIO generated by oxidative activation of the dextran-coat with subsequent reduction of Schiff's base. SPDP conjugation allowed approximately a 4-fold increase in the number of Tf molecules attached per iron oxide nanoparticle and resulted in a more than 10-fold improvement of binding and uptake by cells. This translated into an imaging probe that was 16 times better for imaging gene expression in a cellular MRI assay. This novel probe for MRI may substantially increase the sensitivity for the detection of endogenous or genetically induced transferrin receptor expression in small numbers of cells and may significantly reduce the imaging dose from over 100 mg/kg to doses of iron oxides that are currently used in clinical imaging. Honda, S., F. A. Modine, et al. (2000). "The formation of high-coercivity, oriented, nanophase cobalt precipitates in Al 2O 3 single crystals by ion implantation." Nanophase and Nanocomposite Materials III. Symposium 581: 71-6. Ion-implantation and thermal-processing methods have been used to form nanophase magnetic precipitates of metallic cobalt that are embedded in the near-surface region of single crystals of Al/sub 2/O/sub 3/. The Co

precipitates are isolated, single-crystal particles that are crystallographically oriented with respect to the host Al/sub 2/O3 lattice. Embedded nanophase Co precipitates were formed by the implantation of Co/sup +/ at an energy of 140 keV and a dose of 8 x 10/sup 16/ ions/cm/sup 2/ followed by annealing in a reducing atmosphere. The implanted/annealed Co depth profile, particle size distributions and shapes, and the orientational relationship between the nanophase precipitates and the host crystal lattice were determined using RBS/channeling, transmission electron microscopy, and X-ray diffraction. Magneto-optical effects arising from Co precipitates formed in the near-surface region of Al/sub 2/O/sub 3/ were observed and characterized using magnetic circular dichroism. Magnetic properties of the Co-particle/host nanocomposites were investigated in the temperature range of 77 to 295 K in applied fields of up to 10 kG using a superconducting quantum interference device (SQUID) magnetometer. Implantation of the Co particles by Pt or Xe ions produced a large anisotropic increase in their coercivity. Accordingly, these magnetic nanoparticle systems may be of interest for magnetic data storage applications. Details of the magnetic properties of the Co/Al/sub 2/O/sub 3/ nanocomposites including their retentivity, coercivity, saturation field, and magnetic anisotropy are presented. (6 References). Howard, K. A., P. R. Dash, et al. (2000). "Influence of hydrophilicity of cationic polymers on the biophysical properties of polyelectrolyte complexes formed by self-assembly with DNA." Biochimica et Biophysica Acta 1475(3): 245-55. To investigate the possibility of producing charge-neutral gene delivery complexes with extended, non-particulate structures, DNA was allowed to self-assemble with a series of hydrophilic cationic polymers containing quaternary charged trimethylammonio ethylmethacrylate (TMAEM, 5, 15, 50, 100 mol%) copolymerised with hydrophilic N-(2hydroxypropyl)methacrylamide (HPMA, 95, 85, 50, 0 mol%, respectively). Copolymers were all able to bind DNA, assessed using ethidium bromide fluorescence, although copolymers with low TMAEM content did not expel ethidium bromide. Increasing TMAEM content of the copolymers changed the morphology of the complexes from extended (5-15 mol% TMAEM), through partially condensed particles (50 mol%) to discrete nanoparticles (100 mol% TMAEM). Complexes based on copolymers with low TMAEM content (5-50 mol%) showed less resistance to degradation by nucleases and lower surface charge (21.2+/-5.9-45.1+/-3.9 mV) than those formed using 100 mol% TMAEM (57.8+/-8.2 mV). They also showed significantly less association with phagocytic cells in vitro (human leucocytes, uptake decreased by up to 92.3%; murine peritoneal macrophages, uptake decreased by up to 69.6%), although in vivo their hepatic accumulation was only slightly decreased (maximum decrease 27.6%). Finding the appropriate balance of hydrophilicity and stability is key to development of effective vectors for gene delivery. Hrkach, J. S., M. T. Peracchia, et al. (1997). "Nanotechnology for biomaterials engineering: structural characterization of amphiphilic polymeric nanoparticles by 1H NMR spectroscopy." Biomaterials 18(1): 27-30. Nanoparticles composed of diblock poly(D,L-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) or a branched, multiblock PLA-(PEG)3 were prepared by the single emulsion technique. Results of previous studies of these nanoparticles suggested that their structure is of the core-corona type with a polyester core and an outer PEG coating. In the present study, 1H NMR spectroscopy was utilized to provide direct evidence of the structure of these nanoparticles suspended in an aqueous environment. The results confirm the existence of the corecorona structure under these conditions, and show that the PEG moieties extend out from the nanoparticle core into the aqueous environment, and exhibit chain mobility similar to that of PEG in solution. Hu, Z., X. Lu, et al. (2000). "Polymer gel nanoparticle networks." Advanced Materials 12(16): 1173-6. A new class of nanostructured polymer gel is reported here, in which polymer nanoparticles, rather than monomers, are covalently crosslinked. Since their building blocks are nanoparticles, the thus formed networks have novel and unique properties compared with conventional gels, for example, a very high surface area for better bioadhesion, and a uniform and tunable mesh size for controlled drug delivery. Several networks are presented, including one with a fast shrinkage rate, a colored network, and a co-nanoparticle network as a potential multifunctional drug delivery carrier. (22 References). Huang, S., G. Tsutsui, et al. (2000). "A large-scaled 2D array of alkanethiol-encapsulated gold particles fabricated using Langmuir-Blodgett technique." Digest of Papers Microprocesses and Nanotechnology(00EX387): 180-1. Assembly of metal nano-particles in ordered two-dimensional (2D) or three-dimensional (3D) arrays is believed capable of providing new materials not only for electronic engineering but also for basic studies, therefor has attracted a lot of research attention. In our previous work, an approach to fabrication of 2D array of alkanethiolencapsulated gold particles was developed utilizing a self-organized process. However it is hard to fabricate a large-scaled perfect monolayer and well-controlled multilayer structures using this method. For this reason, in the present work, Langmuir-Blodgett (LB) technique was used to fabricate a large-scaled monolayer of nanoscaled gold particles. Comparing to other reports about LB films of gold particles, we got a much larger, higher-ordered 2D nanostructure. (4 References). Huber, C. G., A. Premstaller, et al. (1999). "Evaluation of volatile eluents and electrolytes for high-performance liquid chromatography-electrospray ionization mass spectrometry and capillary electrophoresis-electrospray ionization mass

spectrometry of proteins. II. Capillary electrophoresis." Journal of Chromatography A 849(1): 175-89. Peptides and proteins were separated by capillary electrophoresis (CE) in fused-silica capillaries coated with an irreversibly adsorbed monolayer of derivatized polystyrene nanoparticles. Whereas phosphate buffer, pH 3.10, enabled the highly efficient separation of basic proteins with plate counts up to 1,400,000 m-1, volatile buffer components such as formic acid or acetic acid titrated with ammonia to the desired pH had to be used for the direct coupling of CE with electrospray ionization mass spectrometry (ESI-MS). Compared to 40 mM phosphoric acid-sodium hydroxide, pH 3.10, a background electrolyte containing 125 mM formic acid-ammonia, pH 4.00, was shown to yield equivalent separation efficiency. Investigation of the influence of buffered electrolytes on the ESIMS signal of lysozyme at pH 2.70-4.00 showed that the charge state distribution shifted to lower charge states at higher pH with a concomitant five-fold decrease in signal intensity of the most abundant signal. The presence of trifluoroacetic acid in the background electrolyte greatly increased the level of baseline noise and completely inhibited the observation of any mass signals related to proteins. Full scan spectra could be acquired from 50-500 fmol amounts of proteins during coupled CE-ESI-MS utilizing 100-125 mM formic acid-ammonia, pH 3.10. However, compared to UV detection, considerable band broadening is observed with ESI-MS detection which is mainly attributed to column overloading, band spreading in the interface, and scanning data acquisition. Finally, the major whey proteins beta-lactoglobulin A, beta-lactoglobulin B, and alpha-lactalbumin were identified in a whey drink by comparison of molecular masses determined by CE-ESI-MS to molecular masses calculated from the amino acid sequence. Huisken, F., B. Kohn, et al. (1999). "Silicon carbide nanoparticles produced by CO2 laser pyrolysis of SiH4/C2H2 gas mixtures in a flow reactor." Journal of Nanoparticle Research 1: 293-303. Huisken, F., H. Hofmeister, et al. (2000). "Laser production and deposition of light-emitting silicon nanoparticles." Applied Surface Science 154(155): 305-13. Silicon clusters and nanoparticles are produced by CO/sub 2/-laser-induced decomposition of silane in a flow reactor. In contrast to conventional techniques, the particles are expanded, directly after production, through a conical nozzle into a high vacuum chamber and then transferred into a molecular beam apparatus where they are analyzed in situ by time-of-flight mass spectrometry (TOF-MS). The analysis reveals that the flow reactor emits, besides small clusters, also high-purity silicon crystallites with diameters between 2 and 20 nm. It is found that the particles' velocity strongly correlates with their mass. This feature and the fact that the particles are produced in the pulsed mode enable us, by introducing a chopper into the cluster beam, to considerably reduce the dispersion of their size distribution and to perform size-selected low-energy cluster deposition on various substrates. Highresolution transmission electron micrographs demonstrate the capabilities of the new apparatus and reveal interesting details of the crystalline structure of silicon nanoparticles as a function of their size. The monodispersed silicon films have been further characterized by studying their luminescence and Raman scattering behavior. As predicted by theoretical models, the peak of the luminescence curve shifts with decreasing particle size to smaller wavelengths (higher energies). Structured thin films are obtained by shaping the cluster beam with a mask and depositing the nanocrystals at low energy on a sapphire substrate. Upon illumination with ultraviolet radiation, the structured film exhibits strong photoluminescence (PL) in the red. (18 References). Hultaker, A. and G. A. Niklasson (2000). "Dielectric characterization of thin films consisting of tin doped indium oxide nanoparticles." Nanophase and Nanocomposite Materials III. Symposium 581: 491-6. In recent years there has been a growing interest in cheap and easy production techniques for transparent conducting thin films. One way of making these uses a nanoparticle dispersion. We prepared thin films of tin doped indium oxide by spin-coating of a solution of nanoparticles. The sintering behavior of these ceramic particles was studied by dielectric spectroscopy and by grazing incidence X-ray diffraction. The grain growth was found to start at 1000 degrees C and to be prominent at 1250 degrees C. However, the electrical conductivity reached a maximum below these temperatures. (17 References). Hung, A. F. Marshall, et al. (1999). "Strain directed assembly of nanoparticle arrays within a semiconductor." Journal of Nanoparticle Research 1: 329-347. Hussain, N., P. U. Jani, et al. (1997). "Enhanced oral uptake of tomato lectin-conjugated nanoparticles in the rat." Pharmacetical Research 14(5): 613-8. PURPOSE: To investigate the usefulness of a surface-conjugated, bioadhesive molecule, tomato lectin, to augment intestinal uptake of orally administered inert nanoparticles. METHODS: Fluorescent 500 nm polystyrene nanoparticles with tomato lectin covalently surface coupled using a carbodiimide reaction were administered to female Wistar rats by oral gavage daily for 5 days. RESULTS: Analysis of tissue extracted polymer by gel permeation chromatography revealed a 23% systemic uptake of tomato lectin conjugated nanoparticles compared to &lt; 0.5% of TL nanoparticles blocked with N-acetylchitotetraose thus representing an increase of almost 50 fold across the intestine. Intestinal uptake of tomato lectin-conjugated nanoparticles via the villous tissue was 15

times higher than uptake by the gut-associated lymphoid tissue. CONCLUSIONS: The application of tomato lectin as a bioadhesive agent in vivo has been demonstrated to enhance subsequent intestinal transcytosis of colloidal particulates to which it is bound. Hussain, N. and A. T. Florence (1998). "Utilizing bacterial mechanisms of epithelial cell entry: invasin-induced oral uptake of latex nanoparticles." Pharmacetical Research 15(1): 153-6. Hussain, N. (2001). "Fluorometric method for the simultaneous quantitation of differently-sized nanoparticles in rodent tissue." International Journal of Pharmacology 214(1-2): 55-61. The oral absorption and systemic translocation of particulate matter via the gastrointestinal tract has been shown by a number of laboratories using a wide variety of particles in different animal species. While there is debate on the magnitude of particle intestinal translocation, which is encumbered by the differing experimental protocols, particularly the method of quantitation of absorbed material, few have sought to examine the pharmacokinetic aspects of particle absorption. We describe in this communication the development of a simple and a rapid fluorometric assay of quantifying tissue-laden fluorescent nanoparticles that is able to isolate, detect and quantify the presence of two or more particle populations differing both in their size and fluorescent label. Six types of polystyrene nanoparticles incorporating different fluorescent markers were spiked in whole livers. The fluorophores were extracted using our previously developed method of freeze-drying the tissue and using chloroform as the extractive solvent. Only two types of particle populations, orange-labelled 40 nm and Fluoroscein-emitting 500 nm nanoparticles, were sufficiently recoverable and provided a high signal-to-noise ratio for further work. The amount of tissue and type of biological tissue type also impacted on the nanoparticle recovery and detection, reflecting, perhaps, the quenching effects of interacting tissue-derived molecules. In addition, the results also indicate that the use of nanoparticles incorporating fluorescent dyes that have emission over 500 nm overcome the tissue interfering autofluorescence for low doses of nanoparticles. The use of this fluorometric method has several advantages compared with other modes of quantitation in that it is rapid, nonradioactive and the marker is non-leaching. More importantly, it allows the simultaneous detection of multiple fluorophores such that two or more different fluorescent particle populations can be detected in the same sample. This may enable the uncharted area of pharmacokinetic parameters, such as the impedance, augmentation or site of gut uptake of differently sized particles to be studied. Iijima, S. and T. Ichihashi (1986). "Structural instability of ultrafine particles of metals." Physical Review Letters 56(6): 616619. Illum, L., P. D. Jones, et al. (1984). "Tissue distribution of poly(hexyl 2-cyanoacrylate) nanoparticles coated with monoclonal antibodies in mice bearing human tumor xenografts." Journal of Pharmacology and Experimental Therapeutics 230(3): 733-6. The tissue distribution of naked and either normal immunoglobulin G or monoclonal antibody (antitumor osteogenic sarcoma)-coated poly(hexyl-2-cyanoacrylate) nanoparticles was studied in mice bearing human tumor xenografts to evaluate the applicability of the systems for tumor targeting. All systems were shown to deposit mainly in the liver and spleen and no significant uptake was found in the tumors for either the naked or antibodycoated nanoparticles. Inouye, H., K. Tanaka, et al. (2000). "Ultrafast optical switching in a silver nanoparticle system." Japanese Journal of Applied Physics Part 39(9A): 5132-3. An ultrafast response of a silver nanoparticle system, as fast as 360 fs, was observed in a femtosecond opticalKerr-shutter experiment. The ultrafast response is attributed to a self-diffraction of a pump pulse due to transient grating. We estimated chi /sup (3)/ of the silver nanoparticle system to be 1.5*10/sup -7/ esu in the femtosecond region. (11 References). Irache, J. M., C. Durrer, et al. (1994). "Preparation and characterization of lectin-latex conjugates for specific bioadhesion." Biomaterials 15(11): 899-904. This paper reports on the preparation and characterization of certain bioadhesive model drug deliver systems formed by a carrier (e.g. modified nanoparticles of polystyrene) and a ligand (e.g. tomato lectin, asparagus pea lectin, Mycoplasma gallisepticum lectin or albumin). Three different manufacturing methods (carbodiimide and glutaraldehyde coupling and physical adsorption) were studied. The activity of the lectin-latex conjugates and albumin-latex conjugate (control) were tested with gastric pig mucin. The manufacturing method had an insignificant effect on the activity, but all lectin-latex conjugates interacted two or three times more with mucin than with the control. Ishizaka, S. and K. Nakamura (2000). "Propagation of solitons of the magnetization in magnetic nanoparticle arrays." Journal of Magnetism and Magnetic Materials 210: 1-3. It is clarified for the first time that solitons originating from the dipolar interaction in ferromagnetic nanoparticle

arrays are stably created. The characteristics can be well controlled by the strength of the dipolar interaction between particles and the shape anisotropy of the particle. The soliton can propagate from a particle to a neighbor particle at a clock frequency even faster than 100 GHz using materials with a large magnetization. Such arrays of nanoparticles might be feasible in an application such as a signal transmission line. (11 References). Iwamoto, Y., K. I. Kikuta, et al. (2000). "Synthesis of poly-titanosilazanes and conversion into Si 3N 4-TiN ceramics." Nippon Seramikkusu Kyokai Gakujutsu Ronbunshi Journal of the Ceramic Society of Japan 108(4): 350-6. Poly-titanosilazanes were synthesized by chemical modification of commercially available perhydropolysilazane (PHPS) with TiX/sub 4/X=N(CH/sub 3/)/sub 2/, OCH(CH/sub 3/)/sub 2/ and the synthesized polymeric precursors were found to contain some N-Ti bonds by chemical structure analyses using IR and /sup 1/H NMR techniques. The poly-titanosilazane derived from PHPS and Ti(N(CH/sub 3/)/sub 2/)/sub 4/ yielded Si/sub 3/N/sub 4/-TiN ceramics by pyrolysis at 1000 degrees C in NH/sub 3/, followed by heat treatment at 1800 degrees C in N/sub 2/. TiN was observed as particles with diameter of smaller than 100 nm; the poly-titanosilazane was found to be suitable for the synthesis of TiN nanoparticle-dispersed. (31 References). Jamet, M., W. Wernsdorfer, et al. (2001). "Magnetic anisotropy of a single cobalt nanocluster." Physical Review Letters 86(20): 4676-9. Using a new micro-SQUID setup, we investigate magnetic anisotropy in a single 1000-atom cobalt cluster. This system opens new fields in the characterization and understanding of the origin of magnetic anisotropy in such nanoparticles. For this purpose, we report three-dimensional switching field measurements performed on a 3 nm cobalt cluster embedded in a niobium matrix. We are able to separate the different magnetic anisotropy contributions and evidence the dominating role of the cluster surface. Janes, D. B., M. Batistuta, et al. (2000). "Swelling and shrinking of poly(N-isopropylacrylamide) chains adsorbed on the surface of polystyrene nanoparticles." Journal of Macromolecular Science Physics(3): 407-14. As a thermally sensitive polymer, poly(N-isopropylacrylamide) (PNIPAM) is hydrophilic at temperatures below its lower critical solution temperature (LCST, ~32 degrees C), but undergoes a coil-to-globule transition in water at higher temperatures. The adsorption of PNIPAM on polystyrene (PS) nanoparticles resulted in a core-shell nanostructure. In the first heating-and-cooling cycle there existed a hysteresis in terms of the thickness of the adsorbed PNIPAM layer; this could be attributed to additional binding of the adsorbed PNIPAM chains to the surface. Moreover, the surface shifted the coil-to-globule transition to a lower temperature and made the transition less sharp. The temperature dependence of the ratio of the radius of gyration to the hydrodynamic radius (<R/sub g/>/<R/sub h/>) revealed that the PNIPAM shell is highly swollen, and the density of the shell in the collapsed state approached that of the PS core. (16 References). Janes, K. A., P. Calvo, et al. (2001). "Polysaccharide colloidal particles as delivery systems for macromolecules." Advances in Drug Delivery Review 47(1): 83-97. Mucosal delivery of complex molecules such as peptides, proteins, oligonucleotides, and plasmids is one of the most intensively studied subjects. The use of colloidal carriers made of hydrophilic polysaccharides, i.e. chitosan, has arisen as a promising alternative for improving the transport of such macromolecules across biological surfaces. This article reviews the approaches which have aimed to associate macromolecules to chitosan in the form of colloidal structures and analyzes the evidence of their efficacy in improving the transport of the associated molecule through mucosae and epithelia. Chitosan has been shown to form colloidal particles and entrap macromolecules through a number of mechanisms, including ionic crosslinking, desolvation, or ionic complexation, though some of these systems have been realized only in conjunction with DNA molecules. An alternative involving the chemical modification of chitosan has also been useful for the association of macromolecules to self-assemblies and vesicles. To date, the in vivo efficacy of these chitosan-based colloidal carriers has been reported for two different applications: while DNA-chitosan hybrid nanospheres were found to be acceptable transfection carriers, ionically crosslinked chitosan nanoparticles appeared to be efficient vehicles for the transport of peptides across the nasal mucosa. The potential applications and future prospects of these new systems for mucosal delivery of macromolecules are highlighted at the end of the chapter. Janzen, C., P. Roth, et al. (1999). "Characteristics of Fe2O3 nanoparticles from doped low-pressure H2/O2/Ar flames." Journal of Nanoparticle Research 1: 163-167. Jaulin, N., M. Appel, et al. (2000). "Reduction of the uptake by a macrophagic cell line of nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate)." Journal of Drug Targeting 8(3): 165-72. Amphiphilic and fluorescent covalently labelled core-shell nanoparticles based on poly(methyl methacrylate) (PMMA), were prepared by random copolymerisation of N-Vinyl carbazole (NVC) with MMA, initiated on polysaccharidic radicals, yielding diblock copolymers of either dextran-P(MMA-NVC) (Nanodex* particles), or heparin-P(MMA-NVC) (Nanohep* particles). Nanoparticles made from random copolymers of P(MMA-NVC) (PMMA*) were used as controls. The interactions between particles and a J774A1 murine macrophage-like cell

line were quantified by direct measurement of the cell-associated fluorescence. The association with the cells occurred within 30 min. Nanodex* and Nanohep* showed considerably less association than the control PMMA* particles. Some of the particle uptake could be attributed to phagocytosis, but more than 50% of the cellassociated fluorescence persisted at low temperature or in the presence of cytochalasin B. The results suggest that both the adsorption and the internalisation processes can be inhibited by the presence of the polysaccharide chains. In conclusion, these results confirm that nanoparticles prepared with heparin or dextran chains on their surface, probably in a brush-like configuration, show &quot;stealth&quot; properties in vitro as had previously been observed in vivo. If this biomimetic approach can also be applied to biodegradable polymers, these systems would provide at least an alternative to PEG-modified particles as long-circulating drug carriers systems or imaging agents. Jenning, V., A. F. Thunemann, et al. (2000). "Characterisation of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids." International Journal of Pharmaceutics 199(2): 167-77. A drug carrier of colloidal lipid particles with improved payloads and enhanced storage stability was investigated. Based on the experiences with hard fats nanoparticles, a new type of solid lipid nanoparticles (SLN) has been developed by incorporating triglyceride containing oils in the solid core of said particle. The structure and mixing behaviour of these particles were characterised and practical implications on controlled release properties tested. Nanoparticles were characterised by their melting and recrystallisation behaviour as recorded by differential scanning calorimetry (DSC). Polymorphic form and bilayer arrangement were assigned by wide-angle X-ray scattering (WAXS) and small-angle X-ray scattering (SAXS). Size distribution and storage stability were investigated by laser diffractometry (LD). Release properties were studied by drug release model according to Franz. A medium chain triglyceride oil was incorporated successfully in a matrix of a solid long chain glyceride. The crystal order was greatly disturbed, however, the carrier remained solid. The oil inside the particle remained in a liquid state and induced a slight shift form the beta' polymorph to the beta(i) form. Long spacings varied within 0.1 nm with increasing oil loads. Nanoparticles with low oil concentrations showed sustained release properties. Improved drug load levels were encapsulated by lipid particles supplemented with oily constituents. Thus, the presented carrier adds additional benefits to the well-known opportunities of conventional SLN and is suited for topical use. Jenning, V., K. Maeder, et al. (2000). "Solid lipid nanoparticles (SLN ) based on binary mixtures of liquid and solid lipids: A 1H-NMR study." International Journal of Pharmaceutics 205(1-2): 15-21. SLN with improved payloads and enhanced storage stability were investigated. Based on the experiences with solid lipid nanoparticles, a new type of solid lipid nanoparticle has been developed by incorporating triglyceride containing oils in the solid shell of the particle. The structure and mixing behaviour of these particles was characterised by DSC and 1H-NMR. DSC yields information on the melting and crystallisation behaviour of the solid and liquid constituents of the particles. NMR is especially suited for the characterisation of the liquid oil domains inside the SLN. In this study a medium chain triglyceride oil was successfully incorporated in a matrix of a solid long chain glyceride (glyceryl behenate). The resulting particles were solid but the oil inside the particle remained in a liquid state. The relation between oil supplementation and melting point depression of glyceryl behenate proved to be linear. Mobility of the oil molecules inside the particles was considerably reduced compared to the emulsified oil. Moreover, two different chemical shifts for each of the lipid signals were observed indicating two different chemical environments. The experimental data is in line with a model describing uniform distribution of the oil molecules in the glyceryl behenate for low oil loads. However, at higher oil loads our data indicate the formation of oil clusters within the solid nanoparticle. Jenning, V., M. Schaefer-Korting, et al. (2000). "Vitamin A-loaded solid lipid nanoparticles for topical use: Drug release properties." Journal of Controlled Release 66(2-3): 115-126. Burst release as well as sustained release has been reported for SLN suspensions. For dermal application, both features are of interest. Burst release can be useful to improve the penetration of a drug. Sustained release becomes important with active ingredients that are irritating at high concentrations or to supply the skin over a prolonged period of time with a drug. Glyceryl behenate SLN were loaded with vitamin A and the release profiles were studied. Franz diffusion cells were used to assess the release kinetic over a period of 24 h. Within the first 6 h retinol SLN displayed controlled release. After longer periods (12-24 h) the release rate increased and even exceeded the release rate of comparable nanoemulsions. Pure SLN dispersions are characterised by low viscosity. In contrast to membranous vesicles, SLN can also be stably incorporated in convenient topical dosage forms like hydrogels or creams. In the Franz diffusion cell these preparations showed a controlled release over 12-18 h. Similar to SLN dispersions an increase in release rate over a 24-h period was found. A good correlation between polymorphic transitions and increased drug release was observed in this study. Sustained release was often related to the metastable beta' polymorph. Drug expulsion is explained by a reduction of amorphous regions in the carrier lattice due to a beta'fwdarwbetai polymorphic transition. This transformation can be controlled with surfactant mixtures or, in the case of the hydrogel and oil/water cream, with humectants or gelling agents. Thus, the release rate for the topical route of application is adjustable.
TM

Jenning, V. and S. Gohla (2000). "Comparison of wax and glyceride solid lipid nanoparticles (SLN )." International Journal of Pharmaceutics 196(2): 219-222. The present study compares solid lipid nanoparticles (SLN) formulated with either wax or glyceride bulk material. While most published data deal with glyceride SLN, little knowledge is reported on wax carriers. The two types were compared with respect to drug encapsulation efficacy, particle size distribution after production and storage, and crystal packing. The inclusion of retinol as a model drug was investigated. Retinol is chemically unstable in water and rather stable in lipid phases. Thus, rapid degradation of retinol indicates rapid drug expulsion from the carrier. Good stability indicates an effective drug encapsulation in the lipid phase of the nanoparticles. Particle size distribution was measured by laser diffractometry. Subcell packing and assignment of polymorphic forms was investigated by WAXS measurements. Glyceride SLN showed good drug encapsulation, while physical stability was poor. In contrast, wax SLN possessed good physical stability but lacked sufficient drug encapsulation in the solidified state. These differences were attributed in part to different crystal packing. Less ordered crystal lattices favour successful drug inclusion, as in the case of glyceryl monosterate and glyceryl behenate SLN. The highly ordered crystal packing of wax SLN comprised of beeswax or cetyl palmitate, for instance, leads to drug expulsion, but also to superior physical stability. Jenning, V., A. Gysler, et al. (2000). "Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin." European Journal of Pharmaceutics and Biopharmaceutics 49(3): 211-8. To evaluate the potential use of solid lipid nanoparticles (SLN) in dermatology and cosmetics, glyceryl behenate SLN loaded with vitamin A (retinol and retinyl palmitate) and incorporated in a hydrogel and o/w-cream were tested with respect to their influence on drug penetration into porcine skin. Conventional formulations served for comparison. Excised full thickness skin was mounted in Franz diffusion cells and the formulations were applied for 6 and 24 h, respectively. Vitamin A concentrations in the skin tissue suggested a certain drug localizing effect. High retinol concentrations were found in the upper skin layers following SLN preparations, whereas the deeper regions showed only very low vitamin A levels. Because of a polymorphic transition of the lipid carrier with subsequent drug expulsion following the application to the skin, the drug localizing action appears to be limited for 6-24 h. Best results were obtained with retinol SLN incorporated in the oil-in-water (o/w) cream retarding drug expulsion. The penetration of the occlusion sensitive drug retinyl palmitate was even more influenced by SLN incorporation. Transepidermal water loss (TEWL) and the influence of drug free SLN on retinyl palmitate uptake exclude pronounced occlusive effects. Therefore enhanced retinyl palmitate uptake should derive from specific SLN effects and is not due to non-specific occlusive properties. Jenning, V., M. Schafer-Korting, et al. (2000). "Vitamin A-loaded solid lipid nanoparticles for topical use: drug release properties." Journal of Controlled Release 66(2-3): 115-26. Burst release as well as sustained release has been reported for SLN suspensions. For dermal application, both features are of interest. Burst release can be useful to improve the penetration of a drug. Sustained release becomes important with active ingredients that are irritating at high concentrations or to supply the skin over a prolonged period of time with a drug. Glyceryl behenate SLN were loaded with vitamin A and the release profiles were studied. Franz diffusion cells were used to assess the release kinetic over a period of 24 h. Within the first 6 h retinol SLN displayed controlled release. After longer periods (12-24 h) the release rate increased and even exceeded the release rate of comparable nanoemulsions. Pure SLN dispersions are characterised by low viscosity. In contrast to membranous vesicles, SLN can also be stably incorporated in convenient topical dosage forms like hydrogels or creams. In the Franz diffusion cell these preparations showed a controlled release over 12-18 h. Similar to SLN dispersions an increase in release rate over a 24-h period was found. A good correlation between polymorphic transitions and increased drug release was observed in this study. Sustained release was often related to the metastable beta' polymorph. Drug expulsion is explained by a reduction of amorphous regions in the carrier lattice due to a beta'--&gt;beta(i) polymorphic transition. This transformation can be controlled with surfactant mixtures or, in the case of the hydrogel and oil/water cream, with humectants or gelling agents. Thus, the release rate for the topical route of application is adjustable. Jenning, V. and S. H. Gohla (2001). "Encapsulation of retinoids in solid lipid nanoparticles (SLN)." Journal of Microencapsulation 18(2): 149-58. SLN have been suggested for a broad range of applications, such as intravenous injection, peroral, or dermal administration. The incorporation of the drug in the core of the SLN has to be ensured for these applications, but the inclusion of drugs in SLN is poorly understood. This study is a contribution to further describe the inclusion properties of colloidal lipids and to propose incorporation mechanisms. Besides the well known methods to investigate entrapment of actives in nanoparticles such as DSC or microscopy, the present study focussed on yet a different approach. Based on the different chemical stability of retinoids in water and in a lipid phase, a method to derive information on the distribution of the drug between SLN-lipid and the water phase was established. Comparing different lipids, glyceryl behenate gave superior entrapment compared to tripalmitate, cetyl palmitate and solid paraffin. Comparing three different drugs, entrapment increased with decreasing polarity of the molecule

(tretinoin < retinol < retinyl palmitate). The encapsulation efficacy was successfully enhanced by formulating SLN from mixtures of liquid and solid lipids. These particles were solid and provided better protection of the sensitive drugs than an emulsion. X-ray investigations revealed that good encapsulation correlated with a low degree of crystallinity and lattice defects. With highly ordered crystals, as in the case of cetyl palmitate, drug expulsion from the carrier was more pronounced. Jensen, T. R., M. Duval Malinsky, et al. (2000). "Nanosphere lithography: tunable localized surface plasmon resonance spectra of silver nanoparticles." Journal of Physical Chemistry B 104(45): 10549-56. The wavelength corresponding to the extinction maximum, lambda /sub max/, of the localized surface plasmon resonance (LSPR) of silver nanoparticle arrays fabricated by nanosphere lithography (NSL) can be systematically tuned from ~400 nm to 6000 nm. Such spectral manipulation was achieved by using (1) precise lithographic control of nanoparticle size, height, and shape, and (2) dielectric encapsulation of the nanoparticles in SiO/sub x/. These results demonstrate an unprecedented level of wavelength agility in nanoparticle optical response throughout the visible, near-infrared, and mid-infrared regions of the electromagnetic spectrum. It will also be shown that this level of wavelength tunability is accompanied with the preservation of narrow LSPR bandwidths (fwhm), Gamma . Additionally, two other surprising LSPR optical properties were discovered: (1) the extinction maximum shifts by 2-6 nm per 1 nm variation in nanoparticle width or height, and (2) the LSPR oscillator strength is equivalent to that of atomic silver in gas or liquid phases. Furthermore, it will be shown that encapsulation of the nanoparticles in thin films of SiO/sub x/ causes the LSPR lambda /sub max/ to red shift by 4 nm per nm of SiO/sub x/ film thickness. The size, shape, and dielectric-dependent nanoparticle optical properties reported here are likely to have significant impact in several applications including but not limited to the following: surfaceenhanced spectroscopy, single-molecule spectroscopy, near-field optical microscopy, nanoscopic object manipulation, chemical/biological sensing, information processing, data storage, and energy transport in integrated optical devices. (72 References). Jeon, H. J., Y. I. Jeong, et al. (2000). "Effect of solvent on the preparation of surfactant-free poly(DL-lactide-co-glycolide) nanoparticles and norfloxacin release characteristics." International Journal of Pharmacy 207(1-2): 99-108. The surfactant-free nanoparticles of poly(DL-lactide-co-glycolide) (PLGA) were prepared by dialysis method without surfactant and physicochemical properties such as particle size and drug contents were investigated against used initial solvent. The size of PLGA nanoparticles and drug contents were significantly changed by used initial solvent. The size of PLGA nanoparticles prepared from dimethylacetamide (DMAc), dimethylformamide (DMF), and dimethylsulfoxide (DMSO) as a initial used solvent was smaller than that of acetone. Selected initial solvent used to dissolve the copolymer significantly affects the size of nanoparticles and drug contents. It was shown that PLGA nanoparticles have spherical shapes from the results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations. It was thought that surfactant-free nanoparticles of PLGA entrapping norfloxacin (NFX) has nice drug loading capacity without free-drug on the surface of nanoparticles through the analysis of X-ray powder diffraction. From these results, it was showed the potential that the PLGA nanoparticles could be formed successively by dialysis method without surfactant. Release kinetics of NFX used as a model drug was governed by not only drug contents but also particle size parameter. The higher the drug contents and the larger the particle size resulted in slower the drug release. Jeong, Y. I., J. B. Cheon, et al. (1998). "Clonazepam release from core-shell type nanoparticles in vitro." Journal of Controlled Release 51(2-3): 169-78. Block copolymers consisting of poly(gamma-benzyl L-glutamate) (PBLG) as the hydrophobic block and poly(ethylene oxide) (PEO) as the hydrophilic block were synthesized and characterized. Core-shell type nanoparticles of the block copolymers (abbreviated as GE) were prepared by the diafiltration method. The particle size diameter obtained by dynamic light scattering of GE-1 (PBLG content: 60.5 mol%), GE-2 (PBLG content: 40.0 mol %), GE-3 (PBLG content: 124.4 mol %) copolymer was 309.9 +/- 160.9, 251.9 +/- 220.6 and 200.5 +/177.1nm, respectively. The shape of the nanoparticles by SEM or TEM was almost spherical. The critical micelle concentration of the block copolymers obtained by fluorescence spectroscopy was dependent on the chain length of hydrophobic PBLG. The micelle structure of the copolymers nanoparticle was very stable against sodium dodecyl sulfate. Clonazepam (CZ) was loaded onto the core part of the nanoparticle as the crystalline state. Release of CZ from the nanoparticles in vitro was dependent on the drug loading contents and PBLG chain length. Jeong, Y. I., J. W. Nah, et al. (1999). "Adriamycin release from flower-type polymeric micelle based on star-block copolymer composed of poly(gamma-benzyl L-glutamate) as the hydrophobic part and poly(ethylene oxide) as the hydrophilic part." International Journal of Pharmacy 188(1): 49-58. Star-block copolymer based on PBLG as the hydrophobic part and PEO as the hydrophilic one (as abbreviated GEG) was synthesized and characterized. Polymeric micelle was prepared by the diafiltration method. From the measurement of photon correlation spectroscopy, the nanoparticle sizes of GEG-1, GEG-2 and GEG-3 were 106.5+/-59.2, 43.8+/-0.7 and 13.5+/-1.0 nm in number average, respectively, indicating of the formation of

polymeric micelle. Also, the nanoparticle sizes were dependent on the PBLG chain length, i.e. the more PBLG content in the copolymer, the larger the particle size. From the observation of transmission electron microscope(TEM), GEG-2 block copolymer had almost spherical shapes with size range about 20-70 nm, that was similar to particle size measurement. Fluorescence spectroscopy measurement indicated that GEG block copolymers associated in water to form polymeric micelles and critical micelle concentration (CMC) values of the block copolymers decreased with increasing PBLG chain length in the block copolymer. Characteristic peaks of the protons of the benzyl group in the PBLG and the methylene protons adjacent to the benzyl group of the PBLG segment in the GEG-2 nanoparticles appeared in 7.2 approximately 7.4 and 5.0 approximately 5.2 ppm, respectively, and disappeared in D(2)O, indicating the restricted motions of these protons within the micellar core and the very rigid structure of the PBLG core in the GEG polymeric micelles. Release of ADR from the polymeric micelles in vitro was slower in longer PBLG chain length and higher loading contents of ADR. Jiang, X. H., G. T. Liao, et al. (1995). "[The antihepatoma effect of lyophilized aclacinomycin A polyisobutylcyanoacrylate nanoparticles in vitro and in vivo]." Yao Xue Xue Bao 30(3): 179-83. This paper reports the results of experiments on the antihepatoma effects of live targeted drug delivery system-lyophilized aclacinomycin A polyisobutylcyanoacrylate nanoparticle (ACM-IBC-NP) in vitro and in vivo. The median inhibition concentration were found to be 0.28 micrograms.ml-1 and 0.34 micrograms.ml-1 of lyophilized ACM-IBC-NP and ACM respectively in vitro. The inhibition ratio of colony formation were found to be 99% and 88% of lyophilized ACM-IBC-NP and ACM respectively in vitro. The antihepatoma activity was shown to be significantly concentration dependent. The results showed that lyophilized ACM-IBC-NP and ACM possess strong cytotoxicity on human hepatoma cell 7703, and the cytotoxicity was not significantly different between lyophilized ACM-IBC-NP and ACM in vitro. The model of orthotopic transplantation of human hepatoma in nude mice were used for evaluation of the activity of lyophilized ACM-IBC-NP against hepatoma. The tumor inhibition rate were found to be 86.84% for lyophilized ACM-IBC-NP and 46.69% for ACM. The cell proliferative activity of hepatoma were found to be 20.83% by lyophilized ACM-IBC-NP and 72.50% by ACM. All the results indicate that lyophilized ACM-IBC-NP and ACM have clinical application potential and the antihepatoma activity of lyophilized ACM-IBCNP was obviously higher than that of ACM. Jiang, X. and G. Liao (1995). "[Adsorption of aclacinomycin A onto polyisobutylcyanoacrylate nanoparticles]." Hua Xi Yi Ke Da Xue Xue Bao 26(2): 163-6. The mechanism of adsorption of aclacinomycin A onto polyisobutylcyanoacrylate nanoparticle and the factors effecting the adsorption were studied. The adsorption process reached equilibrium in 15 minutes. The results showed that the surface charge densities of the nanoparticles, pH, ionic strength and temperature effected the adsorption. Adsorption isotherms of aclacinomycin A onto polyisobutylcyanoacrylate nanoparticles could be described with Freundlich equation Y = 1.0188 C0.6494 (r = 0.9945) and with Langmuir equation C/Y = 0.7363C + 0.4027 (r = 0.9331) respectively. The main actions between aclacinomycine A and polyisobutylcyanoacrylate nanoparticles were electrostatic and ionic action. Jiang, Y., P. T. Wilson, et al. (2000). "Synthesis of Si nanoparticles within buried layers of SiO x ." Materials Science Forum 343(346): 488-93. A combination of SiO vapor deposition and direct wafer bonding is used to produce buried layers of SiO/sub x/. Film stress in the SiO/sub x/ is identified as the major factor inhibiting the water bonding process. By thermally induced decomposition, Si nanocrystals embedded in SiO/sub 2/ are obtained. Decomposition of the silicon suboxide is studied by observing the Si-O-Si stretching vibration in the infrared range. Phase separation is found to start as low as 400 degrees C and to be mostly complete after 1 hour at 800 degrees C. Annealing at 1000 degrees C yields well established Si nanocrystallites of considerable density buried in the interface layer between the bonded silicon wafers. An intense photoluminescence emission centered around 820 nm is observed for crystalline nanoparticles of diameter 2.8+or-0.7 nm. (21 References). Jin, J., T. Iyoda, et al. (2001). "Self-assembly of uniform spherical aggregates of magnetic nanoparticles through pi-pi interactions." Angewandte Chemistry International Edition English 40(11): 2135-2138. Jiwen, Z., Z. Zihua, et al. (2000). "Nanopatterned assembling of colloidal gold nanoparticles on silicon." Langmuir 16(10): 4409-12. A quasi-one-dimensional (quasi-1D) Au nanocolloids array has been fabricated on silicon by combining the techniques of atomic force microscopy (AFM)-based nanooxidation and chemical assembling of colloidal nanoparticles. The silicon substrate, modified with an octadecyltrichlorosilane (OTS) monolayer, was first subjected to a localized chemical oxidation by using conductive AFM to form silicon oxide lines. After further modification of the oxidized region with an aminopropyltriethoxylsilane (APTES) monolayer via selective chemical adsorption, the substrate was exposed to a colloidal suspension of gold for deposition of gold nanoparticles. It is found that the Au nanoparticles can be selectively immobilized onto the AFM tip-defined amino-terminating regions of the silicon surface, forming quasi-1D gold nanoparticle arrays. The patterned structure is highly

controllable and reproducible, which, we believe, will contribute to studies of nanodevices and mesoscopic phenomena. (0 References). Jonsson, P., M. F. Hansen, et al. (2000). "Nonequilibrium dynamics in an interacting Fe-C nanoparticle system." Physical Review B Condensed Matter 61(2): 1261-6. Nonequilibrium dynamics in an interacting Fe-C nanoparticle sample, exhibiting a low-temperature spin-glass-like phase, has been studied by low-frequency ac susceptibility and magnetic relaxation experiments. The nonequilibrium behavior shows characteristic spin-glass features, but some qualitative differences exist. The nature of these differences is discussed. (18 References). Joo, S. H., S. J. Choi, et al. (2001). "Ordered nanoporous arrays of carbon supporting high dispersions of platinum nanoparticles." Nature 412(6843): 169-72. Nanostructured carbon materials are potentially of great technological interest for the development of electronic, catalytic and hydrogen-storage systems. Here we describe a general strategy for the synthesis of highly ordered, rigid arrays of nanoporous carbon having uniform but tunable diameters (typically 6 nanometres inside and 9 nanometres outside). These structures are formed by using ordered mesoporous silicas as templates, the removal of which leaves a partially ordered graphitic framework. The resulting material supports a high dispersion of platinum nanoparticles, exceeding that of other common microporous carbon materials (such as carbon black, charcoal and activated carbon fibres). The platinum cluster diameter can be controlled to below 3 nanometres, and the high dispersion of these metal clusters gives rise to promising electrocatalytic activity for oxygen reduction, which could prove to be practically relevant for fuel-cell technologies. These nanomaterials can also be prepared in the form of free-standing films by using ordered silica films as the templates. Jose-Yacaman, M., L. Rendon, et al. (1996). "Maya Blue Paint: An Ancient Nanostructured Material." Science 273(5272): 223-5. Maya blue paint was often used in Mesoamerica. The origin of its color and its resistance to acids and biocorrosion have not been fully understood. High-resolution transmission electron microscopy, electron energy loss spectroscopy, and x-ray microanalysis studies of authentic samples show that palygorskite crystals in the paint form a superlattice that probably occurs as a result of mixing with indigo molecules. An amorphous silicate substrate contains inclusions of metal nanoparticles encapsulated in the substrate and oxide nanoparticles on the surface. The beautiful tone of the color is obtained only when both the particles and the superlattice are present. Joshi, A. (1994). "Microparticulates for ophthalmic drug delivery." Journal of Ocular Pharmacology 10(1): 29-45. Microparticulates are drug-containing small polymeric particles (erodible, non-erodible or ion-exchange resins) that are suspended in a liquid carrier medium. Upon administration of particle suspension in the eye, the particles reside at the delivery site (cul-de-sac, sub conjunctiva or vitreous cavity) and the drug is released from the particles through diffusion, chemical reaction, polymer degradation, or ion-exchange mechanism. Several distinct approaches have been used to formulate drugs in microparticulate dosage form for intraocular and topical application. These include erodible microparticulates, swelling mucoadhesive particulates, pH responsive microparticulates, nanoparticles/latex systems, ion-exchange resins, etc. Injection of bioerodible microparticulates in the vitreous for treating infections of posterior segment and the release of acceptable levels of drug up to two weeks has been demonstrated. Both corneal and non-corneal routes of drug entry in the eye from topical instillations are postulated. The in vitro and in vivo studies have shown that this dosage form holds great promise for sustained drug release in the eye. However, several formulation challenges, including production of stable suspensions, uniform dose per unit volume, efficient drug entrapment, reproducible and large scale manufacturing, uniform particle size, etc., have to be addressed. Fruitful resolution of technological challenges will result in a superior dosage form for both topical and intraocular ophthalmic application. Recent developments and future challenges of microparticulate ophthalmic drug delivery system are discussed in this review. Joswig, J. O., M. Springborg, et al. (2000). "Structural and electronic properties of cadmium sulfide clusters." Journal of Physical Chemistry B 104(12): 2617-22. Crystalline cadmium sulfide is a semiconductor for which the wurtzite and zinc blende structures are energetically almost degenerate. Due to quantum-confinement effects, it is possible to tune the optical properties of finite cadmium sulfide clusters by varying their size. Here, we report results of a theoretical study devoted to the properties of stoichiometric Cd/sub n/S/sub n/ clusters as a function of their size n. We have optimized the structure, whereby our initial structures are spherical parts of either of the two crystal structures, and we have studied systems with up to almost 200 atoms. The calculations were performed by using a simplified LCAO-DFTLDA scheme. The results include the structure, electronic energy levels (in particular the frontier orbitals HOMO and LUMO), and stability as a function of size. The results allow for a unique definition of a surface region. The Mulliken populations indicate that the bonds within this region are more ionic than in the bulk. Furthermore, whereas the HOMO is delocalized over major parts of the nanoparticle, the LUMO is a surface state, which confirms recent experimental findings. Finally, the relative stability of the zinc blende and wurtzite structures is

strongly dependent on the size of the system, and there is a close connection between the HOMO-LUMO energy gap and stability. (49 References). Jung, T., A. Breitenbach, et al. (2000). "Sulfobutylated poly(vinyl alcohol)-graft-poly(lactide-co-glycolide)s facilitate the preparation of small negatively charged biodegradable nanospheres." Journal of Controlled Release 67(2-3): 157-69. The manufacturing conditions for small nanoparticles (NP) in the range of 100-500 nm are difficult to control. Novel biodegradable, brush-like branched polyesters with a negatively charged hydrophilic backbone, poly(2sulfobutyl-vinyl alcohol)-g-poly(lactide-co-glycolide), facilitate their preparation by a modified solvent displacement procedure. Furthermore, the structure and the surface properties of the colloidal systems are investigated. NP were characterized by photon correlation spectroscopy (PCS), zeta-potential measurement (ZPM), particle charge detection (PCD), nuclear magnetic resonance spectroscopy (NMR) and transmission electron microscopy (TEM). Varying the manufacturing conditions NP with mean diameters of about 100 up to 500 nm and, depending on polymer composition, negatively charged surfaces were obtained. The NP visualized by TEM showed smooth surfaces. Furthermore, surface characterization and NMR studies suggested a core/corona structure of the particles. This study demonstrates that a simple solvent displacement technique can be used for the reproducible preparation of discrete NP with defined negatively charged surfaces and narrow size distributions. These NP may have potential for peroral or parenteral protein delivery systems. Jung, T., W. Kamm, et al. (2001). "Tetanus toxoid loaded nanoparticles from sulfobutylated poly(vinyl alcohol)-graftpoly(lactide-co-glycolide): evaluation of antibody response after oral and nasal application in mice." Pharmacology Research 18(3): 352-60. PURPOSE: Aim of the study was the evaluation of the potential of novel tetanus toxoid (TT) loaded nanoparticles (NP) for electing an immune response in mice against TT. METHODS: Six week-old female Balb/c mice were immunized by oral (p.o.), nasal (i.n.) and intraperitoneal (i.p.) application of TT NP loaded by adsorption. As polymer a novel polyester, sulfobutylated poly(vinyl alcohol)-graft-poly(lactide-co-glycolide), SB(43)-PVAL-gPLGA was used. Blood samples were collected 4 and 6 weeks after immunization and assayed for serum IgG- as well as IgA antibody titers by ELISA. NP formulations varying in size and loading were compared to alum adsorbates as well as to TT solutions. RESULTS: Both, p.o. and i.n. administration of TT associated NP increased serum titers up to 3 x 10(3) (IgG) and 2 x 10(3) (IgA). While small NP induced significantly higher titers then larger ones after oral administration, intermediate NP induced antibodies after nasal application. Of the mucosal routes investigated, i.n. seems to be more promising compared to p.o. immunization. CONCLUSIONS: Antigen loaded NP prepared from surface modified polyesters combined with CT show considerable potential as a vaccine delivery system for mucosal immunization. The results warrant further experiments to explore in more detail the potential use of NP as mucosal vaccine delivery system. Junghans, M., J. Kreuter, et al. (2000). "Antisense delivery using protamine-oligonucleotide particles." Nucleic Acids Research 28(10): E45. Protamine, a polycationic peptide (mol. wt 4000-4500), was evaluated as a potential penetration enhancer for phosphodiester antisense oligonucleotides (ODNs). Unique complexes in the form of nanoparticles were spontaneously formed, which we call 'proticles'. The stability of the particles and the ODNs bound into the proticles was examined in foetal calf serum and cell culture medium. FITC-labelled ODNs bound to protamine showed an increased cellular uptake into human histiocytic lymphoma U 937 cells compared to free ODNs. Proticles significantly decreased cellular growth in a cell proliferation assay using ODNs against the c- myc protooncogene. Junghans, M., J. Kreuter, et al. (2001). "Phosphodiester and phosphorothioate oligonucleotide condensation and preparation of antisense nanoparticles." Biochimica et Biophysica Acta 1544(1-2): 177-88. Protamine is a cationic peptide with a molecular mass of approx. 4000 Da that is able to condense DNA. In the present study it was used to complex antisense oligonucleotides (ODNs) and to form solid particles with initial diameters of 90-150 nm. The reaction was very rapid and occurred by simple mixing of diluted solutions of the polycation with the oligonucleotide. The aggregation was dependent on the oligonucleotide chain length and the protamine/ODN mass ratio. Particle formation required a minimal chain length of nine nucleotides and a mass ratio of 0.5:1. The particle surface charge and the number of particles depended on the mass ratio. With increasing amounts of the peptide, the number of particles and the zeta potential increased. Both negatively and positively charged particles improved the stability of oligonucleotides against DNase I digestion. Above a mass ratio of 2.5:1 no degradation was found. The uptake of unbound rhodamine-labelled ODNs and its complexes with protamine was determined with Vero cells under in vitro cell culture conditions at 37 degrees C and 4 degrees C. At 37 degrees C the cellular uptake increased with increasing mass ratio. The internalized oligonucleotides were localized in the cytoplasm and in the nucleus of the cells. When Vero cells were treated with these samples at 4 degrees C for 4 h, no fluorescence could be detected inside the cells. Therefore, our data indicate an energy dependent endocytotic uptake mechanism. In contrast, spermine and spermidine, which are also known condensation agents, did not aggregate with oligonucleotides into nanoparticles under the same conditions.

Kamalakaran, R., A. K. Singh, et al. (2000). "Formation and characterization of nanoparticle-bearing threads of silicon, germanium and tin." Journal of Physics Condensed Matter 12(12): 2681-9. We report the formation and characterization of nanoparticles and their assemblage to form a threadlike microstructure of silicon, germanium and tin, by the process of thermal deposition in helium ambient under varied conditions of pressure. The structural characterization of the nanoparticles was done by transmission electron microscope (Philips CM12). Resistance versus temperature (R-T) measurements, on the thin films embodying nanothreads, exhibited anomalous behaviour embodying erratic changes in R-T variations. This was suggestive of variation of nanoparticle distribution with increase in temperature. (22 References). Kang, S. O., T. W. Kim, et al. (2000). "Room-temperature observation of the Coulomb blockade effects in Al two-terminal diodes fabricated using a focused ion-beam nanoparticle process." Applied Physics Letters 76(8): 1036-8. Al two-terminal diodes were fabricated on a basis of an artificial pattern formation method using focused ion-beam (FIB) techniques. The results of current-voltage and conductance-voltage measurements at room temperature showed the Coulomb staircase and the Coulomb blockade effects, respectively. The Coulomb blockade effects originate from the many nanoparticles created by the defects due to the Ga/sup +/ ion beam. These results indicate that Al two-terminal diodes fabricated by using the FIB system hold promise for potential applications in single-electron transistors operating at room temperature. (16 References). Kante, B., P. Couvreur, et al. (1982). "Toxicity of polyalkylcyanoacrylate nanoparticles I: Free nanoparticles." Journal of Pharmaceutical Sciences 71(7): 786-90. Kaplun, A. P., L. B. Son, et al. (1999). "[Liposomes and other nanoparticles as drug delivery systems]." Voprosy Meditsinskoi Khimii 45(1): 3-12. The basic principles of designing of nanoparticle drug delivery systems are considered. The special attention is paid to liposomes, because the greatest success has been achieved in this area. The modern condition in such intensively developing areas as antitumor and, antibacterials drugs, gene therapy, vaccines is reviewed. Kasperovich, V., K. Wong, et al. (2000). "Electron capture by the image charge of a metal nanoparticle." Physical Review Letters 85(13): 2729-32. We have measured absolute cross sections for the capture of low-energy electrons by large free sodium nanoclusters (~10/sup 4/ atoms, or 4 nm radius). To explain the results, it is necessary to go beyond the commonly used induced-dipole approximation and to employ the full image-charge interaction potential which accounts fur the finite size of the particle. This potential yields an exact analytical expression for the capture cross section and leads to good agreement with the data. It is suggested that electron capture may provide a useful tool for size characterization of nanoparticle beams. (32 References). Kaszuba, M. (1999). " The measurement of nanoparticles using photon correlation spectroscopy and avalanche photo diodes." Journal of Nanoparticle Research 1: 405-409. Kattan, J., J. P. Droz, et al. (1992). "Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles." Investigational New Drugs 10(3): 191-9. Doxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60, 60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions. Keating, S., P. A. McCarron, et al. (2000). "Preparation of nanoparticles with enhanced loading of 5-fluorouracil." Journal of Pharmacy and Pharmacology 52(Supplement): 4. Kellar, K. E., D. K. Fujii, et al. (1999). "'NC100150', a preparation of iron oxide nanoparticles ideal for positive-contrast MR

angiography." Magma 8(3): 207-13. A laboratory-scale synthesis of NC100150 (iron oxide particles with an oxidized starch coating) was characterized by magnetization measurements (vibrating sample magnetometry, VSM), relaxometry (1/T1 NMRD profiles and 1/T2 at 10 and 20 MHz), and dynamic light scattering (photon correlation spectroscopy, PCS). The results were related to give a self-consistent physical description of the particles: a water-impenetrable part making up 12% of the total particle volume, 82% of this volume consisting of an iron oxide core and the remaining 18% consisting of an oxidized starch rind; and, a water-penetrable part making up 88% of the total particle volume, consisting of oxidized starch polymers and entrained water molecules. Relating the magnetization to the relaxometry results required that the oxidized starch coating slows the diffusivity of solvent water molecules in the vicinity of the iron oxide cores. The effect of the organic coating on water diffusivity, not previously considered in the application of relaxation theory to iron oxide nanoparticles, is supported by the much greater (factor of about 2) diameter obtained from the dynamic light scattering measurements in comparison to that obtained from the magnetization measurements. The present work shows that three physical techniques--VSM, relaxometry, and PCS--are needed for properly assessing iron oxide nanoparticles for use as contrast agents for magnetic resonance angiography (MRA). It is also shown that NC100150 has a narrow range of diameters and the smallest value of r2/r1 reported to date, an asset for MRA. Kellar, K. E., D. K. Fujii, et al. (2000). "NC100150 Injection, a preparation of optimized iron oxide nanoparticles for positive-contrast MR angiography." Journal of Magnetic Resonance Imaging 11(5): 488-94. A preparation of monocrystalline iron oxide nanoparticles with an oxidized starch coating, currently in clinical trials (NC100150 Injection; CLARISCAN), was characterized by magnetization measurements, relaxometry, and photon correlation spectroscopy. By combining the results with a measure of iron content, one can obtain the size and magnetic attributes of the iron cores, including the relevant correlation times for outer sphere relaxation (tau(SO) and tau(D)), and information about the interaction of the organic coating with both core and solvent. The results are 6.43 nm for the iron oxide core diameter, a magnetic moment of 4.38x10(-17) erg/G, and a waterpenetrable coating region of oxidized oligomeric starch fragments and entrained water molecules. The latter extends the hydrodynamic diameter to 11.9 nm and lowers the average diffusivity of solvent about 64% (which increases tau(D) accordingly). The nanoparticles show little size-polydispersity, evidenced by the lowest value of r(2)/r(1) at 20 MHz reported to date, an asset for magnetic resonance angiography. Ketai, L. H., B. A. Muggenberg, et al. (1999). "CT imaging of intrathoracic lymph nodes in dogs with bronchoscopically administered iodinated nanoparticles." Academic Radiology 6(1): 49-54. RATIONALE AND OBJECTIVES: The purpose of the study was to determine if airway instillation of iodinated nanoparticles results in contrast material enhancement of tracheobronchial lymph nodes in dogs. MATERIALS AND METHODS: Eight dogs underwent intrabronchial instillation of iodinated nanoparticles; six dogs received 900 mg each, and two dogs received 450 mg each. Spiral computed tomography (CT) was then performed 2-34 days later. RESULTS: CT scans obtained 2 days after instillation showed the presence of contrast material within the lung parenchyma but no nodal enhancement. Scans obtained 6-34 days after instillation showed enhancement of the right, left, and middle tracheobronchial lymph nodes (analogous to the mediastinal nodes in humans). Mean nodal attenuation on CT images was 117 HU +/- 43, and the mean nodal volume was 129 mm3 +/- 113. Histologic specimens of the nodes showed macrophage hyperplasia. CONCLUSION: Iodinated nanoparticles instilled into small airways are transported to the tracheobronchial lymph nodes, where they result in contrast enhancement. Kharitonov, A. B., A. N. Shipway, et al. (1999). "An Au nanoparticle/bisbipyridinium cyclophane-functionalized ionsensitive field-effect transistor for the sensing of adrenaline." Analytical Chemistry 71(23): 5441-3. A film consisting of polyethyleneimine (PEI), Au nanoparticles (12 +/- 1 nm) and coadsorbed cyclobis(paraquat-pphenylene) (1) was assembled as a sensing interface on the Al2O3 insulating layer of an ion-sensitive field-effect transistor (ISFET). Adrenaline (2) was sensed by the functionalized ISFET with a detection limit of 1 x 10(-6) M. The sensing ability of the nanostructured device for the analysis of adrenaline originates from the preconcentration of the analyte in the cyclophane by pi-pi donor-acceptor interactions. Analysis of adrenaline is accomplished by the measurement of the source-drain current, Isd, or by the gate-source voltage, Vgs. The sensing device is reusable (at least 100 cycles) and exhibits high stability. Kim, Y. I., L. Fluckiger, et al. (1997). "The antihypertensive effect of orally administered nifedipine-loaded nanoparticles in spontaneously hypertensive rats." British Journal of Pharmacology 120(3): 399-404. 1. The therapeutic use of nifedipine is limited by the rapidity of the onset of its action and its short biological halflife. In order to produce a form devoid of these disadvantages we made nanoparticles of nifedipine from three different polymers, poly-epsilon-caprolactone (PCL), polylactic and glycolic acid (1:1) copolymers (PLAGA), and Eudragit RL/RS (Eudragit). Nifedipine in polyethylene glycol 400 (PEG) solution was used as a control. 2. The average diameters of the nanoparticles ranged from 0.12 to 0.21 micron; the encapsulation ratio was 82% to 88%. 3. In spontaneously hypertensive rats (SHR), the initial rapid fall in systolic arterial blood pressure following

oral administration of nifedipine in PEG solution (from 193 +/- 3 to 102 +/- 2 mmHg) was not seen following administration of the same dose in Eudragit nanoparticles (from 189 +/- 2 to 156 +/- 2 mmHg); with PCL and PLAGA nanoparticles the initial fall in blood pressure was significantly reduced (nadirs PCL 124 +/- 2 and PLAGA 113 +/- 2 mmHg). Ten hours following administration, blood pressure in rats administered the nifedipine/PEG preparation had returned to normal (183 +/- 3 mmHg) whereas that of animals given nifedipine in nanoparticles (PCL 170 +/- 3, PLAGA 168 +/- 2, Eudragit 160 +/- 3 mmHg) was still significantly reduced. 4. All of the nanoparticle dosage forms decreased Cmax and increased Tmax and the mean residence time (MRT) values. Relative bioavailability was significantly increased with Eudragit nanoparticles compared to the nifedipine/PEG solution. 5. There was an inverse linear correlation between the fall in blood pressure and plasma nifedipine concentration with all preparations. 6. The nanoparticle nifedipine preparations represent sustained release forms with increased bioavailability, a less pronounced initial antihypertensive effect and a long-lasting action. Kim, S. Y., H. J. Doh, et al. (1999). "Oral immunization with Helicobacter pylori-loaded poly(D, L-lactide-co-glycolide) nanoparticles." Helicobacter 4(1): 33-9. BACKGROUND: Helicobacter pylori is a major cause of chronic antral gastritis and peptic ulcer diseases. Many researchers have examined the possibility of immunologically-mediated prevention of H. pylori infection using an oral vaccine. The purpose of this study is to investigate whether mucosal and systemic immune responses are induced by oral immunization with H. pylori lysate-loaded poly(D, L-lactide-coglycolide)[PLG] nanoparticles, and if so, how the distribution of serum IgG subclasses are produced. METHODS: PLG nanoparticles (H. pylori-PLG) with encapsulated H. pylori lysates were prepared by the solvent evaporation method, and the physical properties of the nanoparticles were investigated. Following the oral immunization of the H. pylori-PLG nanoparticles into mice, antibody induction was assayed in serum and gut washings, and the pattern of serum IgG subclasses was determined by ELISA. RESULTS: The prepared H. pylori-PLG nanoparticles were spherical, nonporous particles with a mean diameter of less than 1 microm. The multiple oral immunization with H. pylori-PLG nanoparticles induced significantly H. pylori-specific mucosal IgA response as well as serum IgG responses. The serum antibody subclasses elicited were predominantly IgG1 and IgG2b. CONCLUSION: Our results suggested that oral immunization of H. pylori-PLG nanoparticles induced the H. pylori-specific mucosal and systemic responses in mice and enhanced Th2-type responses. Kim, Y. K., K. Y. Lee, et al. (2000). "Size dependence of electroluminescence of nanoparticle (rutile-TiO2) dispersed MEHPPV films." Synthetic Metals 111(112): 207-11. Polymer/nanoparticle composites show the enhanced optical and electronic properties. In this study, poly(2methoxy-5-ethylhexyloxy-1,4-phenylene vinylene) (MEH-PPV)/rutile-TiO/sub 2/ composite films were made with various sizes from 7 to 23 nm and their electroluminescent characteristics were investigated, where the device structure of indium tin oxide (ITO)/nanoparticle dispersed MEH-PPV/Alq/sub 3//Li:Al was used. It was found that the luminance efficiency increases from 7 to 23 nm. In comparison with single polymer device, the brightness and luminescence efficiency of multi-layer device improved five times under 9 V dc. (17 References). Kim, I. S., Y. I. Jeong, et al. (2000). "Core-shell type polymeric nanoparticles composed of poly(L-lactic acid) and poly(Nisopropylacrylamide)." International Journal of Pharmacy 211(1-2): 1-8. Poly(L-lactic acid)/poly(N-isopropylacrylamide) (abbrevi ated as LN) block copolymers were synthesized and the LN nanoparticles were prepared by simple diafiltration method. The thermal transition of the LN nanoparticles was at 32.3 degrees C, the lower critical solution temperature (LCST) of the polymer. The fluorescence spectroscopy data showed that LN was self-assembled in water to form core-shell structure nanoparticles, and the critical association concentration (CAC) value was estimated as 1.3x10(-2) g/l. From the transmission electron microscope observations, the LN nanoparticles were spherically shaped and ranged in size between 30 and 50 nm below the LCST. The hydrated size was measured by photon correlation spectroscopy, and reversible size changes were investigated by the factor of temperature. The release of indomethacin from the LN nanoparticles was thermo-sensitive due to the unique characteristic of poly(N-isopropylacrylamide). Kim, I. S., Y. I. Jeong, et al. (2000). "Self-assembled hydrogel nanoparticles composed of dextran and poly(ethylene glycol) macromer." International Journal of Pharmacy 205(1-2): 109-16. Biodegradable hydrogel nanoparticles were prepared from glycidyl methacrylate dextran (GMD) and dimethacrylate poly(ethylene glycol) (DMP). GMD was synthesized by coupling of glycidyl methacrylate to dextran in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) using dimethylsulfoxide (DMSO) as an aprotic solvent. DMP was synthesized from poly(ethylene glycol) (PEG) and methacryloyl chloride. GMD/DMP (abbreviated as DP) hydrogel was prepared by radical polymerization of GMD and DMP using ammonium peroxydisulfate (APS) as an initiator and UV curing. DP hydrogel nanoparticles were obtained by diafiltration method using DMSO solution. The GMD and DMP were characterized by fourier transform infrared spectroscopy. Fluorescence probe technique was used to investigate the self-assembly of DP in water using pyrene as a hydrophobic probe. The critical association concentration (CAC) was determined to be 5.6 x 10(-2) g/l. The shape of DP hydrogel nanoparticles was spherical when observed by transmission electron microscope (TEM). The size range of DP

hydrogel nanoparticles was about 20 approximately 50 nm. The hydrodynamic size of DP hydrogel nanoparticles was measured by photon correlation spectroscopy (PCS) and gradually increased with time in PBS (0.1 M, pH 7.4). Drug release study was performed using clonazepam (CNZ) as a hydrophobic model drug. In vitro release rate of CNZ from the DP hydrogel nanoparticles was dependent on the existence of dextranase and the pH of the release medium. Kishimoto, N., N. Umeda, et al. (2000). "In-beam growth and rearrangement of nanoparticles in insulators induced by high-current negative copper ions." Vacuum 58(1): 60-78. In fabricating metal nanoparticles in insulators, high-current negative ions have been shown to cause efficient and spontaneous growth of nanospheres. The in-beam growth is inevitably subjected to rearrangement of implanted atoms, departing from initially deposited positions. For high-current techniques for insulators, we discuss important experimental factors and explore possible mechanisms of the in-beam growth and atomic rearrangement of nanoparticles. Experimental data of interest are for negative Cu ion implantation at 60 keV into insulators, amorphous (a-), crystalline (c-) SiO/sub 2/ and a spinel oxide, MgAl/sub 2/O/sub 4/. Dose rates ranged up to 260 mu A/cm/sup 2/, with a total dose of 3.0*10/sup 16/ ions/cm/sup 2/. Nanoparticle morphology and surface morphology by AFM were significantly dependent not only on dose rate but also on the boundary conditions. With increasing dose rate, the in-beam growth of nanoparticles became pronounced and the atomic profile shifted toward the surface. Since beam heating, especially in vacuum, is of concern, thermal analysis was carried out with a one-dimensional simulation code. Candidate mechanisms are depth-oriented gradients of deposited nuclear/electronic energy, chemical/elastic potentials and thermal effects. The relevant mechanisms are explored among these candidates. (25 References). Kishimoto, N., C. G. Lee, et al. (2000). "Sputtering effects and two dimensional arrangement of nanoparticles in insulators under high flux Cu implantation." Nanophase and Nanocomposite Materials III. Symposium 581: 181-6. Application of negative heavy ions, alleviating surface charging on insulators, enables us to conduct low-energy and high-flux implantation, and leads to a well-defined tool to fabricate near-surface nanostructures. Negative Cu ions of 60 keV, at high doses, have generated nanocrystals in amorphous(a-)SiO/sub 2/ with a size (~10 nn) suitable for nonlinear optical devices. The kinetic processes, inside the solid and at the surface, are studied by cross-sectional TEM and tapping AFM, respectively. In a-SiO/sub 2/, nanoparticles spontaneously grow with dose rate, being controlled by the surface tension and radiation-induced diffusion. Furthermore, the nanospheres give rise to a two-dimensional (2D) arrangement around a given dose rate. The 2D-distribution occurs in coincidence with enhanced sputtering where a considerable Cu fraction sublimates from the surface. The dose-rate dependence of nanoparticles indicates that the surface-sputtering process influences the intra-solid process and contributes to the 2D-distribution. A self-assembling mechanism for 2D-arrangement of nanospheres is discussed taking into account contribution of the surface sputtering. (17 References). Kityk, I. V., A. Kassiba, et al. (2000). "Vacancies in SiC nanopowders." Materials Science and Engineering B Solid State Materials for Advanced Technology(2): 147-58. Origin of vacancies in the large-sized SiC nanocrystals (higher than 10 nm) has been investigated using theoretical band structure calculations and experimental electronic paramagnetic resonance (EPR) measurements. Influence of geometry sizes on appearance of concrete vacancy has been studied. The theoretical approach includes self-consistent norm-conserving pseudopotential band energy calculations and geometry structure optimisation. The performed calculations show that the presence of the vacancies is a necessary attribute of the SiC nanocrystallites. Moreover, the type and concentration of the vacancies are dependent on the nanoparticle geometry. We have revealed that spin-polarised states of intracrystallite vacancies differ essentially from vacancies in the bulk crystals. A comparison between the performed theoretical simulations and obtained EPR experimental data shows the possibility of using the proposed methods for prediction of vacancy appearance in the binary nanocrystallites and possibility for their operation. (48 References). Klaus, T., R. Joerger, et al. (1999). "Silver-based crystalline nanoparticles, microbially fabricated." Proceedings of the National Academy of Sciences U S A 96(24): 13611-4. One mechanism of silver resistance in microorganisms is accumulation of the metal ions in the cell. Here, we report on the phenomenon of biosynthesis of silver-based single crystals with well-defined compositions and shapes, such as equilateral triangles and hexagons, in Pseudomonas stutzeri AG259. The crystals were up to 200 nm in size and were often located at the cell poles. Transmission electron microscopy, quantitative energydispersive x-ray analysis, and electron diffraction established that the crystals comprise at least three different types, found both in whole cells and thin sections. These Ag-containing crystals are embedded in the organic matrix of the bacteria. Their possible potential as organic-metal composites in thin film and surface coating technology is discussed. Kleindienst, G., C. G. Huber, et al. (1998). "Capillary electrophoresis of peptides and proteins in fused-silica capillaries coated with derivatized polystyrene nanoparticles." Electrophoresis 19(2): 262-9.

High-resolution capillary electrophoretic separation of proteins and peptides was achieved by coating the inner wall of 75 microm ID fused-silica capillaries with 40-140 nm polystyrene particles which have been derivatized with alpha-omega-diamines such as ethylenediamine or 1,10-diaminodecane. A stable and irreversibly adsorbed coating was obtained upon deprotonation of the capillary surface with aqueous sodium hydroxide and subsequent flushing with a suspension of the positively charged particles. At pH 3.1, the detrimental adsorption of proteins to the capillary inner wall was suppressed efficiently because of electrostatic repulsion of the positively charged proteins from the positively charged coating which enabled protein separations with maximum efficiencies of 400000 plates per meter. A substantial improvement of separation efficiency in particle-coated capillaries was observed after in-column derivatization of amino functionalities with 2,3-epoxy-l-propanol, resulting in a more hydrophilic coating. Five basic and four acidic proteins could be separated in less than 7 min with efficiencies up to 1900000 theoretical plates per meter. Finally, coated capillaries were applied to the high-resolution analysis of protein glycoforms and bioactive peptides. Klugherz, B. D., N. Meneveau, et al. (1999). "Sustained intramural retention and regional redistribution following local vascular delivery of polylactic-coglycolic acid and liposomal nanoparticulate formulations containing probucol." Journal of Cardiovascular Pharmacology and Therapy 4(3): 167-174. BACKGROUND: Probucol reduces restenosis after angioplasty, provided oral administration is begun 1 month before the procedure. Local vascular delivery of a nonoparticulate formulation of probucol may obviate the need for drug loading by acutely raising arterial intramural concentration while providing sustained intramural retention. To test this hypothesis, we compared the retention and redistribution of (35)S-probucol encapsulated in either liposomal or polylactic-coglycolic acid (PLGA) nanoparticles after local vascular delivery. METHODS: Nanoparticles were delivered using a Crescendo microporous infusion catheter (Cordis, Warren, NJ) after balloon angioplasty of rabbit iliac arteries (n = 12-18 arteries per formulation per time point). Animals were euthanized on day 0, 3, or 7 after delivery. Iliac arteries, perivascular fat, and downstream tissues were harvested and the radioactivity disintegrations per minute was measured. Autoradiographic and confocal microscopic analyses of tissue sections were performed to evaluate intramural distribution of probucol. RESULTS: Immediately after delivery, radioactivity in the iliac arteries (log[dpm/mg], mean +/- SEM) was greater with PLGA (2.72 +/- 0.08) than with liposomal encapsulation (2.10 +/- 0.08, P = 0.001). Intramural retention of probucol was 23% at 7 days using liposomes and 10% using PLGA, corresponding to a probucol concentration of 0.1 ng/mg tissue for both formulations. By the third day after delivery, radioactivity in peri-iliac fat, femoral arteries, and hindlimb muscle increased by 88%, 29%, and 154%, respectively. Thereafter, radioactivity decreased to 56%, 43%, and 134% of initial dpm respectively, by day 7. CONCLUSIONS: although delivery efficiency was superior with PLGA encapsulation, intramural probucol concentrations were similar on day 7 using both formulations. Radial and axial redistribution of probucol was observed, indicating that this technique can be exploited to increase adjacent tissue delivery. Knauth, M., T. Egelhof, et al. (2001). "Monocrystalline iron oxide nanoparticles: possible solution to the problem of surgically induced intracranial contrast enhancement in intraoperative MR imaging." American Journal of Neuroradiology 22(1): 99-102. BACKGROUND AND PURPOSE: Intraoperative MR imaging is increasingly being used to control the extent of surgical resection; however, surgical manipulation itself causes intracranial contrast enhancement, which is a source of error. Our purpose was to investigate the potential of monocrystalline iron oxide nanoparticles (MIONs) to solve this problem in an animal model. METHODS: In male Wistar rats, surgical lesions of the brain were produced. The animals underwent MR examination immediately afterward. In the first group, a paramagnetic contrast agent was administered, whereas the second group of animals received MIONs 1 day before surgery. In a third group of animals, malignant glioma cells were stereotactically implanted in the caudoputamen. Two weeks later, MIONs were IV injected and the tumor was (partially) resected. Immediately after resection, MR examination was performed to determine the extent of residual tumor. RESULTS: Surgically induced intracranial contrast enhancement was seen in all animals in which a paramagnetic contrast agent was used. Conversely, when MIONs had been injected, no signal changes that could be confused with residual tumor were detected. In the animals that had undergone (partial) resection of experimental gliomas, MR assessment of residual tumor was possible without any interfering surgically induced phenomena. CONCLUSION: Because MIONs are stored in malignant brain tumor cells longer than they circulate in the blood, their use offers a promising strategy to avoid surgically induced intracranial contrast enhancement, which is known to be a potential source of error in intraoperative MR imaging. Kneuer, C., M. Sameti, et al. (2000). "A nonviral DNA delivery system based on surface modified silica-nanoparticles can efficiently transfect cells in vitro." Bioconjugate Chemistry 11(6): 926-32. Diverse polycationic polymers have been used as nonviral transfection agents. Here we report the ability of colloidal silica particles with covalently attached cationic surface modifications to transfect plasmid DNA in vitro and make an attempt to describe the structure of the resulting transfection complexes. In analogy to the terms lipoplex and polyplex, we propose to describe the nanoparticle-DNA complexes by the term

&quot;nanoplex&quot;. Three batches, Si10E, Si100E, and Si26H, sized between 10 and 100 nm and with zeta potentials ranging from +7 to +31 mV at pH 7.4 were evaluated. The galactosidase expression plasmid DNA pCMVbeta was immobilized on the particle surface and efficiently transfected Cos-1 cells. The transfection activity was accompanied by very low cytotoxicity, with LD(50) values in the milligrams per milliliter range. The most active batch, Si26H, was produced by modification of commercially available silica particles with N-(6aminohexyl)-3-aminopropyltrimethoxysilane, yielding spherical nanoparticles with a mean diameter of 26 nm and a zeta potential of +31 mV at pH 7.4. Complexes of Si26H and pCMVbeta plasmid DNA formed at w/w ratios of 10 were most effective in promoting transfection of Cos-1 cells in the absence of serum. At this ratio, &gt;90% of the DNA was associated with the particles, yielding nanoplexes with a net negative surface charge. When the transfection medium was supplemented with 10% serum, maximum gene expression was observed at a w/w ratio of 30, at which the resulting particle-DNA complexes possessed a positive surface charge. Transfection was strongly increased in the presence of 100 &amp;mgr;M chloroquine in the incubation medium and reached approximately 30% of the efficiency of a 60 kDa polyethylenimine. In contrast to polyethylenimine, no toxicity was observed at the concentrations required. Atomic force microscopy of Si26H-DNA complexes revealed a spaghettimeatball-like structure. The surface of complexes prepared at a w/w ratio of 30 was dominated by particles halfspheres. Complex sizes correlated well with those determined previously by dynamic light scattering. Kneuer, C., M. Sameti, et al. (2000). "Silica nanoparticles modified with aminosilanes as carriers for plasmid DNA." International Journal of Pharmacy 196(2): 257-61. We synthesised silica nanoparticles (SiNP) with covalently linked cationic surface modifications and demonstrated their ability to electrostatically bind, condense and protect plasmid DNA. These particles might be utilised as DNA carriers for gene delivery. All nanoparticles were sized between 10 and 100 nm and displayed surface charge potentials from +7 to +31 mV at pH 7.4. They were produced by modification of commercially available (IPAST) or in-house synthesised silica particles with either N-(2-aminoethyl)-3-aminopropyltrimethoxysilane or N-(6aminohexyl)-3-aminopropyltrimethoxysilane. All particles formed complexes with pCMVbeta plasmid DNA as evidenced by ratio dependent retardation of DNA in the agarose gel and co-sedimentation of soluble DNA with nanoparticles. High salt and alkaline pH did inhibit complex formation. Absorption onto the particles also decreased the hydrodynamic dimensions of plasmid DNA as shown by photon correlation spectroscopy. Complexes formed in water at a w/w ratio of Si26H:DNA (pCMVbeta) of 300 were smallest with a mean hydrodynamic diameter of 83 nm. For effective condensation a w/w ratio of Si26H:DNA of 30 was sufficient. Further, the absorbed DNA was protected from enzymatic degradation by DNase I. Knize, R. J., B. V. Zhdanov, et al. (2000). "Electrocrystallized platinum nanoparticle on carbon substrate." Electrochemistry Communications 2(11): 800-4. Platinum nanoparticles were electrocrystallized on a 4-aminophenyl monolayer-grafted carbon substrate. These Pt-modified surfaces were characterized by scanning tunneling microscopy (STM). The characterization by STM revealed that the platinum nanoparticles obtained had good size monodispersity and were well separated from one another on HOPG surfaces. (31 References). Kociak, M., L. Henrard, et al. (2000). "Plasmons in layered nanospheres and nanotubes investigated by spatially resolved electron energy-loss spectroscopy." Physical Review B Condensed Matter 61(20): 13936-44. We present an extensive electron energy loss spectroscopy study of the low-loss energy region, recorded on multishell carbon and boron-nitride nanotubes and carbon hyperfullerenes. Collections of spectra were recorded in a scanning transmission electron microscope by scanning a subnanometer probe from vacuum into the center of the nano-objects. This experimental technique provides the unique ability of disentangling and identifying the different excitation modes of a nanoparticle. We concentrate on the study of surface modes excited in a near-field geometry where the coupling distance between the electron beam and the surface of the nano-objects is accurately monitored. Similarities between surface collective excitations in the different layered nanostructures (cylindrical or spherical, boron nitride, or carbon constituted) are pointed out. Two surface modes at 12-13 eV and 17-18 eV are experimentally clearly evidenced. We show that these modes are accurately described by a classical continuum dielectric model taking fully into account the anisotropic character and the hollow geometry of the nanoparticles. These two modes are shown to be directly related to the in-plane and out-of-plane components of the dielectric tensor. The higher-energy mode (in-plane mode) is shown to shift to higher energy with decreasing impact parameter, as a result of an increase in the weights of the high-order multipolar modes while reaching the surface of the nano-objects. (60 References). Kodama, R. H., A. E. Berkowitz, et al. (1996). "Surface spin disorder in NiFe2O4 nanoparticles." Physical Review Letters 77(2): 394-397. Koenig, S. H. and K. E. Kellar (1995). "Theory of 1/T1 and 1/T2 NMRD profiles of solutions of magnetic nanoparticles." Magnetic Resonance in Medicine 34(2): 227-33. Organically coated iron oxide crystallites with diameters of 5-50 nm (&quot;nanoparticles&quot;) are potential

magnetic resonance imaging contrast agents. 1/T1 and 1/T2 of solvent water protons are increased dramatically by magnetic interactions in the &quot;outer sphere&quot; environment of the nanoparticles; subsequent diffusive mixing distributes this relaxation throughout the solvent. Published theory, valid for the solute magnetic energy small compared with thermal energy, is applicable to small magnetic solutes (e.g., gadolinium and manganese diethylenetriaminopentaacetic acid, and nitroxide free radicals) at generally accessible fields (&lt; or = 50 T). It fails for nanoparticles at fields above approximately 0.05 T, i.e., at most imaging fields. The authors have reformulated outer sphere relaxation theory to incorporate progressive magnetic saturation of solute nanoparticles and, in addition, indicate how to use empirical magnetization data for realistic particles when their magnetic properties are not ideal. It is important to handle the effects of rapid thermally induced reorientation of the magnetization of the nanoparticles (their &quot;superparamagnetism&quot;) effectively, including their sensitivity to particle size. The theoretical results are presented as the magnetic field dependence (NMRD profiles) of 1/T1 and 1/T2, normalized to Fe content, for three sizes of particles, and then compared with the limited data extant for well-characterized material. Koenig, S. H. and K. E. Kellar (1996). "Theory of proton relaxation in solutions of magnetic nanoparticles, including the superparamagnetic size range." Academic Radiology 3 Suppl 2(16): S273-6. Koenig, S. H. (1998). "Solvent relaxation by uniformly magnetized solute spheres. The classical-quantal connection." Investigative Radiology 33(11): 822-7. RATIONALE AND OBJECTIVES: Large magnetic entities, with diameters in the range of 4 nm to 4 microns, are becoming of increasing interest for magnetic resonance imaging (MRI). The smaller are iron oxide nanoparticles, used for the RE system, and the larger are deoxygenated blood cells, for functional MRI. It can be useful to model such systems as magnetized solute spheres in water. Classical computations of 1/T2 have been reported for the larger particles, in the micron range, where the computational complexities are simplified by Monte Carlo methods. For smaller particles, the quantum mechanical (quantal) expressions for outer sphere relaxation, for both 1/T1 and 1/T2, have been available for some time, and are particularly simple to apply at MRI fields. The questions that arise, and which the author addresses, are how to interrelate the classical and quantal approaches and when to use which. METHODS: The author compares published results of Monte Carlo calculations of 1/T2 for diamagnetic polystyrene solute spheres of various sizes in water, made paramagnetic by addition of dysprosium-(DTPA)2-, with quantum mechanical outer sphere theory applied to the same system. The latter includes the usual assumption of motional narrowing and yields both 1/T1 and 1/T2. RESULTS: For particles with diameters less than about 1 micron, both approaches give identical results for 1/T2. For larger particles, the conditions for motional narrowing breakdown, and quantal theory overestimates 1/T2. In addition, in the particular system studied, relaxation becomes so effective near solute that there is insufficient time for all water molecules to experience their maximal effect. Classical theory handles this well whereas quantal theory does not. CONCLUSIONS: In comparing the classical and quantal approaches, one balances computational complexity but broader applicability with more limited but far simpler mathematics. In addition, because the quantal approach shows that 1/T1 and 1/T2 are intimately related, the author suggests, by analogy, how to extend classical methods to computation of 1/T1. Kofman, R., P. Cheyssac, et al. (2001). "Comment on "Melting of isolated tin nanoparticles"." Physical Review Letters 86(7): 1388. Kohno, H., S. Takeda, et al. (2000). "Plasmon-loss imaging of chains of crystalline-silicon nanospheres and silicon nanowires." Journal of Electron Microscopy 49(2): 275-80. Nanostructures in chains of crystalline-silicon nanospheres and silicon nanowires were investigated using energyfiltered transmission electron microscopy (TEM). Observation of the shape of the silicon nanospheres in the chains provided the direct evidence that the chains were formed via the surface oxidation process, which may preferentially work at the necks. The diverse nanostructures in silicon nanowires were revealed, and we found smooth-shaped wires which have periodically modulated silicon cores. Nanostructures in wire-chain transition regions were also investigated for the first time. The wire-chain transition is not a simple junction of a silicon nanowire and a chain of silicon nanospheres, but has a periodically modulated silicon core in the wire region near the transition position. Komiyama, H. S. a. H. (1999). "Migration-coalescence of Nanoparticles during Deposition of Au, Ag, Cu, and GaAs on Amorphous SiO2." Journal of Nanoparticle Research 1: 17-30. Kong, G., R. D. Braun, et al. (2000). "Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size." Cancer Research 60(16): 4440-5. The efficacy of novel cancer therapeutics has been hampered by the ability to deliver these agents to the tumor at effective concentrations. Liposomes have been used as a method to overcome some delivery issues and, in combination with hyperthermia, have been shown to increase drug delivery to tumors. Particle size has been

shown to affect the delivery of liposomes, but it is not known how hyperthermia affects size dependence. This study investigates the effect of hyperthermia (42 degrees C) on the extravasation of different sized nanoparticles (albumin; 100-, 200-, and 400-nm liposomes) from tumor microvasculature in a human tumor (SKOV-3 ovarian carcinoma) xenograft grown in mouse window chambers. In this model (at 34 degrees C), no liposomes were able to extravasate into the tumor interstitium. Hyperthermia enabled liposome extravasation of all sizes. The magnitude of hyperthermia-induced extravasation was inversely proportional to particle size. Thus, at normothermia (34 degrees C), the pore cutoff size for this model was between 7 and 100 nm (e.g., liposomes did not extravasate). At 42 degrees C, the pore cutoff size was increased to >400 nm, allowing all nanoparticles tested to be delivered to the tumor interstitium to some degree. With hyperthermia, the 100-nm liposome experienced the largest relative increase in extravasation from tumor vasculature. Hyperthermia did not enable extravasation of 100-nm liposomes from normal vasculature, potentially allowing for tumor-specific delivery. These experiments indicate that hyperthermia can enable and augment liposomal drug delivery to tumors and potentially help target liposomes specifically to tumors. Kong, G., R. D. Braun, et al. (2001). "Characterization of the effect of hyperthermia on nanoparticle extravasation from tumor vasculature." Cancer Research 61(7): 3027-32. The efficacy of novel cancer therapeutics can be hampered by inefficient delivery of agents to the tumor at effective concentrations. Liposomes have been used as a method to overcome some delivery issues and, in combination with hyperthermia, have been shown to increase drug delivery to tumors. This study investigates the effects of a range of temperatures (34-42 degrees C) and hyperthermia treatment scheduling (time between hyperthermia and drug administration as well as between consecutive hyperthermia treatments) on the extravasation of nanoparticles (100-nm liposomes) from tumor microvasculature in a human tumor (SKOV-3 ovarian carcinoma) xenograft grown in athymic nude mouse window chambers. Under normothermic conditions (34 degrees C) and at 39 degrees C, nanoparticles were unable to extravasate into the tumor interstitium. From 40 to 42 degrees C, nanoparticle extravasation increased with temperature, reaching maximal extravasation at 42 degrees C. Temperatures higher than 42 degrees C led to hemorrhage and stasis in tumor vessels. Enhanced nanoparticle extravasation was observed several hours after heating, decaying back to baseline at 6 h postheating. Reheating (42 degrees C for 1 h) 8 h after an initial heating (42 degrees C for 1 h) did not result in any increased nanoparticle extravasation, indicating development of vascular thermotolerance. The results of this study have implications for the application and scheduling of hyperthermia combined with other therapeutics (e.g., liposomes, antibodies, and viral vectors) for the treatment of cancer. Konno, T., K. Kurita, et al. (2001). "Preparation of nanoparticles composed with bioinspired 2-methacryloyloxyethyl phosphorylcholine polymer." Biomaterials 22(13): 1883-9. The poly(L-lactic acid) nanoparticles immobilized with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer, which has excellent blood compatibility, were prepared by a solvent evaporation technique using the watersoluble amphiphilic MPC polymer as an emulsifier and a surface modifier. The diameter and zeta-potential of the obtained nanoparticles strongly depended on the concentration of the MPC polymer. When the nanoparticles were prepared in 1.0 mg/ml of an MPC polymer aqueous solution, the diameter was 221 nm which was determined by atomic force microscopy and dynamic light scattering measurements. The X-ray photoelectron spectroscopic analysis indicated that the phosphorylcholine groups of the MPC unit were located at the surface of the nanoparticles, that is, the MPC polymer was immobilized on the PLA particles and the surface zeta-potential was -2.5 mV. Various hydrophobic fluorescence probes could permeate through the MPC polymer layer and adsorb on the PLA surface. The amount of bovine serum albumin adsorbed on the nanoparticles was significantly smaller compared with that on the conventional polystyrene nanoparticles. It is suggested that the nanoparticles immobilized with the MPC polymer have the potential for use as both a novel drug carrier and diagnostic reagent which can come in contact with blood components. Koper, O., E. Lucas, et al. (1999). "Development of reactive topical skin protectants against sulfur mustard and nerve agents." Journal of Applied Toxicology 19 Suppl 1(1): S59-70. The potential for highly reactive nanoparticles (RNP) to absorb destructively, i.e. to neutralize highly toxic substances such as the warfare agents GA, GB, HD and VX, has been demonstrated in the laboratory. Reactive nanoparticles represent a new class of nanoscale particles of metals and metal oxides that differ from other nanoparticles in reactivity and crystalline morphology. The potential for incorporating RNP into a protective barrier skin cream also has been demonstrated. Preliminary studies indicate that RNP are physically and chemically compatible with a base cream provided by the Army Medical Research Office and, importantly, remain reactive with chemical agents while promising to be compatible with skin contact. Kossovsky, N., A. Gelman, et al. (1995). "Surface-modified diamond nanoparticles as antigen delivery vehicles." Bioconjugate Chemistry 6(5): 507-11. Recognition of antigens by immunocompetent cells involves interactions that are specific to the chemical sequence and conformation of the epitope (antigenic determinant). Adjuvants that are currently used to enhance

immunity to antigens tend to either alter the antigen conformation through surface adsorption or shield potentially critical determinants, e.g., functional groups. It is demonstrated here that surface-modified diamond nanoparticles (5-300 nm) provide conformational stabilization, as well as a high degree of surface exposure to protein antigens. By enhancing the availability and activity of the antigen in vivo, a strong, specific immune response can be elicited. Results are demonstrated for mussel adhesive protein (MAP), a substance for which conventional adjuvants have proven only marginally successful in evoking an immune response. Surface-modified diamond nanoparticles as antigen delivery vehicles are a novel example of the exciting marriage of materials science, chemistry, and biology. Kottmann, J. P., O. J. Martin, et al. (2001). "Non-regularly shaped plasmon resonant nanoparticle as localized light source for near-field microscopy." Journal of Microscopy 202(Pt 1): 60-5. We study numerically two-dimensional nanoparticles with a non-regular shape and demonstrate that these particles can support many more plasmon resonances than a particle with a regular shape (e.g. an ellipse). The electric field distributions associated with these different resonances are investigated in detail in the context of near-field microscopy. Depending on the particle shape, extremely strong and localized near-fields, with intensity larger than 105 that of the illumination wave, can be generated. We also discuss the spectral dependence of these near-fields and show that different spatial distributions are observed, depending which plasmon resonance is excited in the particle. Kovtyukhova, N. I., E. V. Buzaneva, et al. (2000). "Ultrathin nanoparticle ZnS and ZnS:Mn films: surface sol-gel synthesis, morphology, photophysical properties." Materials Science and Engineering B Solid State Materials for Advanced Technology 70(19): 411-17. Ultrathin films of ZnS and Mn-doped ZnS were grown on silicon substrates using surface sol-gel reactions, and the film growth process was characterized by ellipsometry, atomic force microscopy, X-ray photoelectron spectroscopy, UV-visible absorbance and photoluminescence (PL) spectroscopy. The Si substrates were pretreated by chemical oxidation. On the oxidized Si/SiO/sub x/ surface, nanoparticulate films of ZnS and Mn-doped ZnS were grown by sequential immersion in aqueous metal acetate and sodium sulfide solutions. During the first four adsorption cycles, there was little film growth, but thereafter the amount of material deposited was linear with the number of adsorption cycles. This behavior is consistent with the formation of ZnS nuclei at low coverage, followed by particle growth in subsequent cycles. PL spectra are consistent with incorporation of Mn/sup 2+/ into the ZnS nanoparticles. (34 References). Kremar, M., W. M. Saslow, et al. (2000). "Optical materials by a modified sol-gel nanoparticle process." Proceedings of SPIE the International Society for Optical Engineering 3943: 74-84. Optical sol-gel materials have been of interest for many years. The reason is that through the preparation of sols with nanoparticulate liquid structures, transparent coatings of many inorganic oxides can be produced. By using oxides for example, with different refractive indices, reflective or antireflective coatings can be fabricated. To obtain stable layers, the gel coating have to be densified at higher temperatures, in general between 400 and 600 degrees C. This may be suitable for glass surfaces, but not for temperature sensitive substrates like plastics. In addition to this, if multilayer coatings have to be produced, between each step a densification process has to be carried out before the net coating step takes place. This leads to an unsatisfying situation if industrial low cost processing is required. In addition to this, the dip coating process is not suitable for high speed or large area coating techniques. This is one of the reasons whey the sol-gel process never has gained a real high significance for industrial coatings on glass and is limited to special products so far. (39 References). Krenn, J. R., M. Salerno, et al. (2001). "Light field propagation by metal micro- and nanostructures." Journal of Microscopy 202(Pt 1): 122-8. The ability to sustain plasmon oscillations gives rise to unique properties of metal nanostructures, which can be exploited for the controlled manipulation of light fields on the nanoscale. In this context we investigate electromagnetic coupling effects within lithographically produced ensembles of gold nanoparticles with a photon scanning tunnelling microscope. To provide an interface between these nano-optical devices and classical farfield optics, we investigate surface plasmon propagation on microstructured metal thin films. Kreuter, J. (1978). "Nanoparticles and nanocapsules--new dosage forms in the nanometer size range." Pharmaceutica Acta Helvetiae 53(2): 33-9. Kreuter, J. and E. Liehl (1981). "Long-term studies of microencapsulated and adsorbed influenza vaccine nanoparticles." Journal of Pharmaceutical Sciences 70(4): 367-71. Incorporation of antigens into nanometer-sized polymer particles was recently shown to lead to a good adjuvant effect. An optimal antibody response with killed influenza virus antigens was achieved with 0.5% poly(methyl methacrylate). Long-term experiments showed prolonged antibody response of polymer adjuvants with incorporated or adsorbed influenza virus. Adsorption also yielded an optimal adjuvant effect with 0.5%

poly(methyl methacrylate). The antibody response was accompanied by protection of the mice against infection with mice-adapted influenza virus. In addition, the polymer vaccines were more stable against temperature inactivation than were vaccines with aluminum hydroxide or without adjuvants. Kreuter, J., M. Nefzger, et al. (1983). "Distribution and elimination of poly(methyl methacrylate) nanoparticles after subcutaneous administration to rats." Journal of Pharmaceutical Sciences 72(10): 1146-9. Poly(methyl [1-14C]methacrylate) nanoparticles were injected subcutaneously into rats. Almost all of the radioactivity stayed at the injection site. After an initial urinary and fecal excretion of approximately 1% of the administered dose per day, the rate of elimination dropped to a low level (approximately 0.005%/day via the feces and approximately 0.0005%/day via the urine) within 70 days. After 200 days, the fecal elimination increased exponentially until a greater than 100-fold increase was observed after 287 days in one rat. After this time, a tendency for an increase in fecal elimination was also observed in the other animals, and the radioactivity in all organs and tissue increased by approximately 100 times in all animals in comparison with the organ radioactivity determinations at earlier times. Kreuter, J. and H. R. Hartmann (1983). "Comparative study on the cytostatic effects and the tissue distribution of 5fluorouracil in a free form and bound to polybutylcyanoacrylate nanoparticles in sarcoma 180-bearing mice." Oncology 40(5): 363-6. The binding of 5-fluorouracil to polybutylcyanoacrylate nanoparticles yielded an enhanced efficacy against Crocker sarcoma S 180 and a higher toxicity of the drug measured by induced leukopenia, body weight loss and premature death. The efficacy was further increased by an increase in the polymer-to-drug ratio. The nanoparticles yielded a prolonged persistence of the 5-fluorouracil in all organs examined including the tumor. These particles hold promise as carriers for cytostatics, since their distribution may be favorably altered by coating them with certain proteins or surfactants or by the attachment of monoclonal antibodies. Kreuter, J. (1983). "Evaluation of nanoparticles as drug-delivery systems. III: materials, stability, toxicity, possibilities of targeting, and use." Pharmaceutica Acta Helvetiae 58(9-10): 242-50. Kreuter, J. (1983). "Evaluation of nanoparticles as drug-delivery systems. II: Comparison of the body distribution of nanoparticles with the body distribution of microspheres (diameter greater than 1 micron), liposomes, and emulsions." Pharmaceutica Acta Helvetiae 58(8): 217-26. Kreuter, J., C. G. Wilson, et al. (1984). "Toxicity and association of polycyanoacrylate nanoparticles with hepatocytes." Journal of Microencapsulation 1(3): 253-7. The degradation of polybutylcyanoacrylate (PBC) and polyhexylcyanoacrylate (PHC) nanoparticles, together with their association with and toxicity towards isolated hepatocytes, were determined. Nanoparticles were not taken up by rat hepatocytes at a significant level. The LD50S of PBC and PHC nanoparticles towards hepatocytes were 0.4 mg/2 x 10(6) cells and greater than 1 mg/2 x 10(6) cells respectively. This hepatocyte toxicity cannot be attributed solely to the formaldehyde formed during degradation. Kreuter, J. (1985). "Poly(alkyl acrylate) nanoparticles." Methods in Enzymology 112(1): 129-38. Kreuter, J. (1988). "Possibilities of using nanoparticles as carriers for drugs and vaccines." Journal of Microencapsulation 5(2): 115-27. Kreuter, J. (1991). "Liposomes and nanoparticles as vehicles for antibiotics." Infection 19(Suppl 4(1)): S224-8. Colloidal drug carriers such as liposomes and nanoparticles are easily taken up by phagocytic cells and accumulate in the organs of the reticuloendothelial system. Therefore, they hold promise as carriers for the treatment of intracellular infections with antibiotics that would normally not find easy access to intracellular sites. Consequently, in in vitro and in vivo experiments the therapeutic efficacy of substances such as amphotericin B, dihydrostreptomycin, amikacin, ampicillin, stibogluconate against a number of microorganisms including Leishmania donovani, Candida albicans, Staphylococcus aureus, Mycobacterium avium, Listeria monocytogenes, and Salmonella typhimurium was increased significantly by binding to liposomes and nanoparticles. Kreuter, J. (1994). "Drug targeting with nanoparticles." European Journal of Drug Metabolism and Pharmacokinetics 19(3): 253-6. Nanoparticles are colloidal polymeric particles (size &lt; 1000 nm) to which drugs are bound by sorption, incorporation, or chemical binding. After intravenous injection they normally distribute into the organs of the reticuloendothelial system (liver, spleen, lungs, bone marrow). However, their body distribution can be altered by coating with surfactants or with physiological components such as serum complement factors. The influence of these coatings on the body distribution and possible mechanisms for the alteration of this distribution are discussed. Differently coated nanoparticles can be used for the targeting of bound drugs to tumors, to the brain,

and to inflamed areas in the body. Kreuter, J., R. N. Alyautdin, et al. (1995). "Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles)." Brain Research 674(1): 171-4. Transport of the hexapeptide dalargin across the blood-brain barrier was accomplished using a nanoparticle formulation. The formulation consisted of dalargin bound to poly(butyl cyanoacrylate) nanoparticles by sorption, coated with polysorbate 80. Intravenous injection of this formulation to mice resulted in an analgesic effect. All controls, including a simple mixture of the three components (drugs, nanoparticles, and surfactant) mixed directly before i.v. injection, exhibited no effect. Analgesia was also prevented by pretreatment with naloxone. Fluorescent and electron microscopic studies indicated that the passage of the particle-bound drug occurred by phagocytic uptake of the polysorbate 80-coated nanoparticles by the brain blood vessel endothelial cells. Kreuter, J. (1995). "Nanoparticles as adjuvants for vaccines." Pharmaceutical Biotechnology 6(6): 463-72. PMMA nanoparticle adjuvants can be manufactured in a physicochemically reproducible manner. Their particle size can be controlled within narrow limits. Immunogens may be either incorporated or adsorbed to these nanoparticles. PMMA nanoparticles induced significantly higher and more prolonged antibody responses against a variety of immunogens, including influenza virions and subunit vaccines, BSA, and HIV-1 and HIV-2 split vaccines. In addition, a protective immune response against challenge with live influenza virus was induced and a better stability of the immunogen was observed after incorporation or adsorption of influenza virions or subunits to PMMA nanoparticles. The observation that PMMA did not induce antibodies against gp120 contained in the HIV-2 split vaccine demonstrates that different adjuvants or carriers may be required for different antigens. A combination of two or more different adjuvants or carriers may be necessary to induce the optimal immune response against antigen mixtures as present in most vaccine preparations. PMMA seems to be a safe adjuvant material. It is very slowly biodegradable and has been used in surgery in humans for over 40 years, and now warrants continued investigation as a vaccine adjuvant. Kreuter, J. (1996). "Nanoparticles and microparticles for drug and vaccine delivery." Journal of Anatomy 189(Pt 3)(5293): 503-5. Nanoparticles are polymeric particles in the nanometer size range whereas microparticles are particles in the micrometre size range. Both types of particle are used as drug carriers into which drugs or antigens may be incorporated in the form of solid solutions or solid dispersions or onto which these materials may be absorbed or chemically bound. These particles have been shown to enhance the delivery of certain drugs across a number of natural and artificial membranes. In addition, the particles were shown to accumulate in areas of the intestine that appear to be the Peyer's patches. Possibly because of the combination of both effects these particles were able to significantly improve the bioavailability of some drugs after peroral administration in comparison with solutions. Recently nanoparticles coated with polysorbate 80 enabled the passage of small peptides and other drugs across the blood-brain barrier and the exhibition of a pharmacological effect after intravenous injection. Without the use of this type of nanoparticles the drugs did not cross this barrier and yielded no effect. Kreuter, J. (2001). "Nanoparticulate systems for brain delivery of drugs." Advances in Drug Delivery Review 47(1): 65-81. The blood--brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics, antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especially neuropeptides. One of the possibilities to overcome this barrier is a drug delivery to the brain using nanoparticles. Drugs that have successfully been transported into the brain using this carrier include the hexapeptide dalargin, the dipeptide kytorphin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/576, and doxorubicin. The nanoparticles may be especially helpful for the treatment of the disseminated and very aggressive brain tumors. Intravenously injected doxorubicin-loaded polysorbate 80-coated nanoparticles were able to lead to a 40% cure in rats with intracranially transplanted glioblastomas 101/8. The mechanism of the nanoparticlemediated transport of the drugs across the blood-brain barrier at present is not fully elucidated. The most likely mechanism is endocytosis by the endothelial cells lining the brain blood capillaries. Nanoparticle-mediated drug transport to the brain depends on the overcoating of the particles with polysorbates, especially polysorbate 80. Overcoating with these materials seems to lead to the adsorption of apolipoprotein E from blood plasma onto the nanoparticle surface. The particles then seem to mimic low density lipoprotein (LDL) particles and could interact with the LDL receptor leading to their uptake by the endothelial cells. After this the drug may be released in these cells and diffuse into the brain interior or the particles may be transcytosed. Other processes such as tight junction modulation or P-glycoprotein (Pgp) inhibition also may occur. Moreover, these mechanisms may run in parallel or may be cooperative thus enabling a drug delivery to the brain. Kriwet, B., E. Walter, et al. (1998). "Synthesis of bioadhesive poly(acrylic acid) nano- and microparticles using an inverse emulsion polymerization method for the entrapment of hydrophilic drug candidates." Journal of Controlled Release 56(13): 149-58. Bioadhesive latices of water-swollen poly(acrylic acid) nano-and microparticles were synthesized using an inverse

(W/O) emulsion polymerization method. They are stabilized by a co-emulsifier system consisting of SpanTM 80 and TweenTM 80 dispersed in aliphatic hydrocarbons. The initial polymerization medium contains emulsion droplets and inverse micelles which solubilize a part of the monomer solution. The polymerization is initiated by free radicals, and particle dispersions with a narrow size distribution are obtained. The particle size is dependent on the type of radical initiator used. With water-soluble initiators, for example ammonium persulfate, microparticles were obtained in the size range of 1 to 10 micrometer indicating that these microparticles originate from the emulsion droplets since the droplet sizes of the W/O emulsion show similar distribution. When lipophilic radical initiators, such as azobis-isobutyronitrile, are used, almost exclusively nanoparticles are generated with diameters in the range of 80 to 150 nm, due to the limited solubility of oligomeric poly(acrylic acid) chains in the lipophilic continuous phase. These poly(acrylic acid) micro- and nanoparticles yielded excellent bioadhesive properties in an in-vitro assay and may, therefore, be suitable for the encapsulation of peptides and other hydrophilic drugs. Kroll, R. A., M. A. Pagel, et al. (1998). "Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers." Neurosurgery 43(4): 879-86; discussion 886-9. OBJECTIVE: To compare transient blood-brain barrier disruption (BBBD) by hypertonic mannitol with pharmacological modification of the blood-tumor barrier by the vasoactive peptide bradykinin for delivery of small and large agents to nude rat intracerebral xenografts. METHODS: Female nude rats (n = 104) with 6-day intracerebral human small cell lung carcinoma tumors were treated using BBBD (n = 24), intracarotid bradykinin (n = 38), or saline (controls, n = 32) administered intra-arterially. During or immediately after infusion, the rats were given radiolabeled agent (methotrexate or dextran 70; Dupont NEN, Boston, MA). The rats were killed 10 minutes later, and samples of tumor and brain regions were obtained for scintillation counting. Twenty-two additional rats were examined using magnetic resonance imaging after administering one of two contrast agents (gadoteridol or iron oxide nanoparticles) or saline (controls) in conjunction with BBBD or bradykinin. RESULTS: After BBBD, the delivery of both small (methotrexate) and large (dextran 70) radiolabeled tracers was increased 2- to 6-fold in the tumor and 3- to 20-fold in surrounding brain, as compared with saline controls. After bradykinin treatment, there was minimal change in delivery of methotrexate or dextran 70 to tumor and brain around tumor, with the greatest increase less than 60% over controls. Magnetic resonance imaging demonstrated increased delivery of both small and large contrast agents to the treated hemisphere after BBBD. In comparison, no increased tumor enhancement could be detected after bradykinin treatment. CONCLUSION: BBBD resulted in global delivery of a variety of agents in a wide range of sizes. In this human brain tumor xenograft model, bradykinin was not effective at increasing delivery to the tumor of any agent tested. Krzic, M., M. Sentjurc, et al. (2001). "Improved skin oxygenation after benzyl nicotinate application in different carriers as measured by EPR oximetry in vivo." Journal of Control Release 70(1-2): 203-11. The development of formulations, which increase skin oxygenation and of methods for measuring oxygen levels in skin are important for dealing with processes affected by the level of oxygen, e.g., rate of healing and efficiency of radiation oncology. In this study we have investigated the role of carriers on the efficacy of benzyl nicotinate (BN) action in skin after dermal application in different formulations by EPR oximetry in vivo. The time course of pO2 in the skin after application of rubefacient is followed directly for the first time. The results obtained proved the applicability of in vivo EPR oximetry as a sensitive method by which small alterations in pO2 can be detected. We have found that the type of vehicle significantly influences the time when BN starts to act, the duration of its action, and the maximal increase in pO2. The ranking of vehicle efficiency was: lipid nanoparticles in hydrophilic gel>liposomes in hydrophilic gel>hydrophilic gel>hydrophobic ointment>hydrophobic cream. Primarily the semisolid vehicle determines the lag-time of action, but the maximal oxygen level is influenced decisively by the particulate carrier systems. BN effectiveness was dose dependent. 2.5% w/w concentration of BN appears to be the most appropriate for therapeutic application. After repeated application a successive increase of pO2 base line in skin and of the maximal pO2 was noticed. Kubiak, C., P. Couvreur, et al. (1989). "Increased cytotoxicity of nanoparticle-carried Adriamycin in vitro and potentiation by verapamil and amiodarone." Biomaterials 10(8): 553-6. The cytotoxicities of free cyanoacrylic nanoparticles, free Adriamycin, Adriamycin-loaded nanoparticles and a mixture of Adriamycin and nanoparticles are compared in cancer cell cultures. Increased cytotoxicity was observed in the sensitive (DC3F) subline when Adriamycin was in particulate form rather than free. In the derived pleiotropic resistant subline (DC3F AD/AZA), sensitivity to Adriamycin was completely restored with the conjugate. Addition of verapamil or amiodarone allowed an enhancement of efficiency of tenfold for free Adriamycin and between two- and fourfold for its conjugate form. Vectorization by nanoparticles and pharmacological modulation of cell membrane can act in synergy in synergy to overcome the resistance to Adriamycin in vitro. Kubitschko, S., J. Spinke, et al. (1997). "Sensitivity enhancement of optical immunosensors with nanoparticles." Analytical

Biochemistry 253(1): 112-22. In recent years, several optical sensor techniques have been developed for the direct monitoring of biomolecular recognition processes at the surface of a sensor chip. Applications of these immunosensors for the determination of substances in serum could be demonstrated only for a few analytes due to the lack of sensitivity. Beside nonspecific binding of serum components to the sensor surface, the analytical sensitivity of these sensors is limited by the molecular weight of the analyte, so that smaller analyte molecules give only a moderate sensor response. In order to enhance the sensor signal, the use of mass labels, such as latex particles, was proposed in the literature. However, detection limits comparable to those of conventional ELISA techniques could not be realized so far. We demonstrate the optimization of a &quot;nanoparticle enhanced immunosensor assay&quot; for the detection of thyroid stimulating hormone, with respect to the particle coating, size, and nonspecific binding. The developed prototype assay requires a sample volume of 225 &amp;mgr;L and has a measuring range up to 35 mIU/L. For the first time, we obtained a detection limit of 0.03 mIU/L (0.1 pm), which is fully competitive to conventional ELISA techniques. The assay allows serum samples to be measured with good precision and dilution linearity. The sensor can be reused several times and shows an excellent correlation to a commercial enzyme immunoassay. Kukan, M., S. Bezek, et al. (1989). "Fate of 14C-terpolymer (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles after peroral administration to rats." Pharmazie 44(5): 339-40. The fate of 14C-terpolymer (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles was studied in male Wistar rats after peroral administration. These nanoparticles may reach systemic circulation as evidenced by the plasma 14C level, excretion of the label in the urine, as well as organ label deposition. It was found that at least 2% of the dose of 14C was absorbed from the gastrointestinal tract. As expected, the radioactive nanoparticles were excreted predominantly via the feces. The amount of the label in the gastrointestinal tract, liver, and carcasses fell below the limit of detection on day seven after administration. However in the spleen and lung some slight radioactivity persisted after 7 d of experiment. Kukan, M., V. Koprda, et al. (1991). "Disposition of lypophilized (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles in rats and their effect on zoxazolamine paralysis time." Pharmazie 46(1): 37-9. The fate of lyophilized (methylmethacrylate-14C, 2-hydroxyethylmethacrylate, butylacrylate) nanoparticles was studied in male Wistar rats after p.o. administration. It was found that at least 4% of the dose of 14C was absorbed from the gastrointestinal tract after a single dose with these nanoparticles. Some radioactivity (less than 0.15% of dose) was found 7 d after administration in lung, spleen and liver. As expected excretion of the label was predominated via the feces. Ten d of p.o. treatment of rats with lyophilized nanoparticles (1 g/kg of body weight) was shown to prolong significantly zoxazolamine paralysis time. This result suggests that lyophilized nanoparticles decreased elimination of zoxazolamine. Kumbhojkar, N., V. V. Nikesh, et al. (2000). "Photophysical properties of ZnS nanoclusters." Journal of Applied Physics 88(11): 6260-4. Optical measurements on ZnS nanoclusters have been carried out to investigate surface effects along with quantum size effects. ZnS nanocrystals have been synthesized in the range of 1.5-2.5 nm, using different chemical methods as well as electronic passivating procedures. The size of nanoparticles has been estimated from empirical pseudopotential calculations. We have obtained a significantly narrower size distribution of ZnS nanocrystals than reported in earlier published results. We observed band gap luminescence in mercaptoethanol capped ZnS nanocrystals. Effects of various defect levels on the luminescent behavior of ZnS nanoparticles have been examined. (30 References). Kunioka, Y. and T. Ando (1996). "Innocuous labeling of the subfragment-2 region of skeletal muscle heavy meromyosin with a fluorescent polyacrylamide nanobead and visualization of individual heavy meromyosin molecules." Journal of Biochemistry (Tokyo) 119(6): 1024-32. We have studied transglutaminase-catalyzed incorporation of monodansylcadaverine and monobiotincadaverine into rabbit skeletal muscle heavy meromyosin (HMM). The incorporation of dansylcadaverine reached saturation at 4 mol per 1 mol of HMM. An electrophoretogram of the chymotryptic digest of the dansyl-labeled HMM revealed that the labeling took place primarily in the S-2 region of HMM. Atomic force microscopic images and electron micrographs of the complexes of the biotinylated HMM and UltraAvidin-coated fluorescent polyacrylamide nanoparticles revealed that the biotinylated site on S-2 was very close to the C-terminus (near the S-2/light meromyosin junction). In keeping with this result, together with HMM's key sites being localized on the S1 region, the enzymatic conjugation of biotincadaverine had no influence upon the actin-activated ATPase activity of HMM or upon the ability of HMM to actuate sliding of actin filaments in in vitro motility assay. Attachment of an UltraAvidin-coated fluorescent nanobead to the biotinylated HMM also did not alter the motile activity of HMM. Thus, we can optically pinpoint individual HMM molecules in a sample, which will facilitate handling and manipulation of single HMM molecules and observation of their functional behavior.

Kwak, S. Y., S. H. Kim, et al. (2001). "Hybrid organic/inorganic reverse osmosis (RO) membrane for bactericidal antifouling. 1. Preparation and characterization of TiO2 nanoparticle self-assembled aromatic polyamide thin-film-composite (TFC) membrane." Environment and Science Technology 35(11): 2388-94. Hybrid organic/inorganic reverse osmosis (RO) membranes composed of aromatic polyamide thin films underneath titanium dioxide (TiO2) nanosized particles have been fabricated by a self-assembly process, aiming at breakthrough of biofouling problems. First, positively charged particles of the colloidal TiO2 were synthesized by a sol-gel process, and the diameter of the resulting particles in acidic aqueous solution was estimated to be approximately 2 nm by analyzing the UV-visible absorption characteristics with a quantum mechanical model developed by Brus. Transmission electron microscopy (TEM) further confirmed the formation of the quantumsized TiO2 particles (approximately 10 nm or less). The TiO2 particles appeared to exist in the crystallographic form of anatase as observed with the X-ray diffraction (XRD) pattern in comparison with those of commercial 100% rutile and commercial 70:30% anatase-to-rutile mixture. The hybrid thin-film-composite (TFC) aromatic polyamide membranes were prepared by self-assembly of the TiO2 nanoparticles on the polymer chains with COOH groups along the surface. They showed improved RO performance in which the water flux even increased, though slightly. Field-emission scanning electron microscopy (FESEM) exhibited the TiO2 nanoparticles well adsorbed onto the surface. X-ray photoelectron spectroscopy (XPS) demonstrated quantitatively that a considerable amount of the adsorbed particles were tightly self-assembled at the expense of the initial loss of those that were loosely bound, and became stabilized even after exposure to the various washing and harsh RO operating conditions. The antibacterial fouling potential of the TiO2 hybrid membrane was examined and verified by measuring the viable numbers and determining the survival ratios of the Escherichia coli (E. coli) as a model bacterium, both with and without UV light illumination. The photocatalytic bactericidal efficiency was remarkably higher for the TiO2 hybrid membrane under UV illumination, compared to that of the same membrane in darkness, as well as those for the neat membranes under either light condition. Kwon, G. S. (1998). "Diblock copolymer nanoparticles for drug delivery." Critical Reviews in Therapeutic Drug Carrier Systems 15(5): 481-512. Diblock copolymers can form nanoparticles, that is, micelles and nanospheres, that are being studied as carriers for hydrophobic drugs and genes. The synthetic carriers mimic the spherical, supramolecular core/shell structure of lipoproteins and viruses. Hence, diblock copolymer nanoparticles may be functional, having the ability to solubilize, protect, and release drugs at sustained rates. Several studies have illustrated prolonged residence times in blood for diblock copolymer nanoparticles. They have also enhanced drug effects in animals. Diblock copolymer nanoparticles are potentially useful carriers for site-specific drug delivery. La Porta, A., G. A. Voth, et al. (2001). "Fluid particle accelerations in fully developed turbulence." Nature 409(6823): 10179. The motion of fluid particles as they are pushed along erratic trajectories by fluctuating pressure gradients is fundamental to transport and mixing in turbulence. It is essential in cloud formation and atmospheric transport, processes in stirred chemical reactors and combustion systems, and in the industrial production of nanoparticles. The concept of particle trajectories has been used successfully to describe mixing and transport in turbulence, but issues of fundamental importance remain unresolved. One such issue is the Heisenberg-Yaglom prediction of fluid particle accelerations, based on the 1941 scaling theory of Kolmogorov. Here we report acceleration measurements using a detector adapted from high-energy physics to track particles in a laboratory water flow at Reynolds numbers up to 63,000. We find that, within experimental errors, Kolmogorov scaling of the acceleration variance is attained at high Reynolds numbers. Our data indicate that the acceleration is an extremely intermittent variable--particles are observed with accelerations of up to 1,500 times the acceleration of gravity (equivalent to 40 times the root mean square acceleration). We find that the acceleration data reflect the anisotropy of the largescale flow at all Reynolds numbers studied. Labhasetwar, V., C. Song, et al. (1998). "Arterial uptake of biodegradable nanoparticles: effect of surface modifications." Journal of Pharmaceutical Sciences 87(10): 1229-34. Restenosis is the reobstruction of an artery following interventional procedures such as balloon angioplasty or stenting. Local pharmacotherapeutic approaches using controlled release systems are under investigation to inhibit the regional pathophysiologic process of restenosis. We have been investigating biodegradable nanoparticles (100 +/- 39 nm in diameter, mean +/- sd) for the local intra-arterial drug delivery. The purpose of this study was to investigate nanoparticle surface modifications (see Table 1) to enhance their arterial uptake. The PLGA (polylactic polyglycolic acid copolymer) nanoparticles were formulated by an oil-in-water emulsion solvent evaporation technique using a 2-aminochromone (U-86983, Upjohn and Pharmacia) (U-86) as a model antiproliferative agent. The various formulations of nanoparticles were evaluated for the arterial wall uptake by using an ex-vivo dog femoral artery model. The selected formulations were then tested in vivo in acute dog femoral artery and pig coronary artery models. The nanoparticles surface modified with a cationic compound, didodecyldimethylammonium bromide (DMAB), demonstrated 7-10-fold greater arterial U-86 levels compared to the unmodified nanoparticles in different ex-vivo and in-vivo studies. The mean U-86 levels were 10.7 +/- 1.7

microg/10 mg (dog) and 6.6 +/- 0.6 microg/10 mg (pig) in the artery segments ( approximately 2 cm) which were infused with the nanoparticles. The pig coronary studies further demonstrated that the infusion of nanoparticles with higher U-86 loading reduced the arterial U-86 levels, whereas increasing the nanoparticle concentration in the infusion solutions increased the arterial U-86 levels. The biodistribution studies in pigs following coronary arterial administration of nanoparticles demonstrated disposition of U-86 in the myocardium and distally in the liver and the lung. The mechanism of enhanced arterial uptake of the DMAB surface modified nanoparticles seems to be due to the alteration in the nanoparticle surface charge. The unmodified nanoparticles had a zeta potential of -27.8 +/- 0.5 mV (mean +/- sem, n = 5), whereas the DMAB modified nanoparticles demonstrated a zeta potential of +22.1 +/- 3.2 mV (mean +/- sem, n = 5). The adsorption of DMAB to the nanoparticle surface followed the Freundlich isotherm with binding capacity k = 28.1 &amp;mgr;g/mg and affinity constant p = 2. 33. In conclusion, surface modified nanoparticles have potential applications for intra-arterial drug delivery to localize therapeutic agents in the arterial wall to inhibit restenosis. Labib, A., V. Lenaerts, et al. (1991). "Biodegradable nanospheres containing phthalocyanines and naphthalocyanines for targeted photodynamic tumor therapy." Pharmacetical Research 8(8): 1027-31. Preparation methods of cyanoacrylic nanocapsules or nanoparticles containing phthalocyanines and naphthalocyanines are described. Nanocapsules were obtained by interfacial polymerization in an oil-in-water emulsion. Drug encapsulation efficiency depended upon drug concentration, ethanol concentration, and phthalocyanine sulfonation degree and reached 100% in some cases. Nanocapsules size ranged from 150 to 250 nm and varied with phthalocyanine sulfonation degree and pH of the aqueous phase. Nanoparticles were prepared by the addition of monomer to an aqueous phase containing hydrophilic phthalocyanine derivatives. Depending upon the pH, sizes ranged from 10 to 380 nm. Drug binding was between 75 and 80%. These new preparations could prove useful in the photodynamic treatment of tumors. Lacava, L. M., Z. G. Lacava, et al. (2001). "Magnetic resonance of a dextran-coated magnetic fluid intravenously administered in mice." Biophysics Journal 80(5): 2483-6. Magnetic resonance was used to investigate the kinetic disposition of magnetite nanoparticles (9.4 nm core diameter) from the blood circulation after intravenous injection of magnetite-based dextran-coated magnetic fluid in female Swiss mice. In the first 60 min the time-decay of the nanoparticle concentration in the blood circulation follows the one-exponential (one-compartment) model with a half-life of (6.9 +/- 0.7) min. The X-band spectra show a broad single line at g approximately 2, typical of nanomagnetic particles suspended in a nonmagnetic matrix. The resonance field shifts toward higher values as the particle concentration reduces, following two distinct regimes. At the higher concentration regime (above 10(14) cm(-3)) the particle-particle interaction responds for the nonlinear behavior, while at the lower concentration regime (below 10(14) cm(-3)) the particleparticle interaction is ruled out and the system recovers the linearity due to the demagnetizing field effect alone. Lacoste, T. D., X. Michalet, et al. (2000). "Ultrahigh-resolution multicolor colocalization of single fluorescent probes." Proceedings of the National Academy of Sciences U S A 97(17): 9461-6. An optical ruler based on ultrahigh-resolution colocalization of single fluorescent probes is described in this paper. It relies on the use of two unique families of fluorophores, namely energy-transfer fluorescent beads (TransFluoSpheres) and semiconductor nanocrystal quantum dots, that can be excited by a single laser wavelength but emit at different wavelengths. A multicolor sample-scanning confocal microscope was constructed that allows one to image each fluorescent light emitter, free of chromatic aberrations, by scanning the sample with nanometer scale steps with a piezo-scanner. The resulting spots are accurately localized by fitting them to the known shape of the excitation point-spread function of the microscope. We present results of two-dimensional colocalization of TransFluoSpheres (40 nm in diameter) and of nanocrystals (3-10 nm in diameter) and demonstrate distance-measurement accuracy of better than 10 nm using conventional far-field optics. This ruler bridges the gap between fluorescence resonance energy transfer, near- and far-field imaging, spanning a range of a few nanometers to tens of micrometers. Ladizhansky, V., G. Hodes, et al. (2000). "Solid state NMR study of water binding on the surface of CdS nanoparticles." Journal of Physical Chemistry B 104(9): 1939-43. CdS nanoparticles precipitated from aqueous solution were studied by /sup 1/H NMR. The nanoparticles were deliberately not capped by any surface termination agent. The samples had porous structure. Proton high spinning speed magic angle spinning (MAS) NMR spectra revealed that there are three abundant proton species in nanoparticle samples prepared with an excess of Cd, having different chemical shifts: a relatively narrow peak due to hydroxyl groups and two broader lines resulting from adsorbed water molecules with different chemical environments. The relative intensities of the lines were temperature-dependent, reflecting a complicated chemical equilibration processes. A small fraction of water molecules (~5%) experiences anisotropic dynamic motion as deduced from the analysis of the dipolar sideband patterns. The main part of the spectrum was due to rapidly exchanging protons. The exchange between protons of the same type occurs on a time scale not much longer than 1 mu s. The exchange between different lines was studied by 2D exchange MAS spectroscopy. The analysis

of the proton-proton correlation spectra as a function of the mixing time led us to the conclusion that the nanocrystalline surface is covered by clusters of water. The clusters are well separated from each other and are formed by protons occupying sites with the same chemical environment. The size of the pores was also estimated to be of the order of a few nanometers. (16 References). Lakowicz, J. R., I. Gryczynski, et al. (2000). "Time-resolved spectral observations of cadmium-enriched cadmium sulfide nanoparticles and the effects of DNA oligomer binding." Analytical Biochemistry 280(1): 128-36. We measured the steady-state and time-resolved fluorescence spectral properties of cadmium-enriched nanoparticles (CdS-Cd2+). These particles displayed two emission maxima, at 460 and 580 nm. The emission spectra were independent of excitation wavelength. Surprisingly, the intensity decays were strongly dependent on the observation wavelength, with longer decay times being observed at longer wavelengths. The mean lifetime increased from 150 to 370 ns as the emission wavelength was increased from 460 to 650 nm. The wavelengthdependent lifetimes were used to construct the time-resolved emission spectra, which showed a growth of the long-wavelength emission at longer times, and decay-associated spectra, which showed the longer wavelength emission associated with the longer decay time. These nanoparticles displayed anisotropy values as high as 0.35, depending on the excitation and emission wavelengths. Such high anisotropies are unexpected for presumably spherical nanoparticles. The anisotropy decayed with two correlation times near 5 and 370 ns, with the larger value probably due to overall rotational diffusion of the nanoparticles. Addition of a 32-base pair oligomer selectively quenched the 460-nm emission, with less quenching being observed at longer wavelengths. The timeresolved intensity decays were minimally affected by the DNA, suggesting a static quenching mechanism. The wavelength-selected quenching shown by the nanoparticles may make them useful for DNA analysis. Lalande, G., M. C. Denis, et al. (2000). "Pt-based nanocomposites produced by high energy ball milling as electrocatalysts in polymer electrolyte fuel cells." Journal of New Materials for Electrochemical Systems 3(3): 185-92. Ball milling of Pt powder with powders of WO/sub 2/, WO/sub 3/, MoO/sub 2/ or MoO/sub 3/ has been performed to synthesize CO-tolerant nanocomposite anode electrocatalysts for polymer electrolyte membrane fuel cells. In order to increase the specific surface area of the final products and to prevent sticking during milling, MgH/sub 2/ was added to the powders as a dispersing agent. After milling, MgH/sub 2/ was leached away in 1M HCl (lixiviation step). The specific surface areas of the new catalysts range from 12.4 to 33.5 m/sup 2//g. X-ray diffraction indicates that WO/sub 3/-based catalysts are true nanocomposites while MoO/sub x/-based systems display only the Pt structure. Catalysts obtained by milling Pt+WO/sub 3/ are made of Pt nanocrystals and crystallites of WO/sub 3/.H/sub 2/O, H/sub 1.12/WO/sub 3/2H/sub 2/O and H/sub 2/WO/sub 2/H/sub 2/O, while catalysts obtained by milling Pt+WO/sub 2/ are made of Pt nanocrystals and crystallites of WO/sub 3/ and WO/sub 3/.H/sub 2/O. For the Pt+MoO/sub x/ systems, the ball milled Mo oxides decompose into Mo-based species and are leached away during the lixiviation step. X-ray photoelectron spectroscopy of Pt+MoO/sub 2/ indicates that some Mo remains in these catalysts and that it is in solid solution into the Pt structure. In fuel cell tests with H/sub 2/+100 ppm CO at the anode and O/sub 2/ at the cathode, Pt+WO/sub x/ catalysts and commercial PtRu black display comparable CO-tolerance while Pt+MoO/sub x/ powders exhibit lower performances. Pt+WO/sub x/ catalysts lack, however long term stability, their current density at 0.5 V decreasing at about 3%/100 hours. (19 References). Lambert, G., E. Fattal, et al. (1998). "Effect of polyisobutylcyanoacrylate nanoparticles and lipofectin loaded with oligonucleotides on cell viability and PKC alpha neosynthesis in HepG2 cells." Biochimie 80(12): 969-76. The aim of the present study was to evaluate the inhibitory effect on protein kinase C alpha (PKC alpha) neosynthesis of antisense oligonucleotides delivered by two types of carriers. First, PKC alpha antisense oligonucleotides were associated with polyisobutylcyanoacrylate (PIBCA) nanoparticles pre-coated with cetyltrimethyl ammonium bromide (CTAB), a hydrophobic cation. Adsorption of oligonucleotides onto PIBCA nanoparticles was shown to be a saturating process. From these studies, it was possible to identify two types of particles: positively and negatively charged. Secondly, Lipofectin was used as another carrier system. These systems were incubated with HepG2 cells. Toxicity was evaluated by the MTT assay, and PKC alpha neosynthesis was determined by Western blots in conditions where nanoparticles and Lipofectin were not inducing cytotoxicity. It was observed that both mismatch and antisense oligonucleotides induced an inhibition of PKC alpha neosynthesis when loaded onto cationic or anionic nanoparticles as well as when complexed to cationic liposomes (Lipofectin). This non-specific effect was only observed in the phase of PKC alpha neosynthesis when the cells were first depleted in PKC alpha by phorbol 12-myristate beta-acetate (12-PMA) and in the absence of serum. These results strongly suggest that delivery systems, PIBCA nanoparticles or Lipofectin, containing a positively charged component (CTAB or cationic lipids), are able to induce a perturbation in the intracellular metabolic activity. In conclusion, it was shown that the commonly used strategy of oligonucleotides targeting with cationic non-viral vectors may display non-specific effects which can lead to artifactual results. Lambert, G., E. Fattal, et al. (2000). "Polyisobutylcyanoacrylate nanocapsules containing an aqueous core as a novel colloidal carrier for the delivery of oligonucleotides." Pharmacetical Research 17(6): 707-14.

PURPOSE: The goal of the present paper was to encapsulate oligonucleotides in a new particulate carrier in order to protect them from enzymatic degradation. METHODS: Nanocapsules with an aqueous core containing oligonucleotides were prepared by interfacial polymerization of isobutylcyanoacrylate in a W/O emulsion. Ultracentrifugation and re-suspension in water yielded a dispersion of these containing an aqueous core nanocapsules. Zeta potential measurements and quenching of fluorescence of fluorescein-bounded oligonucleotides were used to study the localization of the oligonucleotides. Oligonucleotide degradation studies were carried out in fetal calf serum. RESULTS: Polydisperse nanocapsules of size ranging from 20 to 400 nm were obtained. Oligonucleotide loading did not significantly influence the zeta potential, suggesting they were located within the core of the nanocapsules. Fluorescence quenching assays confirmed this localization. When encapsulated in the nanocapsules and incubated in the presence of serum, the oligonucleotides were efficiently protected from degradation by nucleases, whereas oligonucleotides adsorbed onto nanospheres were protected less efficiently. CONCLUSIONS: This paper describes, for the first time, a nanotechnology able to encapsulate oligonucleotides rather than adsorbing them at the surface of a solid support. Such a formulation has great potential for oligonucleotide delivery. Lambert, G., E. Fattal, et al. (2001). "Nanoparticulate systems for the delivery of antisense oligonucleotides." Advances in Drug Delivery Reviews 47(1): 99-112. Antisense oligonucleotides are molecules that are able to inhibit gene expression being therefore potentially active for the treatment of viral infections or cancer. However, because of their poor stability in biological medium and their weak intracellular penetration, colloidal drugs carriers such as nanoparticles were developed for the delivery of oligonucleotides (ODN). ODN associated to nanoparticles were shown to be protected against degradation and to penetrate more easily into different types of cells. As a consequence, nanoparticles were shown to improve the efficiency of ODNs for the inhibition of the proliferation of cells expressing the point mutated Ha-ras gene. In vivo, polyalkylcyanoacrylate (PACA) nanoparticles were able to efficiently distribute the ODNs to the liver whereas the alginate nanosponges could concentrate the ODNs in the lungs. Finally, ODN loaded to PACA nanoparticles were able to improve in mice, the treatment of RAS cells expressing the point mutated Haras gene. Lamprecht, A., N. Ubrich, et al. (1999). "Biodegradable monodispersed nanoparticles prepared by pressure homogenization-emulsification." International Journal of Pharmacy 184(1): 97-105. The aim of the present work was to investigate the preparation of nanoparticles (NP) as potential drug carriers for proteins. The hydrophilic protein bovine serum albumin (BSA) was chosen as the model drug to be incorporated within NP. Owing to the high solubility of the protein in water, the double emulsion technique has been chosen as one of the most appropriate method. In order to reach submicron size we used a microfluidizer as a homogenization device with a view to obtaining NP with a very high grade of monodispersity. Two different biodegradable polymers, poly[D, L-lactic-co-glycolic acid] 50/50 (PLGA) and poly[epsilon-caprolactone] (PCL) has been used for the preparation of the NP. The drug loading has been optimized by varying the concentration of the protein in the inner aqueous phase, the polymer in the organic phase, the surfactant in the external aqueous phase, as well as the volume of the external aqueous phase. The BSA encapsulation efficiency was high (&gt;80%) and release profiles were characterized by a substantial initial burst release for both PLGA and PCL NP. A higher release was obtained at the end of the dissolution study for PLGA NP (92%) compared with PCL NP (72%). Copyright Lamprecht, B., G. Schider, et al. (2000). "Metal nanoparticle gratings: influence of dipolar particle interaction on the plasmon resonance." Physical Review Letters 84(20): 4721-4. We probe the influence of grating effects on plasmon excitations in gold nanoparticles arranged in regular twodimensional patterns. Samples produced by electron-beam lithography are investigated by femtosecond timeresolved and spectroscopic methods. We find a strong dependence of the plasmon lifetime and resonance wavelength on the grating constant. (17 References). Lamprecht, A., N. Ubrich, et al. (2000). "Influences of process parameters on nanoparticle preparation performed by a double emulsion pressure homogenization technique." International Journal of Pharmacy 196(2): 177-82. The preparation of nanoparticles (NP) as an improved colloidal carrier system for proteins was investigated. Bovine serum albumin (BSA) was used as model drug. Owing to the high solubility of the protein in water, the double emulsion technique has been chosen as one of the most appropriate method. In order to both reaching submicron size as well as increasing the grade of monodispersity compared to previous preparation techniques, a microfluidizer as homogenization device was used. All experiments were performed using two biodegradable polymers, poly[D,L-lactic-co-glycolic acid] 50/50 (PLGA) and poly[varepsilon-caprolactone] (PCL). The homogenization procedure has been optimized with regard to particle size and monodispersity by studying the influence of the homogenization time as well as the amount of polymer and surfactant in the external aqueous phase. The drug loading has been improved by varying the concentration of the protein in the inner aqueous phase. By increasing the protein concentration in the inner aqueous phase the polydispersity was slightly higher,

while the particle size was not influenced significantly. The BSA encapsulation efficiency decreased with higher protein concentration in the inner aqueous phase. All release profiles were characterized by a initial burst effect, a higher release rate was obtained after 4 weeks for PLGA NP (60%) compared with PCL NP (47%). Lamprecht, A., N. Ubrich, et al. (2001). "Design of rolipram-loaded nanoparticles: Comparison of two preparation methods." Journal of Control Release 71(3): 297-306. The aim of the present work was to investigate the preparation of nanoparticles as a potential drug carrier and targeting system for the treatment of inflammatory bowel disease. Rolipram was chosen as the model drug to be incorporated within nanoparticles. Pressure homogenization-emulsification (PHE) with a microfluidizer or a modified spontaneous emulsification solvent diffusion method (SESD) were used in order to select the most appropriate preparation method. Poly(varepsilon-caprolactone) has been used for all preparations. The drug loading has been optimized by varying the concentration of the drug and polymer in the organic phase, the surfactants (polyvinyl alcohol, sodium cholate) as well as the volume of the external aqueous phase. The rolipram encapsulation efficiency was high (>85%) with the PHE method in all cases, whereas with the SESD method encapsulation efficiencies were lower (<40%) when lower surfactant concentrations and reduced volume of aqueous phase were used. Release profiles were characterized by a substantial initial burst release with the PHE method (25-35%) as well as with the SESD method (70-90%). A more controlled release was obtained after 2 days of dissolution with the PHE method (70-90%), no further significant drug release was observed with the SESD method. Landry, F. B., D. V. Bazile, et al. (1996). "Degradation of poly(D,L-lactic acid) nanoparticles coated with albumin in model digestive fluids (USP XXII)." Biomaterials 17(7): 715-23. Entirely biodegradable poly(D, L-lactic acid) (PLA50) nanoparticles coated with albumin were prepared by the solvent evaporation technique. Their degradative properties were investigated in simulated gastric and intestinal fluids (USP XXII). The degradation of the albumin coating was monitored by HPLC, whereas PLA50 degradation was determined by size exclusion chromatography (SEC) as well as by the detection of lactate in bulk solution by enzymatic assay. As expected, the coating effect of albumin, a readily digestible protein, rapidly disappeared in both gastric and intestinal media, thus exposing albumin-free PLA50 cores to hydrolytic processes. In pepsin-rich simulated gastric fluid, no degradation of the PLA50 core was observed over 8 h incubation time. In contrast, in pancreatin-rich simulated intestinal fluid, the PLA50 nanoparticles were rapidly converted into lactate. The results showed that the PLA50 degradation was mainly due to an enzymatic cleavage process. Further experiments showed the involvement of lipases in the degradation of the PLA50 core in simulated intestinal fluid. Landry, F. B., D. V. Bazile, et al. (1998). "Peroral administration of 14C-poly(D,L-lactic acid) nanoparticles coated with human serum albumin or polyvinyl alcohol to guinea pigs." Journal of Drug Targeting 6(4): 293-307. Biodegradable 14C-poly(D,L-lactic acid) (PLA50) nanoparticles coated either with a readily digestible protein albumin or with a non-digestible coating agent, polyvinyl alcohol (PVA), were prepared by the solvent evaporation technique. The nanoparticles were administered perorally to guinea pigs to evaluate the gastro-intestinal degradation of their PLA50 matrix. In the case of PLA50 nanoparticles coated with digestible albumin, substantial gastro-intestinal degradation of the PLA50 matrix occurred, leading to the passage of considerable amount (&gt; or =45%) of water-soluble products across the gastrointestinal barrier. When a non-digestible coating agent like PVA was used, the degradation of the PLA50 matrix in the gastro-intestinal tract was at least two times lower (&gt; or =19%). The results show that it is possible to control the in vivo degradation of PLA50 nanoparticles using appropriate coating agents. The present investigations showed a good correlation between previously observed in vitro results and the in vivo findings. Langer, K., C. Coester, et al. (2000). "Preparation of avidin-labeled protein nanoparticles as carriers for biotinylated peptide nucleic acid." European Journal of Pharmaceutics and Biopharmaceutics 49(3): 303-7. The possibility of preparing protein nanoparticles followed by covalent linkage of avidin was investigated. Free sulfhydryl groups were introduced onto the surface of protein nanoparticles either by aldehyde quenching with cysteine or reaction of free amino groups with 2-iminothiolane. The number of primary amino groups and sulfhydryl groups on the surface of the resulting particles was quantified with site-specific reagents. Avidin was attached to the surface of the thiolated nanoparticles via a bifunctional spacer which reacted in a first step with amino groups of avidin and in a second step with the sulfhydryl groups introduced onto the surface of the nanoparticles. Biotinylated peptide nucleic acid (PNA) as a model compound for biotinylated drugs was effectively coupled to the nanoparticles by complex formation with the covalently attached avidin. Since the formation of the interaction between biotin and avidin is very rapid and stable a highly effective drug carrier system for biotinylated compounds such as PNAs was achieved. Lanza, G. M., D. R. Abendschein, et al. (2000). "In vivo molecular imaging of stretch-induced tissue factor in carotid arteries with ligand-targeted nanoparticles." Journal of the American Society of Echocardiography 13(6): 608-14. Molecular imaging permits tissues to be functionally characterized by identification of specific cell-surface

receptors with targeted contrast agents. In our study, a ligand-targeted acoustic nanoparticle system was used to identify the angioplasty-induced expression of tissue factor by smooth muscle cells within the tunica media. Pig carotid arteries were overstretched bilaterally with balloon catheters, treated with a tissue factor-targeted or a control nanoparticle system, and imaged with intravascular ultrasound (20 MHz) before and after treatment. Carotid wall acoustic reflectivities were unaffected by overstretch injury. Tissue factor-targeted nanoemulsion bound and increased the echogenicity of smooth muscle cells expressing tissue factor within the tunica media. The targeted emulsion increased the arterial wall gray scale (99.4+/-14.5; P<.05) relative to pretreatment (41.8+/11.1, P<0.05) and the control gray scale (pre-emulsion: 49.3+/-9.5; post-emulsion: 43.7+/-6.4; P<.05). The area of acoustic enhancement appeared to coincide with expression of induced tissue factor in the tunica media confirmed by immunohistochemistry. We have demonstrated that this novel nanoemulsion can infiltrate into arterial walls after balloon injury and localize the expression of overstretch-induced tissue factor within pig carotid arteries. Molecular imaging and quantification of complex, biochemical change, such as tissue factor expression after angioplasty, may prove to be a prognostically important predictor of subsequent restenosis. Lanza, G. M., D. R. Abendschein, et al. (2000). "Molecular imaging of stretch-induced tissue factor expression in carotid arteries with intravascular ultrasound." Investigative Radiology 35(4): 227-34. RATIONALE AND OBJECTIVES: Molecular imaging with targeted contrast agents enables tissues to be distinguished by detecting specific cell-surface receptors. In the present study, a ligand-targeted acoustic nanoparticle system is used to identify angioplasty-induced expression of tissue factor by smooth muscle cells within carotid arteries. METHODS: Pig carotid arteries were overstretched with balloon catheters, treated with tissue factor-targeted or a control nanoparticle system, and imaged with intravascular ultrasound before and after treatment. RESULTS: Tissue factor-targeted emulsions bound and increased the echogenicity and gray-scale levels of overstretched smooth muscle cells within the tunica media, versus no change in contralateral control arteries. Expression of stretch-induced tissue factor in carotid artery media was confirmed by immunohistochemistry. CONCLUSIONS: The potential for abnormal thrombogenicity of balloon-injured arteries, as reflected by smooth muscle expression of tissue factor, was imaged using a novel, targeted, nanoparticulate ultrasonic contrast agent. Lanza Gregory, M., R. Abendschein Dana, et al. (2000). "Targeted delivery of doxorubicin to vascular smooth muscle cells using a novel, tissue factor-specific acoustic nanoparticle contrast agent." Circulation 102(18 Supplement): 561. Larsericsdotter, H., S. Oscarsson, et al. (2001). "Thermodynamic analysis of proteins adsorbed on silica particles: Electrostatic effects." Journal of Colloid and Interface Science 237(1): 98-103. Electrostatic effects on protein adsorption were investigated using differential scanning calorimetry (DSC) and adsorption isotherms. The thermal denaturation of lysozyme, ribonuclease A (RNase), and alpha-lactalbumin in solution and adsorbed onto silica nanoparticles was examined at three concentrations of cations: 10 and 100 mM of sodium and 100 mM of sodium to which 10 mM of calcium was added. The parameters investigated were the denaturation enthalpy (DeltaH), the temperature at which the denaturation transition was half-completed (T(m)), and the temperature range of the denaturation transition. For lysozyme and RNase, adsorption isotherms depend strongly on the ionic strength. At low ionic strength both proteins have a high affinity for the silica particles and adsorption is accompanied by a 15-25% reduction in DeltaH and a 3-6 degrees C decrease in T(m), indicating that the adsorbed state of the proteins is destabilized. Also, an increase in the width of the denaturation transition is observed, signifying a larger conformational heterogeneity of the surface bound proteins. At higher ionic strengths, both with and without the addition of calcium, no significant adsorption-induced alteration in DeltaH was observed for all three proteins. The addition of calcium, however, decreases the width of the denaturation transition for lysozyme and RNase in the adsorbed state. Copyright 2001 Academic Press. Laverman, P., M. G. Carstens, et al. (2001). "Recognition and clearance of methoxypoly(ethyleneglycol)2000-grafted liposomes by macrophages with enhanced phagocytic capacity. Implications in experimental and clinical oncology." Biochimica et Biophysica Acta 1526(3): 227-9. Intravenous injection of an endotoxin-free solution of poloxamine-908 to rats can enhance the phagocytic clearance capacity of tissue macrophages, particularly those of the liver and the spleen. Such stimulated cells were able to clear a significant portion of intravenously injected methoxypoly(ethyleneglycol)2000 liposomes (mean size of 87 nm), labelled with technetium-99m via the N-hydroxysuccinimidyl hydrazine nicotinate hydrochloride derivative of distearoyl phosphatidylethanolamine, within 4 h post administration. These liposomes, otherwise, exhibit long circulatory behaviour in control animals, with poor localization to the liver and spleen. We suggest that such technetium-99m-labelled engineered vesicles may be of aid for detection of the liver and spleen macrophages with enhanced phagocytic clearance capacity by gamma scintigraphy. Alterations in the phagocytic activity of liver and spleen macrophages is known to occur during cancer. Therefore, such diagnostic procedures may prove useful for patient selection or for monitoring the progress of treatment with long circulating nanoparticles carrying anti-cancer agents, thus minimizing damage to this important line of body's defence cells, and are discussed.

Lazarides, A. A., K. Lance Kelly, et al. (2000). "Orientational melting of two-shell carbon nanoparticles: molecular dynamics study." Chemical Physics Letters 328: 4-6. The energetic characteristics of two-shell carbon nanoparticles (onions) with different shapes of second shell are calculated. The barriers of relative rotation of shells are found to be surprisingly small; therefore, free relative rotation of shells can take place at room temperature. The intershell orientational melting of the nanoparticle is studied by molecular dynamics. The parameters of the Arrhenius formula for jumprotational intershell diffusion are calculated. The rotation of shells can be observed beginning from a temperature of 70 K. (35 References). Lazarides, A. A. and G. C. Schatz (2000). "DNA-linked metal nanosphere materials: structural basis for the optical properties." Journal of Physical Chemistry B 104(3): 460-7. The structural basis for the aggregation-induced optical properties of colloidal gold nanosphere aggregates is examined by means of electrodynamics calculations. Recently developed methods for calculating the electrodynamic response of aggregates composed of large numbers of small metal nanospheres in a dielectric medium are used to determine the optical changes associated with the formation of spherical aggregates. The calculations use accurate nanoparticle polarizabilities determined from Mie theory, an iterative conjugate gradient solution algorithm, and fast-Fourier transform methods for efficient solution of the electrodynamic interacting nanoparticle equations. The UV extinction lowering and the shifting and broadening of the visible plasmon peak observed experimentally in solutions of DNA-linked gold nanospheres are explained as the collective electromagnetic response of thousands of nanoparticles. (39 References). Lazarides, A. A., K. K. Lance, et al. (2000). "Optical properties of metal nanoparticles and nanoparticle aggregates important in biosensors." Theochem Journal of Molecular Structure 529(8): 59-63. This article describes recent advances in electrodynamics theory that are being used to describe the extinction spectra of noble metal nanoparticles and of aggregates of nanoparticles. In one application we have extended the finite element discrete dipole approximation theory to the description of nonspherical metal particles, including the substrate on which they are sitting. In another application, we have developed a new dynamic effective medium approximation for the description of aggregates of spherical gold nanoparticles that are linked using DNA. (16 References). Lazell, M. and P. O'Brien (2000). "Synthesis of self-capped metal sulfide nanoparticles." Nanophase and Nanocomposite Materials III. Symposium 581: 175-80. We report the synthesis of metal sulfide nanocrystals, (CdS and ZnS), from the thermolysis, between 150-300 degrees C, in a dynamic vacuum, of the novel long chain asymmetric metal dithiocarbamates, bis(NmethyloctadecyIdithiocarbamato) cadmium(II) or zinc(II), M{S/sub 2/CN(C/sub 18/H/sub 37/)(CH/sub 3/)}/sub 2/. These nanoparticles `self-cap' during preparation. Different size nanocrystals were synthesised, at different temperatures and there was a change in phase from cubic to hexagonal CdS at a decomposition temperature greater than 300 degrees C. (22 References). Le Ray, A. M., M. Vert, et al. (1994). "End-chain radiolabeling and in vitro stability studies of radiolabeled poly(hydroxy acid) nanoparticles." Journal of Pharmaceutical Sciences 83(6): 845-51. In order to study the tissue distribution of biodegradable nanoparticles after oral administration in animals, endchain-radiolabeled poly(D,L-lactides) were prepared. Two groups of polymers (Mn = 7500, I = 2.4 and Mn = 28000, I = 1.4 as determined by organic size-exclusion chromatography) were chemically modified by reaction of [14C]acetic anhydride with hydroxyl end-chain groups. The activities of both resulting radioactive poly(D,Llactides) varied from 57 to 1140 microCi/g. Poly(D,L-lactide) or poly(D,L-lactide-co-glycolide) nanoparticles containing various amounts of radioactive polymer were prepared according to the solvent evaporation process with acetone as cosolvent with methylene chloride in the organic phase. Their mean diameter was 133 +/- 25 nm, measured by photon correlation spectroscopy. The radiolabeled-end-group stability of these particles in buffer solutions was found to be greater when the matrix was made from the radiolabeled poly(D,L-lactide) having the highest molecular weight and the lowest polydispersity index. The polymer-chain stability was totally retained for at least 1 week in a phosphate buffer, pH 7.4, i.e. for the selected experiment time. Le Roy Boehm, A. L. and H. Fessi (2000). "[Pharmaceutical applications of the zeta potential--use in characterization of colloidal drug carriers]." Journal de Pharmacie de Belgique 55(2): 40-8. Colloidal drug carriers which mainly involve submicron emulsions, nanoparticles, microparticles, liposomes and lipid complexes have received increasing interest in recent years mainly as vehicles of lipophilic drugs and as improved delivery systems for drug targeting. Size and encapsulation efficiency are, in general, the two parameters used to characterize these pharmaceutical forms. Nevertheless, the surface characteristics of these dispersion have been known to influence their physical, chemical and biological properties. Then, the aim of these study is to evaluate, with some examples and illustrations, the interest of zeta potential determinations to improve the characterization of these colloidal drug carriers.

Le Roy Boehm, A. L., R. Zerrouk, et al. (2000). "Poly epsilon-caprolactone nanoparticles containing a poorly soluble pesticide: formulation and stability study." Journal of Microencapsulation 17(2): 195-205. In 1997, a research program was initiated in the laboratories to assess the ability of nanosperes (NS) to improve the biodelivery of new active ingredients (AI) to plants. The goal was to obtain stable poly (epsilon-caprolactone) NS (PeC-NS) with the smallest size and the largest amount of encapsulated AI, using a nanoprecipitation method. The smallest particles obtained were in the range of 200-250 nm. The highest encapsulation is obtained with Montanox 80 as surfactant and is between 5-10% (expressed in per cent weight relative to the total weight of polymer), which corresponds to an encapsulation yield of 95%. There is no desorption of the AI with time. In contrast, the dilution of the NS suspension in water is followed by a large removal of the AI in the aqueous phase. This suggests that NS are complex dynamic systems in equilibrium with the external medium and disturbances of this system lead to a loss of AI. Lee, C. H., A. Singla, et al. (2001). "Biomedical applications of collagen." International Journal of Pharmacology 221(1-2): 1-22. Collagen is regarded as one of the most useful biomaterials. The excellent biocompatibility and safety due to its biological characteristics, such as biodegradability and weak antigenecity, made collagen the primary resource in medical applications. The main applications of collagen as drug delivery systems are collagen shields in ophthalmology, sponges for burns/wounds, mini-pellets and tablets for protein delivery, gel formulation in combination with liposomes for sustained drug delivery, as controlling material for transdermal delivery, and nanoparticles for gene delivery and basic matrices for cell culture systems. It was also used for tissue engineering including skin replacement, bone substitutes, and artificial blood vessels and valves. This article reviews biomedical applications of collagen including the collagen film, which we have developed as a matrix system for evaluation of tissue calcification and for the embedding of a single cell suspension for tumorigenic study. The advantages and disadvantages of each system are also discussed. Lefebvre d'Hellencourt, C., L. Diaw, et al. (1995). "Immunomodulation by cytokine antisense oligonucleotides." European Cytokine Network 6(1): 7-19. The cytokine network is involved in normal immune reaction and in the progression of several pathologies. Antisense (AS) oligonucleotides, which allow specific inhibition of expression of proteins, offer a new methodology to investigate this complex network. This revi ew focuses on the use of AS to modulate cytokine expression. AS may act in different ways such as blocking fixation or progression of the ribosome along the mRNA, mRNA cleavage by RNase H, or preventing normal RNA maturation. In order to improve AS efficiency, chemical modifications have been developed, and improvement of oligonucleotide uptake has been achieved with different systems of vectorization including liposomes (neutral, cationic, immunoliposome), nanoparticles, or covalent attachment of a carrier. In oncogenesis, intracellular or extracellular autocrine loops have been demonstrated by the use of cytokine AS. Involvement of cytokines in immunological reactions (TH1 and TH2 subset, IgE response, lymphokine activated killer, cytotoxic T lymphocyte...) and in hematopoiesis have also been studied with this approach. Therapeutic application of AS has been suggested by inhibition of inflammatory cytokines in vivo. Clinical trials using AS are under investigation in virological and in oncological diseases. At present, cytokine antisenses primarily represent a tool for dissecting the function of a cytokine in vitro, but they may offer in the future a new way for immunomodulation intervention. Legrand, J., C. Petit, et al. (2000). "Collective effect on magnetic properties of 2D superlattices of nanosized cobalt particles." Applied Surface Science 164(1): 186-92. We report fabrication, structural and magnetic properties of cobalt nanocrystals. They are synthesized in colloidal assemblies. The coated cobalt particles are air stable. Due to the narrow size distribution of these 8 nm particles, they self-assembled after deposition on a flat substrate. The magnetic response depends on the organization. When they are dispersed in a solution, the saturation is not reached at 2 T even at 3 K, they are still a superparamagnetic part in the signal. When particles are organized in 2D superlattices, saturation is reached at lower applied field, compared to isolated particles. This is attributed to an increase of dipolar interaction. However, the hysteresis loop markedly differs with the sample orientation in the applied field. This confirms the dipolar magnetic interactions between cobalt nanoparticles. (11 References). Lehmann, J., M. Merschdorf, et al. (2000). "Surface plasmon dynamics in silver nanoparticles studied by femtosecond time-resolved photoemission." Physical Review Letters 85(14): 2921-4. Multiphoton photoelectron spectroscopy reveals the multiple excitation of the surface plasmon in silver nanoparticles on graphite. Resonant excitation of the surface plasmon with 400 nm femtosecond radiation allows one to distinguish between photoemission from the nanoparticles and the substrate. Two different previously unobserved decay channels of the collective excitation have been identified, namely, decay into one or several single-particle excitations.

Lemoine, D., C. Francois, et al. (1996). "Stability study of nanoparticles of poly(epsilon-caprolactone), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide)." Biomaterials 17(22): 2191-7. The objective was to evaluate the stability of nanoparticles prepared with poly(epsilon-caprolactone), poly(D,Llactide) and poly(D,L-lactide-co-glycolide) polymers and stored at different temperatures and in different media. The stability parameters studied were molecular weight and crystallinity of the polymer, nanoparticle size and pH. The results show that the stability of polymeric nanoparticles depends on (i) the type of polymers with the following increasing order of polymer stability: PLA25GA50 &lt; PLA37.5GA25 &lt; PLA50 = PCL, (ii) the storage temperature: PCL and PLA50 nanoparticles can be kept at 4 degrees C and RT during one year, while PLA37.5GA25 and PLA25GA50 nanoparticles have to be stored at 4 degrees C, and (iii) the storage conditions: buffering or freeze-drying nanoparticles improves stability. Lemoine, D. and V. Preat (1998). "Polymeric nanoparticles as delivery system for influenza virus glycoproteins." Journal of Controlled Release 54(1): 15-27. The objective of this work was to develop a new delivery system which could enhance the mucosal immune response to influenza virus antigens. Poly(D,L-lactide-co-glycolide) nanoparticles of about 200 nm containing hemagglutinin were chosen as the delivery system. Due to the amphiphilic nature of hemagglutinin (hydrophilic HA1 and hydrophobic HA2), nanoparticles were prepared by both classical oil in water solvent evaporation technique as well as by a [(water-in-oil) in water] solvent evaporation technique. Hemagglutinin was well encapsulated in nanoparticles prepared by both techniques. Molecular weight and antigenicity of entrapped hemagglutinin were not affected by the entrapment procedure. Lenaerts, V., J. F. Nagelkerke, et al. (1984). "In vivo uptake of polyisobutyl cyanoacrylate nanoparticles by rat liver Kupffer, endothelial, and parenchymal cells." Journal of Pharmaceutical Sciences 73(7): 980-2. Polyalkyl cyanoacrylate nanoparticles were previously developed as a biodegradable, ultrafine, solid drug carrier. Distribution studies in the rat showed an intense and rapid hepatic uptake. This liver accumulation appears to represent, to a certain extent, extracellularly bound nanoparticles. During liver perfusion, 15-20% of the liverassociated nanoparticles were washed out. The cellular distribution of strongly cell-associated nanoparticles was determined. At different intervals after injection of radioactive nanoparticles to rats, the cells were isolated according to a recently developed, low-temperature procedure during which processing of the carrier was inhibited. At all tested times, a relatively intense capture by Kupffer cells in comparison with endothelial and especially parenchymal cells was observed. This distribution pattern was not influenced by the size of the nanoparticles (0.08-0.215-micron diameter). This specific interaction of nanoparticles with Kupffer cells opens possibilities for the treatment of some parasitic diseases involving this cell type. Lenaerts, V., P. Couvreur, et al. (1984). "Degradation of poly (isobutyl cyanoacrylate) nanoparticles." Biomaterials 5(2): 65-8. Poly(isobutyl cyanoacrylate) nanoparticles were prepared. They were degraded in two enzyme-free media at pH 7 and 12 in the presence of rat liver microsomes. The conventional formaldehyde-producing degradation route was studied, and showed a very low efficiency. Another pathway, consisting of ester hydrolysis, was identified and studied. In contrast to the formaldehyde pathway, ester hydrolysis was shown to be catalysed by enzymes. Finally, the release rate of adsorbed actinomycin from nanoparticles was proved to correlate exactly with the degradation rate of the polymer. Lenaerts, V., P. Raymond, et al. (1989). "New method for the preparation of cyanoacrylic nanoparticles with improved colloidal properties." Journal of Pharmaceutical Sciences 78(12): 1051-2. The purpose of this study was to prepare nanoparticles with a size significantly smaller than 0.1 micron. It was shown that when sulphur dioxide was dissolved in the cyanoacrylic monomer at a high concentration, subsequent anionic polymerization in an aqueous phase produced particles as small as 10 nm. Moreover, the obtained particles displayed an important negative charge which improve their stability against aggregation. Finally, nanoparticles were successfully prepared in double-distilled water, thereby avoiding the use of dextran which can induce anaphylactoid reactions. Leo, E., R. Arletti, et al. (1997). "General and cardiac toxicity of doxorubicin-loaded gelatin nanoparticles." Farmaco 52(67): 385-8. General and cardiac toxicity of doxorubicin loaded gelatin nanoparticles cross-linked by glutaraldheyde were investigated in healthy rats. The rats were treated with free doxorubicin (DXR), unloaded nanoparticles (UNp), physical mixture of doxorubicin and unloaded nanoparticles (DRX/UNp), and DXR-loaded nanoparticles (DXRNp). Each group of animals received the same dose of DXR (3 mg/kg) via i.p. once a week. Both electrocardiogram (ECG) parameters and body weight were measured 24 h before each administration. Rats treated with UNp behaved as controls. DXR/UNp provoked the same toxic effects as free DXR. On the contrary, DXR-Np resulted more toxic since significant variations of both the body weight and the ECG parameters were observed during the first week of treatment. In addition, the rats treated with DXR-Np died between the 3rd and

the 5th day after the 2nd administration. These results demonstrate that, in these experimental conditions, the couplage of DXR to nanoparticles enhanced the cardiotoxicity of the drug. Since DXR was linked to the protein matrix of nanoparticles via glutaraldehyde, the high toxicity of DXR-loaded nanoparticles could be due to the covalent binding of the drug to the carrier. Leo, E., R. Cameroni, et al. (1999). "Dynamic dialysis for the drug release evaluation from doxorubicin-gelatin nanoparticle conjugates." International Journal of Pharmacy 180(1): 23-30. The drug release from doxorubicin (DXR)-gelatin nanoparticle conjugates was evaluated by means of a dynamic dialysis technique. The study was carried out in absence and in presence of a proteolytic enzyme (trypsin) able to degrade the carrier. In a preliminary study the apparent permeability constant (Kcv) of the drug through the dialysis bag was evaluated in several media. On the basis of this screening, a saline solution (NaCl 0.9%, w/v) resulted appropriate to carry out the dialysis study since, in this medium, the Kcv did not depend on the drug concentration in the donor solution. In absence of the enzyme only a little fraction (from 9 to 13%, w/w of the drug content) was released from nanoparticles. This fraction was considered as the evidence of the free drug fraction. After the addition of trypsin, the diffusion of a further drug fraction was observed. This fraction is probably due to a fraction of the DXR-peptide conjugates characterised by a molecular weight lower than membrane cut-off (3500 Da). Leroueil-Le Verger, M., L. Fluckiger, et al. (1998). "Preparation and characterization of nanoparticles containing an antihypertensive agent." European Journal of Pharmaceutics and Biopharmaceutics 46(2): 137-43. Isradipine, an antihypertensive agent, was encapsulated by the nanoprecipitation method using polymers including poly(epsilon-caprolactone), poly(D,L-lactide) and poly(d, L-lactide-co-glycolide). In vitro scanning electron microscopy and differential scanning calorimetry were used to characterize the nanoparticles. The average diameters of the nanoparticles ranged from 110 nm to 208 nm. PCL nanoparticles were larger than nanoparticles prepared with the other polymers. The zeta potential of the nanoparticles was negative, with values of about -25 mV which promoted good stabilization of the particles. The amorphous state of PLA and PLAGA nonloaded nanoparticles and the semi-crystalline state of PCL were demonstrated with X-ray diffraction and differential scanning calorimetry. For all nanoparticles, isradipine was found to be totally amorphous in the polymer which suggested that the drug was molecularly dispersed in the matrix. The colloidal suspensions displayed a sustained release profile in comparison with the drug release profile of isradipine in a PEG solution. Results from this investigation suggest that these nanospheres will be a good candidate delivery system for oral administration, to reduce the initial hypotensive peak and to prolong the antihypertensive effect of the drug. Leroux, J. C., P. Gravel, et al. (1994). "Internalization of poly(D,L-lactic acid) nanoparticles by isolated human leukocytes and analysis of plasma proteins adsorbed onto the particles." Journal of Biomedical Materials Research 28(4): 471-81. The objective of this work was to investigate the interactions of poly(D,L-lactic acid) nanoparticles prepared by a recently developed salting-out process, with lymphocytes and monocytes isolated from healthy human donors. Nanoparticles were labeled with a hydrophobic fluorescent dye and incubated with lymphocytes and monocytes, and their uptake was followed by flow cytometry in the presence and absence of plasma. Plasma protein adsorption increased nanoparticle uptake by monocytes, whereas a decrease of cellular binding of the nanoparticles to lymphocytes was noted. The cellular uptake for both cell types consisted in a passive adsorption and in an energy-requiring process, because the cells became 2-3 times more fluorescent when the incubation temperature was increased from 4 to 37 degrees C. When nanoparticles were coated with polyethylene glycol 20,000, uptake by monocytes decreased by 43 and 78% in phosphate-buffered saline and plasma, respectively; a similar decrease in nanoparticle uptake was observed for lymphocytes. Two-dimensional gel electrophoresis was performed to identify the plasma opsonins adsorbed onto the nanoparticle surface. Protein mappings for uncoated and polyethylene glycol-coated nanoparticles differed for two spot series. These spots, not yet clearly identified, may represent specific apolipoproteins involved in the metabolism of human lipoproteins, indicating the possible involvement of specific receptors in the uptake of the nanoparticles. Leroux, J. C., R. Cozens, et al. (1995). "Pharmacokinetics of a novel HIV-1 protease inhibitor incorporated into biodegradable or enteric nanoparticles following intravenous and oral administration to mice." Journal of Pharmaceutical Sciences 84(12): 1387-91. CGP 57813 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease. This lipophilic compound was successfully entrapped into poly(D,L-lactic acid) (PLA) and pH sensitive methacrylic acid copolymers nanoparticle. The intravenous administration to mice of PLA nanoparticles loaded with CGP 57813 resulted in a 2-fold increase of the area under the plasma concentration-time curve, compared to a control solution. An increase in the elimination half-life (from 13 to 61 min) and in the apparent volume of distribution (1.73.6 L/kg) was observed for the nanoparticle incorporated compound vs control solution. Following oral administration, only nanoparticles made of the methacrylic acid copolymer soluble at low pH provided sufficient plasma levels of CGP 57813. In vitro, these nanoparticles dissolved completely within 5 min at pH 5.8. PLA nanoparticles, which are insoluble in the gastrointestinal tract, did not provide significant plasma concentrations of

CGP 57813. From these observations, one can conclude that the passage of intact PLA nanoparticles across the gastrointestinal mucosa appears to be very low. Leroux, J. C., F. De Jaeghere, et al. (1995). "An investigation on the role of plasma and serum opsonins on the internalization of biodegradable poly(D,L-lactic acid) nanoparticles by human monocytes." Life Sciences 57(7): 695-703. We demonstrate here that polyethylene glycol (PEG) 6,000 protects biodegradable poly(D,L-lactic acid) nanoparticles (PLA NP) from extensive uptake by monocytes in plasma. These results are in agreement with those previously obtained with PEG 20,000 which reduced the uptake of PLA NP by human monocytes in phosphate buffered saline and plasma, and prolonged the NP circulation time in vivo. The coating efficiency of PEG 6,000 and 20,000 was substantially decreased in serum. The difference between the uptake of plain and coated NP clearly reappeared for PEG 20,000-coated NP in heat inactivated serum and in IgG-depleted serum. We suggest that typical plasma proteins, heat labile serum proteins (e.g. complement components) and IgG are involved in the opsonization of plain and coated PLA NP. Other proteins previously found to adsorb onto these NP, namely albumin and apolipoprotein E, did not appear to directly influence the uptake process. Leroux, J. C., R. M. Cozens, et al. (1996). "pH-sensitive nanoparticles: an effective means to improve the oral delivery of HIV-1 protease inhibitors in dogs." Pharm Res 13(3): 485-7. Lescure, F., C. Seguin, et al. (1994). "Preparation and characterization of novel poly(methylidene malonate 2.1.2.)-made nanoparticles." Pharm Res 11(9): 1270-7. Poly(methylidene malonate 2.1.2.) (PMM 2.1.2.) nanoparticles were prepared in phosphate buffer through emulsion polymerization of monomeric units; the kinetics of the reaction was monitored by spectrophotometry at 400 nm. Average nanoparticle sizes, molecular weights, and biodegradability of this potential drug carrier were determined under various conditions. As previously demonstrated for other similar monomers, i.e. IHCA or IBCA, pH influenced the physico-chemical characteristics of the nanoparticles obtained. Ethanol release from the esterbearing side chains indicated that the polymers were susceptible to hydrolysis when incubated in basic pH or in rat plasma. A secondary degradation pathway, yielding formaldehyde through a reverse Knoevenagel's reaction, was minimal. Cytotoxicity studies of this new vector, in vitro, against L929 fibroblast cells demonstrated that PMM 2.1.2. nanoparticles were better tolerated than other poly(alkylcyanoacrylate) (PACA) carriers. Pharmacokinetic studies were also carried out to observe the fate of 14C-labelled PMM 2.1.2. nanoparticles after intravenous administration to rats. Forty eight hour post-injection, more than 80% of the radioactivity was recovered in urine and faeces. The body distribution of the polymer was estimated by measuring the radioactivity associated with liver, spleen, lung and kidneys. Five minutes after injection, a maximum of 24 +/- 2% of the total radioactivity was detected in the liver and less than 0.4% in the spleen. The liver-associated radioactivity decreased according to a biphasic profile and less than 8% of the total radioactivity remained after 6 days. Lesko, S., E. Lesniewska, et al. (2001). "Investigation by atomic force microscopy of forces at the origin of cement cohesion." Ultramicroscopy 86(1-2): 11-21. In cement paste, the cohesion results of the interactions between calcium silicate hydrate (CSH) surfaces in an interstitial ionic solution. (N, V, T) Monte Carlo simulations show that the interactions are due to the ion correlation forces influenced by the surface charge density, the ionic concentration and the ion valence. This paper deals with the direct measurement in solutions by atomic force microscopy (AFM) of the forces and the interaction ranges between a probe and an atomically smooth substrate covered by CSH nanoparticles. Different electrolytic solutions (Ca(OH)2, CaCl2, NaCl, NaOH) have been used in order to determine influent parameters permitting to identify the nature of acting forces. Investigations have been rendered possible by selecting appropriate experimental setup and solutions. The selected probe and substrate on which CSH nanoparticles have previously grown are neutral regarding the reactivity during experiments permitting the exchange of solutions. Results show that a force originates from electrostatic nature and differs from Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. Agreement is found between experiments and (N,V,T) Monte Carlo simulations of ionic correlation forces. These forces are at the origin of the cohesion of cement paste. Letsinger, R. L., R. Elghanian, et al. (2000). "Use of a steroid cyclic disulfide anchor in constructing gold nanoparticleoligonucleotide conjugates." Bioconjugate Chemistry 11(2): 289-91. A new anchoring group is described for binding oligonucleotides to gold surfaces. On the basis of a ketal derived from 4,5-dihydroxy-1, 2 dithiane and epiandrosterone, it is easy to prepare and to link to oligonucleotides. Gold nanoparticle-oligonucleotide conjugates made using this cyclic disulfide linker serve as effective probes for detecting specific oligonucleotide sequences, and they exhibit much greater stability toward dithiothreitol than corresponding conjugates prepared with the conventional mercaptohexyl group or an acyclic disulfide unit. The high stability toward thiol deactivation likely results, in part at least, from anchoring each oligonucleotide to gold through two sulfur atoms. Lettieri, S., O. Fiore, et al. (2000). "Strategy of nanocluster and nanostructure synthesis by conventional pulsed laser

ablation." Applied Surface Science 154(155): 345-52. We describe the basic principles of nanoparticle synthesis by conventional pulsed laser ablation. The generalization of the Zeldovich and Raizer theory of condensation has been performed for inhomogeneous laserinduced plume where the rates of nucleation as well as the condensation times are different for different parts of the plume. The theoretical development and analysis of the experimental results are given for condensation, expansion and properties of silicon nanoclusters. (40 References). Leu, D., B. Manthey, et al. (1984). "Distribution and elimination of coated polymethyl [2-14C]methacrylate nanoparticles after intravenous injection in rats." Journal of Pharmaceutical Sciences 73(10): 1433-7. Surfactant-coated polymethyl [2-14C]methacrylate nanoparticles had significantly different time-course distribution patterns in rats than noncoated and albumin-coated particles. Blood concentrations of poloxamer 188-coated particles were 70-fold higher after 30 min, and the particles persisted at higher levels in the circulation for up to 2 h. The initial and final liver levels were significantly lower (38% after 30 min, 51% after 7 d) and spleen levels were significantly higher (21% after 30 min, 23% after 7 d) than non-coated particles (74% in the liver and 5% in the spleen after 7 d) and the albumin-coated particles (84% in the liver and 5% in the spleen after 7 d). Specific activity was somewhat higher for the surfactant-coated particles in other organs such as the lungs, kidneys, testicles, ovaries, and lymph nodes. The bovine serum albumin sorption behavior of polymethyl methacrylate nanoparticles was followed under various conditions, and adsorption was found to increase with increasing protein concentration and increasing temperature, reaching a maximum at the isoelectric point of pH 4.9 after approximately 12 h of incubation. The zeta potential of the particles decreased with increasing pH, and the change was more pronounced with the albumin-coated particles. Lewin, M., N. Carlesso, et al. (2000). "Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells." Nature Biotechnology 18(4): 410-4. The ability to track the distribution and differentiation of progenitor and stem cells by high-resolution in vivo imaging techniques would have significant clinical and research implications. We have developed a cell labeling approach using short HIV-Tat peptides to derivatize superparamagnetic nanoparticles. The particles are efficiently internalized into hematopoietic and neural progenitor cells in quantities up to 10-30 pg of superparamagnetic iron per cell. Iron incorporation did not affect cell viability, differentiation, or proliferation of CD34+ cells. Following intravenous injection into immunodeficient mice, 4% of magnetically CD34+ cells homed to bone marrow per gram of tissue, and single cells could be detected by magnetic resonance (MR) imaging in tissue samples. In addition, magnetically labeled cells that had homed to bone marrow could be recovered by magnetic separation columns. Localization and retrieval of cell populations in vivo enable detailed analysis of specific stem cell and organ interactions critical for advancing the therapeutic use of stem cells. Lherm, C., P. Couvreur, et al. (1987). "Unloaded polyisobutylcyanoacrylate nanoparticles: efficiency against bloodstream trypanosomes." Journal of Pharmacy and Pharmacology 39(8): 650-2. The potential use of polyisobutylcyanoacrylate nanoparticles in antiparasitic chemotherapy is described. The nanoparticles on their own proved to have trypanocidal activity against Trypanosoma brucei brucei in-vitro but not against Trichomonas vaginalis or Entamoeba histolytica. The trypanocidal activity was partly confirmed in-vivo with T. brucei-infected mice. Li, V. H., R. W. Wood, et al. (1986). "Ocular drug delivery of progesterone using nanoparticles." Journal of Microencapsulation 3(3): 213-8. The objective of this study was to evaluate ocular delivery of a lipid-soluble drug, [3H]progesterone, using nanoparticles. Polybutylcyanoacrylate nanoparticles loaded with [3H]progesterone were prepared by an emulsion polymerization technique using a hydrophilic continuous phase. The resulting nanoparticle suspension contained 2 x 10(-5) M progesterone. It was found that, at equilibrium, 99 per cent of the progesterone resided in the nanoparticles and the remainder in the aqueous phase indicating an excellent encapsulation efficiency. In addition, an appropriate control solution of progesterone was prepared, which did not contain polybutylcyanoacrylate. Concentrations of [3H]progesterone in various ocular tissues of the albino rabbit were monitored at various times following topical administration of either the nanoparticle suspension or the control solutions. Comparison of the concentration-time profiles indicates that tissue concentration of progesterone following topical administration of nanoparticles is generally four to five times less than that obtained with control solutions. This decreased concentration suggests that, due to the high affinity of progesterone for the nanoparticles, the drug is being made less available for absorption during its residence time in the precorneal area. The utility of nanoparticles as an ocular drug delivery system may depend on optimizing lipophilichydrophilic properties of the polymer-drug system, in addition to increasing retention efficiency in the precorneal pocket. Li, C., D. Yu, et al. (1996). "Biodistribution of cyclic carbonate of ioxilan: a radiopaque particulate macrophage imaging agent." Academic Radiology 3(6): 500-6.

RATIONALE AND OBJECTIVES: A biodegradable radiopaque particulate contrast agent formulated from cyclic carbonate of ioxilan (IXC), which is a prodrug of nonionic water-solubel contrast ioxilan, recently has been developed. This contrast agent enhances liver attenuation and is cleared from the body as ioxilan. In the current study, we tested whether the biodistribution of IXC particles would be affected by the characteristics of particles. METHODS: IXC nanoparticles (average diameter = 290 nm) and IXC microparticles (average diameter = 1.7 mm) were prepared, characterized, and injected intravenously (i.v.; 50 mg I/kg body weight) into rats. Two sensitive, reproducible analytic methods--inductively coupled plasma-mass spectrometry (ICP-MS) and high-performance liquid chromatography (HPLC)- were used to quantify tissue iodine and ioxilan concentrations. RESULTS: Both IXC nanoparticles and microparticles were taken up in the liver and spleen. The IXC nanoparticles remained in the liver at high concentrations for 6 hr and were slowly cleared. They also gave a high blood iodine concentration in the first 5 min after i.v. injection, suggesting their potential use as a blood-pool imaging agent. Unlike the nanoparticles, the microparticles had a significantly lower uptake by the kidney. CONCLUSION: Because of reduced renal uptake, microparticles are a preferred macrophage imaging agent. Biodegradable radiopaque particles may be used either as blood-pool imaging agents or as macrophage imaging agents depending on their size and distribution characteristics. The ICP-MS and HPLC methods are useful for biodistribution studies of iodinated contrast agents. Li, J. K., N. Wang, et al. (1997). "A novel biodegradable system based on gelatin nanoparticles and poly(lactic-co-glycolic acid) microspheres for protein and peptide drug delivery." Journal of Pharmaceutical Sciences 86(8): 891-5. Gelatin nanoparticle-poly(lactic-co-glycolic acid) (PLGA) microsphere composites were prepared by encapsulating protein-loaded gelatin nanoparticles in PLGA microspheres. This encapsulation was conducted by using a phase separation method and a solvent extraction method. The average diameter of the gelatin nanoparticle-PLGA microsphere composites is between 160 and 175 microm. Protein loading efficiency is 93.2% for the nanoparticlemicrosphere composite prepared by the phase separation method, while it is 31.31% for the composite prepared by the solvent extraction method. Protein release experiments indicate that this new composite system possesses sustained release characteristics. This system also demonstrates the capability of preventing the denaturation of protein drugs. Li, J. K., N. Wang, et al. (1998). "Poly(vinyl alcohol) nanoparticles prepared by freezing-thawing process for protein/peptide drug delivery." Journal of Controlled Release 56(1-3): 117-26. Poly(vinyl alcohol) (PVA) hydrogel nanoparticles have been prepared by using a water-in-oil emulsion technology plus cyclic freezing-thawing process. The PVA hydrogel nanoparticles prepared by this method are suitable for protein/peptide drug delivery since formation of the hydrogel does not require crosslinking agents or other adjuvants and does not involve any residual monomer. Particularly, there is no emulsifier involved in this new method. Bovine serum albumin (BSA), as a model protein drug, is incorporated into the PVA hydrogel nanoparticles. The PVA hydrogel nanoparticles possess a skewed or log-normal size distribution. The average diameter of the PVA hydrogel nanoparticles is 675.5+/-42.7 nm. Protein drug loading efficiency in the PVA hydrogel nanoparticles is 96.2+/-3.8%. The PVA hydrogel nanoparticles swell in an aqueous solution and the swelling degree increases with the increase of temperature. In vitro release studies show that the BSA release from the nanoparticles can be prolonged to 30 h. The BSA release follows a diffusion-controlled mechanism. The number of freezing-thawing cycle and release temperature both influence BSA release rate considerably. Less freezing-thawing cycle or higher release temperature leads to faster drug release. The BSA is stable during preparation of the PVA hydrogel nanoparticles. Li, J. K., N. Wang, et al. (1998). "Gelatin nanoencapsulation of protein/peptide drugs using an emulsifier-free emulsion method." Journal of Microencapsulation 15(2): 163-72. The nanoencapsulation of a model protein drug, bovine serum albumin (BSA), using gelatin as the matrix material is reported. Nanoencapsulation was conducted using a modified water-in-oil (w/o) emulsion method, which is emulsifier-free and simple. The nanoencapsulation product, BSA-containing gelatin nanoparticles, is characterized in terms of nanoparticle morphology, size and size distribution, water content, and in vitro protein release. The BSA-containing gelatin nanoparticles obtained from this nanoencapsulation process are nearly spherical and have a log-normal size distribution. The average diameter of the BSA-containing gelatin nanoparticles is approximately 840 nm. They can absorb 51-72% of water. In vitro release experiments demonstrate that BSA has been successfully encapsulated in, and can be released from the gelatin nanoparticles. The release of BSA from the gelatin nanoparticulate matrix follows a diffusion-controlled release mechanism. It is found that temperature affects both the water content and the BSA release rate of the gelatin nanoparticles. Li, H., G. Mao, et al. (2000). "AFM study of templated growth of cadmium sulfide nanoparticles using pure and mixed arachidate films." Thin Solid Films 358: 1-2. Langmuir-Blodgett (LB) multilayers of arachidic acid (AA) and octadecylamine (ODA) were used as templates in order to produce cadmium sulfide (CdS) nanoparticle arrays. Both atomic force microscopy (AFM) and X-ray

photoelectron spectroscopy (XPS) were used to characterize the film. In the absence of ODA, the cadmium arachidate trilayers were highly crystalline with a lattice constant of 0.42 nm. Upon reaction with hydrogen sulfide (H/sub 2/S), an ordered array of CdS nanoparticles with a particle separation of 4.2 nm was imaged. The existence of CdS was also confirmed by XPS. No CdS nanoparticles were formed when ODA was used as the sole component. In the presence of ODA, the crystalline structure of the AA film was disturbed, resulted in randomly distributed particles. The average particle height was reduced from 4 to 1 nm when the amount of ODA was increased. It is concluded that there is a direct correlation between the ordering of the organic template and that of the nanoparticle array. There is also a correlation between the particle size and the ratio of AA and ODA. Mixed LB films are promising in synthesizing semiconducting nanoparticle arrays of limited particle sizes. (39 References). Li, Y., X. M. Hong, et al. (2000). "Suzuki cross-coupling reactions catalyzed by palladium nanoparticles in aqueous solution." Org Lett 2(15): 2385-8. Palladium nanoparticles stabilized by poly(N-vinyl-2-pyrrolidone) (PVP) are efficient catalysts for the Suzuki reactions in aqueous medium. The time dependence of the fluorescence intensity of the biphenyl product in the reaction between iodobenzene and phenylboronic acid is used to determine the initial rate of the catalytic reaction. The initial rate depends linearly on the concentration of Pd catalyst, suggesting that the catalytic reaction occurs on the surface of the Pd nanoparticles. Li, Y. P., Y. Y. Pei, et al. (2001). "Stealth polycyanoacrylate nanoparticles as tumor necrosis factor-alpha carriers: pharmacokinetics and anti-tumor effects." Biology and Pharmacology Bulletin 24(6): 662-5. The objective of this study was to investigate the pharmacokinetics and in vivo anti-tumor effect of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) encapsulated in poly(methoxypolyethyleneglycol cyanoacrylate-co-n-hexadecyl cyanoacrylate) (PEG-PHDCA) nanoparticles. Our experimental results showed that PEG-PHDCA nanoparticles could extend the half-life of rHuTNF-alpha to 7.42 h and obviously change the protein biodistribution in tissues, and in particular, increase accumulation of rHuTNF-alpha in tumor. Compared with PHDCA nanoparticles and free rHuTNF-alpha, PEG-PHDCA nanoparticles loaded with rHuTNF-alpha showed higher antitumor potency at the same dose, which might be related to its higher accumulation in tumor tissues and longer plasma circulation time. Therefore, PEG-PHDCA nanoparticles could be an effective carrier for rHuTNFalpha. Li, Y. P., Y. Pei, et al. (2001). "PEGylated polycyanoacrylate nanoparticles as tumor necrosis factor-alpha carriers." Journal of Control Release 71(3): 287-96. The aim of this study was to find an effective carrier for recombinant human tumor necrosis factor-alpha (rHuTNFalpha). The influence of solvent systems containing poly(methoxy-polyethyleneglycol cyanoacrylate-co-nhexadecyl cyanoacrylate) (PEGylated PHDCA) on the biological activity of rHuTNF-alpha was investigated. The PEGylated PHDCA nanoparticles loading rHuTNF-alpha were prepared with the double emulsion method. The influence of main experimental factors on the entrapment efficiency was evaluated by the Uniform Design. The physicochemical characteristics and in vitro release of rHuTNF-alpha from the nanoparticles were determined. The results showed that serum albumin such as human serum albumin (HSA) or bovine serum albumin (BSA) could play a protective action on rHuTNF-alpha in the preparation process. At >/=2.0% (w/v) HSA concentration, more than 85% of rHuTNF-alpha activity remained and the role of HSA was not affected by copolymer concentrations from 0.5 to 3.0% (w/v). The entrapment efficiency of the nanoparticles was about 60% and the nanoparticle size was about 150 nm. The nanoparticles were spherical in shape and uniform with the value of the zeta potential about -9 mV. The rHuTNF-alpha release from the nanoparticle showed an initial burst and then continued in a sustained fashion. The results showed that the PEGylated PHDCA nanoparticles could be an effective carrier for rHuTNF-alpha. Li, Y., Y. Pei, et al. (2001). "PEGylated PLGA nanoparticles as protein carriers: synthesis, preparation and biodistribution in rats." Journal of Control Release 71(2): 203-11. The aim of the present work was to assess the merits of PEGylated poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles as protein and peptide drugs (PPD) carriers. PEG-PLGA copolymer, which could be used to prepare the stealth nanoparticles or long-circulating nanoparticles, was synthesized with methoxypolyethyleneglycol (MePEG) and PLGA. The structure of PEG-PLGA was confirmed with (1)H NMR and Fourier transform infrared (FTIR) spectrum, and molecular weight was determined by gel permeation chromatography (GPC). Bovine serum albumin (BSA), chosen as model protein, was encapsulated within the stealth nanoparticles with the double emulsion method. The particles were characterized in terms of size, zeta potential and in vitro release of the protein. The biological fate of the BSA-loaded nanoparticles following intravenous administration was determined over 24 h in rats. The experimental results showed that PEG-PLGA could be obtained by ring-opening polymerization of lactide and glycolide in the presence of MePEG. (1)H NMR and FTIR spectrum were consistent with the structure of PEG-PLGA copolymer. Molecular weight determined by GPC was 50800. The stealth nanoparticles loading BSA could be prepared by the double emulsion technique.

The entrapment efficiency was 48.6%, particle size about 200 nm and zeta potential -16.1 mV. BSA release from the stealth nanoparticles showed an initial burst release and then sustained release. PEG-PLGA nanoparticles could extend half-life of BSA from 13.6 min of loaded in PLGA nanoparticles to 4.5 h and obviously change the protein biodistribution in rats compared with that of PLGA nanoparticles. Thus, PEG-PLGA nanoparticles could be an effective carrier for PPD delivery. Liance, M., F. Nemati, et al. (1993). "Experience with doxorubicin-bound polyisohexylcyanoacrylate nanoparticles on murine alveolar echinococcosis of the liver." International Journal of Parasitology 23(3): 427-9. The parasiticidal properties of doxorubicin against the metacestode of Echinococcus multilocularis were investigated after binding of that drug to polyisohexylcyanoacrylate nanoparticles, a colloidal biodegradable drug carrier. A reduction of the hepatic parasite development and a reduced viability of the metacestode were observed in mice injected with 5 mg kg-1 body weight-1, but 7.5 mg kg-1 body weight-1 did not appear more efficient. Free doxorubicin or unbound nanoparticles had no antiparasitic activity. Liedtke, S., S. Wissing, et al. (2000). "Influence of high pressure homogenisation equipment on nanodispersions characteristics." International Journal of Pharmaceutics 196(2): 183-185. In this study a comparison of the influence of the homogenising equipment supplied by different manufacturers on the quality of the lipid nanodispersions is given. An Avestin EmulsiFlex-B3 (B3) and APV Micron Lab 40 (LAB 40) were used for high pressure homogenisation. Particle size and particle size distribution were chosen as quality parameters. The influence of different process parameters was evaluated. The two homogenisers were compared in their quality of nanoparticles-production by hot and cold homogenisation technique and in processing nanoemulsions. Working with the B3 appeared as useful for preformulation studies and processing of expensive or rare drugs and excipients. This first scaling up within laboratory scale is evaluated and the problems and remarkable aspects working with the B3 are pointed out. Lin, W., M. C. Garnett, et al. (1999). "Preparation and in vitro characterization of HSA-mPEG nanoparticles." International Journal of Pharmacy 189(2): 161-70. Surface modified human serum albumin (HSA) nanoparticles with a size of approximately 150 nm in diameter were prepared from a PEG-HSA conjugate, methoxy-polyethylene glycol modified human serum albumin (HSAmPEG) using a coacervation method and crosslinked with glutaraldehyde. The zeta-potential of the surface modified nanoparticles was significantly lower than that of unmodified HSA nanoparticles. The existence of a hydrated steric barrier surrounding the nanoparticles was confirmed by electrolyte and pH induced flocculation tests. The surface modified nanoparticles showed a reduced plasma protein adsorption on the particle surface compared with unmodified particles. Lin, L., H. Zhao, et al. (2000). "Study on colloidal Au-enhanced DNA sensing by quartz crystal microbalance." Biochemical and Biophysical Research Communications 274(3): 817-20. Colloidal Au is reported for enhancement the immobilization capacity and ultimately detection limit of DNA using quartz crystal microbalance (QCM). Immobilization of approximately 12 nm-diameter colloidal Au on to an Aucoated QCM resulted in an easier attachment of oligonucleotide, with a mercaptohexyl group at the 5'-phosphate end and an increased capacity for nucleic acid detection. DNA immobilization and hybridization was monitored from QCM frequency changes. Hybridization was induced by exposure of the DNA-containing films to complementary DNA in solution. A much higher sensitivity was obtained for the analyte. The Au nanoparticle films on the Au plate provide a novel means for the fabrication of DNA sensor. Copyright 2000 Academic Press. Lin, H. and J. Xue-hua (2000). "Study on main characteristics of aclarubicin A polylactide nanoparticle." Zhongguo Kangshengsu Zazhi 25(4): 272-273. A polylactide nanoparticle of aclarubicin A was prepared and the main characteristics such as, the drug loading (DL), the embedding ratio (ER), and relationships between the diameter and the distribution of nanoparticle were investigated. The DL and ER were determined by UV, while the diameter and the distribution were determined by laser mastersizerTM. Results showed that the mean DL and ER were 18.5% and 86.7%; and the mean number diameter and the mean volume diameter were 80 and 230nm respectively. It was concluded that relationships between DL and ER; as well as the volume diameter distribution are important characteristics for the preparation of aclarubicin A polylactide nanoparticle. Lin, W., M. C. Garnett, et al. (2001). "Preparation and characterisation of rose Bengal-loaded surface-modified albumin nanoparticles." Journal of Control Release 71(1): 117-26. Surface-modified albumin nanoparticles were prepared from two poly(ethylene glycol)-human serum albumin conjugates: poly(thioetheramido acid)-poly(ethylene glycol) copolymer-grafted HSA (HSA-PTAAC-PEG) and methoxy poly(ethylene glycol)-grafted HSA (HSA-mPEG). Rose bengal (RB) was used as a model drug for encapsulation into the nanoparticles either during the particle production or by adsorption post particle preparation. The drug incorporation and release was affected by the different production methods and the

different polymer compositions. When RB was loaded in HSA and HSA/HSA-PTAAC-PEG nanoparticles, up to 5% (w/w) drug content was achieved. The drug loading in HSA-mPEG nanoparticles was much lower and the results from the microcalorimetry study indicated that the low loading efficiency was due to less drug-protein binding sites available in the HSA-mPEG molecule as compared to the HSA molecule. The release of RB from the albumin nanoparticles was very slow in PBS and dramatically accelerated in the presence of trypsin. Compared with unmodified nanoparticles, the slower release of RB from the surface-modified HSA nanoparticles in the presence of the enzyme suggested that the existence of a steric hydrophilic barrier on the surface of the nanoparticles made digestion of the nanoparticles more difficult. Linden, S., J. Kuhl, et al. (2001). "Controlling the onteraction between light and gold nanoparticles: Selective suppression of extinction." Physical Review Letters 86(20): 4688-91. The interaction of visible light with the particle-plasmon resonance of metallic nanoparticles can be controlled by geometrical arrangement of nanoparticle arrays. These arrays are placed on a substrate that supports guided modes in the wavelength range of the particle plasmon. Coupling of this particle-plasmon resonance to the directly incident light and to the waveguide modes results in almost complete suppression of light extinction within narrow spectral bands due to destructive interference. Variation of the structure parameters allows continuous tuning of these high-transmission bands across the particle-plasmon resonance. Lippacher, A., R. H. Muller, et al. (2000). "Investigation on the viscoelastic properties of lipid based colloidal drug carriers." International Journal of Pharmaceutics 196(2): 227-30. The rheological behaviour of solid lipid nanoparticle dispersions (SLN) prepared by high pressure homogenization was investigated using a Haake RS-100 rheometer. Four preparations differing in their lipid content and macroscopic consistency were tested by continuous shear rheometry and oscillatory testing. Rheological data from continuous shear measurement reveal plastic flow for systems with low lipid content as well as for systems with high lipid content. By using oscillatory testing more detailed information concerning the structure could be achieved. Rheological measurements of 40% lipid dispersions show viscoelastic properties comparable to the data from standard dermal preparations. Therefore high concentrated lipid dispersions might constitute a promising vehicle for topical administration. Lippacher, A., R. H. Muller, et al. (2001). "Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles." International Journal of Pharmacology 214(1-2): 9-12. Aqueous dispersions of solid lipid nanoparticles (SLN) show some interesting features in topical drug delivery. However, to get a semisolid carrier having the appropriate consistency for topical application, the liquid SLN dispersions have to be incorporated in convenient topical dosage forms like hydrogels or creams. This is a timeconsuming production process with several disadvantages. A new one-step production process delivering a semisolid topical formulation including SLN is presented avoiding these disadvantages. The semisolid SLN dispersions were produced by high-pressure homogenization using an APV Lab 40 homogenizer. The resulting dispersions were characterized concerning their particle size and rheological properties. Despite the high lipid content of the SLN dispersions, they retained their colloidal particle size. Viscoelastic measurements proved the existence of a gel-like structure with a prevailing elastic component. Liu, Y., R. Bacon Edward, et al. (2000). "Pharmacokinetics and hepatic disposition of bis(1-(ethoxycarbonyl)propyl)5acetylamino-2,4,6-triiodoisophthalate in rats and isolated perfused rat livers." Drug Metabolism and Disposition 28(7): 731736. Bis(1-(Ethoxycarbonyl)propyl)5-acetylamino-2,4,6-triiodoisophthalate (NC 68183) was designed as a new computed tomography imaging agent. The purpose of this study was to determine the pharmacokinetics and metabolism of NC 68183 in conscious rats and in the isolated perfused rat liver. Animals were i.v. dosed at 69 and 690 mg of iodine/kg. Blood samples were collected at 5, 15, 30, and 60 min, and 7 days after dosing. Tissue samples (liver, kidney, and spleen) were taken at 60 min and 7 days after dosing. NC 68183 was cleared from blood in first order kinetics following an i.v. administration of 69 mg l/kg. The volume of distribution (Vss) at steady state and elimination half-life (t1/2) were estimated as 24 ml and 11 min. The clearance of NC 68183 from blood was changed to zero-order kinetics following administration of 690 mg/kg, and its elimination rate was 16 mug l/mlcntdotmin. The liver and spleen were the only tissues to have the nanoparticle residue at day 7 following administration. NC 68183 (75 mg of agent, 35 mg of l) was injected into the isolated perfused rat liver system. Bile flow increased from 1.0 to 1.3 mul/min/g liver following administration. The biliary excretion rate maximum was estimated as 11 mug/min/g liver. The metabolite was identified using liquid chromatography/mass spectrometry as a monocarboxylic acid product, which exclusively excreted into the bile in a soluble iodinated metabolite. Pharmacokinetics data suggested that NC 68183 primarily resides in the blood pool following an i.v. administration with a plasma half-life appropriate for blood pool imaging. Liu, F. M., L. D. Zhang, et al. (2000). "Preparation and optical properties of GaAs 0.57Sb0.43 nanoparticles embedded in SiO2 films by radio frequency magnetron co-sputtering." Thin Solid Films 375: 1-2.

We have successfully prepared composite films of GaAs/sub 0.57/Sb/sub 0.43/-SiO/sub 2/ onto glass substrates by radio frequency magnetron co-sputtering. Microstructure characterization was performed by X-ray diffraction. It is shown that the GaAs/sub 0.57/Sb/sub 0.43/ nanocrystals formed and dispersed in the SiO/sub 2/ matrix. The average size of the nanocrystals was in the range of 3-10 nm. Room temperature transmission absorption spectra of composite films show that the absorption edge exhibits a very large blue shift at approximately 2.25 eV with respect to the corresponding absorption edge in bulk, which is mainly explained by the quantum confinement effect. Room temperature Raman spectra show that the Raman peak of the composite films have a larger red shift than that of the bulk semiconductor due to the phonon confinement and tensile stress effects. (22 References). Liu, Y., J. Yang, et al. (2000). "Influence of hydrothermal temperature on structures and photovoltaic properties of SnO2 nanoparticles." Journal of Nanoparticle Research 2: 309-313. Lobenberg, R. and J. Kreuter (1996). "Macrophage targeting of azidothymidine: a promising strategy for AIDS therapy." AIDS Research and Human Retroviruses 12(18): 1709-15. Macrophages play an important role in the immunopathogenesis of AIDS. The objective of this study was to investigate the possibility of specific targeting of antivirals such as azidothymidine (AZT) to macrophages, using nanoparticles as a colloidal drug carrier. The body distribution of AZT bound to nanoparticles and as a control solution was studied in rats after intravenous and peroral administration. 14C-Labeled AZT was bound to nanoparticles in the presence of bis(2-ethylhexyl)sulfosuccinate sodium. The radioactivity was measured in different organs including those containing large numbers of macrophages. After intravenous injection, the concentrations of AZT were up to 18 times higher in organs belonging to the reticuloendothelial system (RES) when the drug was bound to nanoparticles than after injection of an aqueous AZT solution. Likewise, after oral administration the nanoparticle formulation delivered AZT more efficiently to the RES than the aqueous solution. In addition, the blood concentration was significantly higher after oral administration of nanoparticles. These results demonstrate that nanoparticles are a promising drug-targeting system for AZT to the RES organs. The increase in drug availability at the sites containing abundant macrophages may allow a reduction in dosage to avoid systemic toxicity. Lobenberg, R., L. Araujo, et al. (1998). "Body distribution of azidothymidine bound to hexyl-cyanoacrylate nanoparticles after i.v. injection to rats." Journal of Controlled Release 50(1-3): 21-30. Cells of the reticuloendothelial system (RES e.g. macrophages) play an important role in the immunopathogenesis of AIDS. The objective of the present study was to investigate the possibility of specifically targeting antiviral drugs such as azidothymidine (AZT) to macrophages using nanoparticles as colloidal drug carriers. In a first series of experiments the body distribution of 14C-labelled AZT bound to nanoparticles and a similarly prepared control solution with unbound AZT were studied in rats after intravenous injection. In a second series of experiments polysorbate 80-coated nanoparticles and a solution of AZT in saline were tested. 14Clabelled AZT was bound to nanoparticles using the surfactant bis(2-ethylhexyl) sulphosuccinate sodium (DOSS). The radioactivity in several organs, including those containing large numbers of macrophages, was measured after intravenous injection of the AZT-nanoparticles and the AZT-control solutions. AZT concentrations were up to 18 times higher in organs belonging to the RES if the drug was bound to nanoparticles compared with unbound AZT. These results demonstrate that nanoparticles are a potential drug targeting system for anti-AIDS drugs. The increase in drug concentration at the sites containing abundant macrophages may allow a reduction in dosage to reduce systemic toxicity. Lobenberg, R., J. Maas, et al. (1998). "Improved body distribution of 14C-labelled AZT bound to nanoparticles in rats determined by radioluminography." Journal of Drug Targeting 5(3): 171-9. The objective of the present study is to visualize differences in the body distribution between radiolabelled AZT bound to nanoparticles and a control solution. Polyhexylcyanoacrylate nanoparticles were manufactured by emulsion polymerization in the presence of AZT and an ionic emulsifier, bis(2-ethylhexyl) sulfosuccinate sodium. The AZT-control solution was equally prepared, but contained no monomer. The two preparations were administered either by i.v. injection or perorally by gavage. After determined time points the animals were sacrificed using carbon dioxide. The cadavers were shock-frozen in cellulose gel and cut into slices using a cryomicrotome. The tissue cross sections were fixed on an adhesive tape and then were freeze dried. The quantification of the radioactive AZT in the different organs and tissues was performed by radioluminography, and the images were generated on a computer. After i.v. injection of AZT-nanoparticles, a high amount of the AZT label was found in the organs belonging to the reticuloendothelial system. In these organs the radioactivity was inhomogeneously distributed showing that the uptake of the particle-associated radioactivity depended on the type of the cells located in the organs and was consistent with uptake by macrophages. The highest radioactivities were found in the GI-tract and in the liver. A difference in the elimination pathway between AZTcontrol solution and AZT bound to nanoparticles also was visible on the images. Similar results were obtained after oral administration. Of course, with the latter route a larger portion of AZT remained in the GI-tract especially

after administration of nanoparticle-bound drug. These results confirmed those obtained by a classically performed quantitative whole body distribution study using liquid scintillation. This demonstrates that radioluminography is a useful method to study the organ distribution of drugs bound to nanoparticles. Lopes, E., A. R. Pohlmann, et al. (2000). "Polymeric colloidal systems containing ethionamide: Preparation and physicochemical characterization." Pharmazie 55(7): 527-530. The association of ethionamide with different colloidal systems was evaluated. Nanocapsules (NC), nanospheres (NS), and nanoemulsions (NE) were prepared by interfacial deposition and spontaneous emulsification techniques. Ethionamide was incorporated before (B) and after (A) preparation of nanoparticles. Ethionamide was assayed by HPLC, the particle size was determined using a Nanosizer(R), and the zeta potential using a Zetasizer(R) 4. Free ethionamide was determined using a combined ultrafiltration-centrifugation technique. The drug release was determined by direct dilution of the nanoparticle dispersion in phosphate-buffer pH 7. All preparations retained acceptable particle size distribution (+-300 nm), except the NE. The zeta potential of all formulations was between -36.6 mV and -46.1 mV. Percentages of ethionamide associated were: NC (B: 62.4%, A: 56.2%), NS (B: 53.0%, A: 43.2%), and NE (B: 38.5%). After 45 days, the percentage of drug association with NC increased (B: 66.8%, A: 60.6%). The release profiles demonstrated that associated ethionamide was more readily released from the NC and NS prepared by procedure A rather than B. The ethionamide amount not released (B) was greater in NS than NC. The drug is mainly adsorbed onto the surface of nanoparticles. However, approximately 10% of ethionamide is encapsulated into NC and 20% entrapped into NS, respectively. Losa, C., P. Calvo, et al. (1991). "Improvement of ocular penetration of amikacin sulphate by association to poly(butylcyanoacrylate) nanoparticles." Journal of Pharmacy and Pharmacology 43(8): 548-52. The main objective of this paper was to investigate the ability of polycyanoacrylate nanoparticles to improve the corneal penetration of hydrophilic drugs. Three different nanoparticle formulations were prepared by changing the nature of the stabilizer agent (Dextran 70000, Synperonic F 68 and sodium lauryl sulphate). The significant influence of the stabilizer type on the particle size, electrophoretic mobility and on the drug loading efficiency was proved. Moreover, the ocular disposition of amikacin was affected by its association to nanoparticles, displaying the most interesting results when Dextran 70000 was employed for preparation of nanoparticles. The increase of the amikacin concentration in cornea and aqueous humour was statistically significant for this nanoparticle formulation with respect to the other formulations and the control solution. The in-vitro release profiles obtained using a dialysis system were similar for all the nanoparticle formulations and for the control solution, indicating that drug molecules are desorbed from the nanoparticles quickly enough to maintain the equilibrium concentration in the dialysis system. Lowe, P. J. and C. S. Temple (1994). "Calcitonin and insulin in isobutylcyanoacrylate nanocapsules: protection against proteases and effect on intestinal absorption in rats." Journal of Pharmacy and Pharmacology 46(7): 547-52. One of the major limiting steps for the absorption of peptide drugs from the intestine is proteolytic degradation. To slow this degradation, human calcitonin was trapped in polyacrylamide nanoparticles, and human calcitonin and insulin were encapsulated with polyisobutylcyanoacrylate. Human calcitonin trapped in polyacrylamide nanoparticles showed no delayed release characteristics and thus would not provide protection from proteases. Proteolytic degradation of human calcitonin and insulin in polyisobutylcyanoacrylate nanocapsules was slower than the free peptides in solution. The plasma pharmacokinetic profiles were consistent with increased survival time of the peptides in the intestine, with higher plasma concentrations of the peptides in the later time samples compared with the controls. However, the nanocapsules gave no significant overall enhancement of peptide absorption. This led to the conclusion that the nanocapsules released the peptides into the intestinal lumen, with small amounts then being absorbed but the rest largely degraded. Lu, S. W., B. I. Lee, et al. (2000). "Synthesis and photoluminescence enhancement of Mn -doped ZnS nanocrystals." Journal of Luminescence 92: 1-2. Mn/sup 2+/-doped ZnS nanoparticles were synthesized by a chemical precipitation method at room temperature. The particle size was estimated to be 2.8 nm from high-resolution transmission electron microscopy (HRTEM) and calculated as 2.6+or-0.4 nm from peak broadening of the X-ray diffraction (XRD) pattern. A 30-fold increase in photoluminescence intensity has been observed from Mn/sup 2+/-doped ZnS nanoparticles after surface passivation by a passivating agent with carboxylic functional groups. (27 References). Lucet, I., R. Filmon, et al. (1994). "[Transmission electron microscopy in the structural study of superparamagnetic contrast agents for MRI]." Bulletin de l Association des Anatomistes 78(240): 57-9. Iron oxide nanoparticles with different crystal sizes and uniform dextran coating were synthesized and analyzed by T.E.M.. The iron oxide core dimension and homogeneity of the preparation were correlated to magnetic properties. The increasing Fe/Dextran ratio used for the synthesis was well correlated with the mean diameter and the magnetic susceptibility. The comparison of the crystal size with the particle size determined by nanosizer in solution suggest that particles consist in nanoaggregates of many crystal subunits.
2+

Luck, M., W. Schroder, et al. (1997). "Identification of plasma proteins facilitated by enrichment on particulate surfaces: analysis by two-dimensional electrophoresis and N-terminal microsequencing." Electrophoresis 18(15): 2961-7. Plasma protein adsorption on intravenously injectable drug carriers is regarded as an important factor for the fate of the particles in the body after their administration. Therefore, the plasma protein adsorption patterns on a number of different carrier systems were analyzed in vitro employing two-dimensional electrophoresis (2-DE). The particulate systems presented in this study were polystyrene (PS) model particles, PS nanoparticles surfacemodified by adsorption of a surfactant, a commercial fat emulsion, and magnetic iron oxide particles used as contrast agents in magnetic resonance imaging. Most of the spots in the plasma protein adsorption patterns could be identified by matching the resulting 2-DE gels with a reference map of human plasma proteins. Several other proteins that indicated preferentially adsorbed proteins on the surface of the particles investigated have either not been identified on the reference map, or their identity was found to be ambiguous. The relevant proteins are all present in plasma in low abundance. Since these proteins were strongly enriched on the surface of the particles, the resulting spots on the 2-DE gels were successfully identified by N-terminal microsequencing. With this approach, two chains of spots, designated PLS:6 and PLS:8, were determined on a plasma reference map: interalpha-trypsin inhibitor family heavy chain-related protein (also named PK-120) and a dimer of fibrinogen gamma, respectively. Plasma gelsolin is presented in a 2-DE adsorption pattern of PS model particles. One of the main proteins adsorbed by droplets of a commercial fat emulsion was identified as apoliprotein H. Moreover, the positions of apolipoproteins apoC-II and apoC-III were also verified on the 2-DE protein map of human plasma. Thus, protein adsorption experiments of the kind presented in this study are increasing our insight into human plasma proteins. Luck, M., B. R. Paulke, et al. (1998). "Analysis of plasma protein adsorption on polymeric nanoparticles with different surface characteristics." Journal of Biomedical Materials Research 39(3): 478-85. Plasma protein adsorption patterns on colloidal drug carriers acquired after i.v. administration depend on their surface characteristics and are regarded as key factors for their in vivo organ distribution. Polymeric latex particles with strongly differing surface properties were synthesized as models for colloidal drug carriers for tissue-specific drug targeting via the intravenous route. Physicochemical characterization was performed for size, surface charge density, zeta potential, and surface hydrophobicity. The interactions with human plasma proteins were studied by way of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Considerable differences in protein adsorption on the latex particles were detected with regard to the total amount of surfacebound protein on the various particle types as well as specific proteins adsorbed, for example, fibrinogen, albumin, and a recently identified plasma glycoprotein. Possible correlations between protein adsorption patterns and the physicochemical characteristics and topography of the polymeric surfaces are shown and discussed. Knowledge about protein-nanoparticle interactions can be utilized for the rational design of colloidal drug carriers and also may be useful for optimizing implants and medical devices. Luck, M., K. F. Pistel, et al. (1998). "Plasma protein adsorption on biodegradable microspheres consisting of poly(D,Llactide-co-glycolide), poly(L-lactide) or ABA triblock copolymers containing poly(oxyethylene). Influence of production method and polymer composition." Journal of Controlled Release 55(2-3): 107-20. Biodegradable particulate systems have been considered as parenteral drug delivery systems. The adsorption of plasma proteins on micro- and nanoparticles is determined by the surface properties and may, in turn, strongly influence the biocompatibility and biodistribution of both carriers. In the present study the influence of the polymer composition and the production method of microspheres on the in vitro plasma protein adsorption were investigated using two-dimensional electrophoresis (2-DE). Microparticles were prepared from poly(l-lactide) (lPLA), poly(d,l-lactide-co-glycolide) (PLGA), and ABA triblock copolymers containing hydrophilic poly(oxyethylene) (B-blocks) domains connected to hydrophobic polyesters (A-blocks). Two different microencapsulation methods were employed, namely the w/o/w emulsion solvent evaporation method and the spray-drying technique. It could be demonstrated that the polymer composition and, especially, the encapsulation technique, influenced the interactions with plasma proteins significantly. For example, the percentages of several apolipoproteins in the plasma protein adsorption patterns of spray-dried PLGA- and l-PLA-particles were distinctly higher when compared to the adsorption patterns of the particles produced by the w/o/w-technique. Some adsorbed proteins were found to be characteristic or even specific for particles produced by the same method or consisting of identical polymers. Polyvinyl alcohol used as stabilizer in the w/o/w-technique may decisively influence the surface properties relevant for protein adsorption. The plasma protein adsorption on particles composed of ABA copolymers was drastically reduced when compared to microspheres made from pure polyesters. The adsorption patterns of ABA-particles were dominated by albumin. The plasma protein adsorption patterns detected on the different microspheres are likely to affect their in vivo performance as parenteral drug delivery systems. Lukowski, G., J. Kasbohm, et al. (2000). "Crystallographic investigation of cetylpalmitate solid lipid nanoparticles." International Journal of Pharmaceutics 196(2): 201-205. Solid lipid nanoparticles (SLN) as alternative intravenous colloidal drug carriers were produced by high pressure

homogenisation of the melted lipid cetylpalmitate. The crystallographic properties of the used cetylpalmitate SLN were characterised by small angle X-ray scattering (SAXS) and X-ray diffraction (XRD). It was found that the SLN are available exclusively in a crystalline form. Different cetylpalmitate formulations showed all the same patterns and a uniform crystal lattice was obtained. A partial indexing of the signals of the cetylpalmitate was carried out and the unit cell of the cetylpalmitate was estimated by the Miller indices. A preferred orientation in 001-direction was observed. This can be explained by an impressive lamellar lattice structure of the cetylpalmitate. The results were compared with the crystal data of cetylpalmitate known from literature. There was no correlation with the monoclinic structure known so far. This could indicate that the SLN consist of crystallites of another modification of the cetylpalmitate. Luo, P. and T. G. Nieh (1996). "Preparing hydroxyapatite powders with controlled morphology." Biomaterials 17(20): 1959-64. We developed a synthesis method for hydroxyapatite particles with different morphologies. The process involved chemical precipitation and spray drying, which produced spherical, agglomerated hydroxyapatite granules with controlled particle sizes and structures. These granules contained nanoparticles with an average crystalline size of about 10 nm. We controlled the morphologies of the granules by adjusting the spray-drying conditions, such as the volume fraction of feed slurry and the atomization pressure. The spray-dried granules were doughnut shapes, solid spheres, or hollow spheres, and their sizes were controlled by varying the atomization pressure and the concentration of the feed slurry. Luo, D. and W. M. Saltzman (2000). "Enhancement of transfection by physical concentration of DNA at the cell surface." Nature Biotechnology 18(8): 893-5. Efficient DNA transfection is critical for biological research and new clinical therapies, but the mechanisms responsible for DNA uptake are unknown. Current nonviral transfection methods, empirically designed to maximize DNA complexation and/or membrane fusion, are amenable to enhancement by a variety of chemicals. These chemicals include particulates, lipids, and polymer complexes that optimize DNA complexation/condensation, membrane fusion, endosomal release, or nuclear targeting, which are the presumed barriers to gene delivery. Most chemical enhancements produce a moderate increase in gene delivery and a limited increase in gene expression. As a result, the efficiency of transfection and level of gene expression after nonviral DNA delivery remain low, suggesting the existence of additional unidentified barriers. Here, we tested the hypothesis that DNA transfection efficiency is limited by a simple physical barrier: low DNA concentration at the cell surface. We used dense silica nanoparticles to concentrate DNA-vector (i.e. DNA-transfection reagent) complexes at the surface of cell monolayers; manipulations that increased complex concentration at the cell surface enhanced transfection efficiency by up to 8.5-fold over the best commercially available transfection reagents. We predict that manipulations aimed at optimizing DNA complexation or membrane fusion have a fundamental physical limit; new methods designed to increase transfection efficiency must increase DNA concentration at the target cell surface without adding to the toxicity. Lvov, Y. M., R. R. Price, et al. (2000). "Imaging nanoscale patterns on biologically derived microstructures." Langmuir 16(14): 5932-5. We have demonstrated a new approach for imaging nanoscale patterns on three-dimensional submicrometer structures using charged particles. Nanoparticle structures were assembled onto lipid tubules through the sequential adsorption of oppositely charged polymers and silica spheres. For tubules of the zwitterionic lipid DC/sub 8,11/PC, this process leads to the formation of caps on the ends of the tubules, with 50-100 silica spheres in each cap. For tubules of DC/sub 8,11/PC mixed with 2% of the charged lipid DC/sub 8,9/PEOH, the sequential adsorption leads to both end caps and helices of nanoparticles winding around the interior of the tubules. These results give new insight into the pattern of charge in lipid tubules. (21 References). Maenosono, S., C. D. Dushkin, et al. (2000). "Doping of CdS nanoparticles by Co ions studied by NMR." Journal of Physical Chemistry B 104(22): 5237-41. Nanoparticles of the diluted magnetic semiconductor Cd/sub 0.991/Co/sub 0.009/S, with diameters D between 3.5 and 29.5 nm, were studied by /sup 113/Cd NMR spectroscopy. Two spectral features could be discerned: (1) a strong line corresponding to cadmium atoms that are removed more than four bonds from cobalt ions and (2) a set of shifted lines resulting from transferred hyperfine (THF) interactions between the d-electrons of Co/sup 2+/ and its next nearest (2N) neighboring cadmium atoms. Significant changes in the /sup 113/Cd spectrum were observed as a function of the size of the nanoparticles. More specifically, these changes were attributed to a structural zinc blende-to-wurtzite phase transition that occurs around D=8 nm. The frequency spread and the fine structure of the spectra indicate that most of the Co/sup 2+/ impurities in the crystals are located at the positions of cadmium sites. These paramagnetic ions are distributed homogeneously in the samples and the transferred hyperfine interactions between the d-electrons of cobalt and the 2N /sup 113/Cd nuclei are of the same order of magnitude as in bulk samples. Inhomogeneous broadening of the lines in the spectra can be attributed to possible distortions of the electronic polarization pathways because of surface and local disorder effects in the
2+

nanocrystals. (20 References). Mafune, F., J. Kohno, et al. (2000). "Structure and stability of silver nanoparticles in aqueous solution produced by laser ablation." Journal of Physical Chemistry B 104(35): 8333-7. Silver nanoparticles were produced by laser ablation of a metal silver plate in aqueous solutions of surfactants, C/sub n/H/sub 2n+1/SO/sub 4/Na (n=8,10,12,16). The nanoparticles thus produced were characterized by electron microscopy and UV-visible absorption spectroscopy. The abundances of the nanoparticles before and after centrifugation were measured as a function of the surfactant concentration. The concentration dependence of the abundance implies that the surfactant coverage and the charge state on the nanoparticle surface are closely related to the stability of the nanoparticles in the solutions. The nanoparticles tend to be aggregated when the coverage is less than unity, while they are very stable when the surface is covered with a double layer of the surfactant molecules. (32 References). Magnusson, M. H., K. Deppert, et al. (1999). "Gold nanoparticles: Production, reshaping, and thermal charging." Journal of Nanoparticle Research 1: 243-251. Maia, C. S., W. Mehnert, et al. (2000). "Solid lipid nanoparticles as drug carriers for topical glucocorticoids." International Journal of Pharmaceutics 196(2): 165-167. Recent investigations both in vitro and in human subjects proved the benefit/risk ratio of prednicarbate (PC) to exceed those of halogenated topical glucocorticoids about 2-fold. To obtain a further highly desired increase by drug targeting to viable epidermis, PC was incorporated into solid lipid nanoparticles (SLN). Keratinocyte and fibroblast monolayer cultures, reconstructed epidermis and excised human skin served to evaluate SLN toxicity and PC absorption. Well-tolerated preparations (e.g. cellular viability 94.5% following 18 h incubation of reconstructed epidermis) were obtained. PC penetration into human skin increased by 30% as compared to PC cream, permeation of reconstructed epidermis increased even 3-fold. The present study shows the great potential of SLN to improve drug absorption by the skin. Maier, M., H. Fritz, et al. (1998). "Quantitation of phosphorothioate oligonucleotides in human blood plasma using a nanoparticle-based method for solid-phase extraction." Analytical Chemistry 70(11): 2197-204. Based on the application of cationic polystyrene nanoparticles, a novel method for solid-phase extraction of phosphorothioate oligonucleotides from human plasma has been developed. A high binding affinity, which is required for an effective isolation out of complex mixtures, is mediated by hydrophobic and multiple electrostatic interactions between the oligonucleotides and the nanoparticles. The principle of the method is based on a pHcontrolled adsorption/desorption mechanism. Analysis of the extracted samples was performed by capillary gel electrophoresis. Extraction conditions were optimized, providing the isolation of oligonucleotides (&gt; or = 10 nucleotide units) in high yields and purity even at concentrations in the low-nanomolar range (down to 5 nM). The low salt contamination of the samples allows their direct analysis by electrospray mass spectrometry. The combined linearity and accuracy of the assay together with absolute recovery rates in the range of 60-90% indicate that the developed solid-phase extraction method is generally applicable to quantitation of oligonucleotides in human plasma. Further improvement was achieved with an optimized carrier system of 2-fold enlarged particles which reduces the time consumption of the extraction procedure to approximately 30 min. Maincent, P., J. P. Devissaguet, et al. (1984). "Preparation and in vivo studies of a new drug delivery system. Nanoparticles of alkylcyanoacrylate." Applied Biochemistry and Biotechnology 10(3): 263-5. Polyhexylcyanoacrylate nanoparticles have been prepared with vincamine as the model drug. These particles had an average size of 200 nm and adsorbed approximately 43% of vincamine. The adsorption of vincamine to nanoparticles modified the distribution of vincamine in tissues. After iv injection the distribution volumes were increased in comparison with an aqueous solution of drug. In comparison with an aqueous solution of drug, the absolute bioavailability of vincamine was also increased after an oral administration of nanoparticles. Maincent, P., R. Le Verge, et al. (1986). "Disposition kinetics and oral bioavailability of vincamine-loaded polyalkyl cyanoacrylate nanoparticles." Journal of Pharmaceutical Sciences 75(10): 955-8. Hexyl cyanoacrylate nanoparticles loaded with vincamine as a drug model were prepared. Disposition kinetics and oral bioavailability of vincamine in rabbits were compared after administration of an aqueous solution of the drug and an aqueous colloidal suspension of nanoparticles. After intravenous administration, total body clearance of vincamine was equal for both dosage forms, but a longer half-life (X 2) and larger distribution volume (X 2) were observed with the suspension of nanoparticles. After oral administration, the bioavailability of vincamine was considerably greater for the drug loaded onto nanoparticles. Maincent, P., P. Thouvenot, et al. (1992). "Lymphatic targeting of polymeric nanoparticles after intraperitoneal administration in rats." Pharmacetical Research 9(12): 1534-9. Following intraperitoneal administration, the lymphatic targeting of polyacrylic nanoparticles has been evaluated in

thoracic duct cannulated rats. The dosage forms administered consisted of carbon-14 polyhexylcyanoacrylate nanoparticles (PHCA) and polymethylmethacrylate (PMMA) nanoparticles. The carbon-14 concentrations were much higher in the excreted thoracic lymph than in the blood for both types of particles. The most dramatic results were found in the mediastinal nodes since the carbon-14 concentrations of rats receiving PHCA and PMMA nanoparticles by the ip route were 70- to more than 2000-fold higher than in the corresponding nodes of animals treated by the intravenous route. This potential lymphatic targeting could prove valuable in cancerology to treat tumors that metastasize in the peritoneal cavity or via lymphatic pathways such as colon carcinomas. Maisels, A., F. E. Kruis, et al. (2000). "Synthesis of tailored composite nanoparticles in the gas phase." Applied Physics Letters 77(26): 4431-3. We report on a method to obtain tailored nanoparticle aggregates of two components in the gas phase. The method is based on the modification of the Brownian collision rate by charging the nanoparticles. Particles of different components are charged oppositely in order to obtain composite nanoparticle aggregates via preferential coagulation. The resulting composite aggregates are uncharged, which allows for their separation from both, charged unaggregated particles and charged aggregates of only one component. The mean size and standard deviation of each particle component can be adjusted by means of differential mobility analysis. Experimental results are presented for composites of PbS and Ag. (13 References). Majetich, S. A. and Y. Jin (1999). "Magnetization directions of individual nanoparticles." Science 284(5413): 470-3. The magnetization directions of individual monodomain nanoparticles as small as 5 nanometers in diameter are determined using the Foucault method of Lorentz microscopy. A model is developed to explain the images and diffraction patterns of samarium cobalt nanoparticles as a function of the aperture shift direction. Thermally induced changes in the magnetization direction of superparamagnetic magnetite nanoparticles were observed but with a much slower rate than expected, due to surface anisotropy. When the time scale for magnetization reversal is much shorter than the data acquisition time, as in carbon-coated iron cobalt alloy nanoparticles, the images show an average of such thermally induced changes. Major, M., E. Prieur, et al. (1997). "Characterization and phase behaviour of phospholipid bilayers adsorbed on spherical polysaccharidic nanoparticles." Biochimica et Biophysica Acta 1327(1): 32-40. In this paper a new drug carrier, the Light-biovector, is described. These biovectors are composed of a neutral, anionic or cationic polysaccharidic core surrounded by phospholipids. They can be prepared with high yield and in a nearly pure form as determined by density analysis on sucrose gradients. These particles showed great stability with no sedimentation being observed after more than one year of storage. Physicochemical studies carried out with dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol mixtures showed that in Light-biovectors, the lipids are organized in bilayer surrounding the polysaccharidic core. In presence of a neutral polysaccharidic core, the gel to liquid phase transition temperature Tm of DPPC was only slightly affected as compared to liposomal dispersions of the lipid. In contrast, for cationic and anionic Lightbiovectors, the Tm of the lipids was affected by the electric charge born by the polysaccharidic core, indicating that electrostatic interactions contribute to the organization of the lipid bilayer in these systems. It was also found that the association of anionic membrane to anionic polysaccharidic cores and the association of cationic membrane to cationic polysaccharidic cores was possible. Malaiya, A. and S. P. Vyas (1988). "Preparation and characterization of indomethacin magnetic nanoparticles." Journal of Microencapsulation 5(3): 243-53. Nanoparticles of polymethylmethacrylate were prepared by the emulsion polymerization technique. The drug was embedded in the nanoparticles. The controlled growth of ferric hydroxide particles in the presence of non-ionic surfactant was effected to obtain nano-size particles and these were subsequently heated to obtain ferroso-ferric oxide (magnetite). The effect of various parameters, i.e. monomer concentration and magnetite concentration, as well as the stirring rate were studied to characterize the particle size and its distribution. Similarly, the factors which affect the total drug payload were assessed. The magno-responsive indomethacin nanoparticles were successfully prepared. Manil, L., L. Roblot-Treupel, et al. (1986). "Isobutyl cyanoacrylate nanoparticles as a solid phase for an efficient immunoradiometric assay." Biomaterials 7(3): 212-6. The interaction of monoclonal antibodies and seric proteins with cyanoacrylic nanoparticles was investigated. A high binding capacity, rapid kinetics of adsorption as well as a good stability of the linkage were found. Furthermore, the immunoreactivity was conserved after coating antibody to nanoparticles. A new competitive immunoradiometric assay was also proposed for determination of alpha-fetoprotein amounts as low as 0.1 ng per assay. Manil, L., J. C. Davin, et al. (1994). "Uptake of nanoparticles by rat glomerular mesangial cells in vivo and in vitro." Pharmacetical Research 11(8): 1160-5.

Glomerular mesangial cells play a major role in the structure of capillary loops, generation of mediators of inflammation, and uptake of macromolecules. We demonstrate here that isobutylcyanoacrylate nanoparticles loaded with actinomycin D (ADNP) concentrate in rat mesangial cells in vitro and in vivo, as compared to the free drug (AD). In normal rats injected with 20 micrograms of 3H-ADNP or 3H-AD, the uptake ratios 3H-ADNP/3H-AD measured in whole kidneys at 30 and 120 min were 2.2 +/- 1.0 and 2.3 +/- 0.9, respectively. The same ratios calculated for isolated rat glomeruli and tubules, were 4.1 +/- 0.5 and 0.8 +/- 0.2 at 30 min, and 2.6 +/- 0.5 and 0.6 +/- 0.3 at 120 min, respectively. In the glomeruli, the absolute uptake of 3H-ADNP corresponded to 7.5 (30 min) and 1.8 (120 min)% I.D./100 mg of protein. In rats with experimental glomerulonephritis, the uptakes of 3H-ADNP and 3H-AD by the glomeruli were 6.9 and 4.0 times higher than in normal rats, respectively. In vitro experiments demonstrated up to 5 times higher uptake by glomerular mesangial cells than by epithelial cells. Uptake was maximum after 60 min, higher at 37 degrees C than at 4 degrees C, dependent on the presence of fresh serum and inhibited by cytochalasin-B. Drug targeting by nanoparticles is thus possible to renal cells involved in inflammatory processes, especially mesangial cells and macrophages. Nanoparticles could also be useful for lowering drug concentration in tubular cells, to reduce any tubular toxicity.(ABSTRACT TRUNCATED AT 250 WORDS) Manil, L., P. Couvreur, et al. (1995). "Acute renal toxicity of doxorubicin (adriamycin)-loaded cyanoacrylate nanoparticles." Pharmacetical Research 12(1): 85-7. Acute doxorubicin-loaded nanoparticle (DXNP) renal toxicity was explored in both normal rats and rats with experimental glomerulonephritis. In normal rats, 2/6 rats given free doxorubicin (DX) (5 mg/kg) died within one week, whereas all control animals and all rats having received free NP or DXNP survived. A 3 times higher proteinuria appeared in animals treated with DXNP than in those treated with DX. Free NP did not provoke any proteinuria. Two hr post-injection, DXNP was 2.7 times more concentrated in kidneys than free DX (p &lt; 0.025). In rats with immune experimental glomerulonephritis, 5/6 rats given DX died within 7 days, in contrast to animals treated by DXNP, NP, or untreated, which all survived. Proteinuria appeared in all series, but was 2-5 times more intense (p &gt; 0.001) and prolonged after doxorubicin treatment (400-700 mg/day), without significant difference between DXNP and DX. Rats treated by unloaded NP behaved as controls. These results demonstrate that, in these experimental conditions, DXNP killed less animals than free DX, despite of an enhanced renal toxicity of the former. Both effects (better survival and nephrosis) are most probably related to an enhanced capture of DXNP by cells of the mononuclear phagocyte system, including mesangial cells. Mao, H. Q., K. Roy, et al. (2001). "Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency." Journal of Control Release 70(3): 399-421. Chitosan-DNA nanoparticles were prepared using a complex coacervation process. The important parameters for the nanoparticle synthesis were investigated, including the concentrations of DNA, chitosan and sodium sulfate, temperature of the solutions, pH of the buffer, and molecular weights of chitosan and DNA. At an amino group to phosphate group ratio (N/P ratio) between 3 and 8 and a chitosan concentration of 100 microg/ml, the size of particles was optimized to approximately 100--250 nm with a narrow distribution, with a composition of 35.6 and 64.4% by weight for DNA and chitosan, respectively. The surface charge of these particles was slightly positive with a zeta potential of +12 to +18 mV at pH lower than 6.0, and became nearly neutral at pH 7.2. The chitosanDNA nanoparticles could partially protect the encapsulated plasmid DNA from nuclease degradation as shown by electrophoretic mobility analysis. The transfection efficiency of chitosan-DNA nanoparticles was cell-type dependent. Typically, it was three to four orders of magnitude, in relative light units, higher than background level in HEK293 cells, and two to ten times lower than that achieved by LipofectAMINE-DNA complexes. The presence of 10% fetal bovine serum did not interfere with their transfection ability. Chloroquine could be co-encapsulated in the nanoparticles at 5.2%, but with negligible enhancement effect despite the fact that chitosan only showed limited buffering capacity compared with PEI. The present study also developed three different schemes to conjugate transferrin or KNOB protein to the nanoparticle surface. The transferrin conjugation only yielded a maximum of four-fold increase in their transfection efficiency in HEK293 cells and HeLa cells, whereas KNOB conjugated nanoparticles could improve gene expression level in HeLa cells by 130-fold. Conjugation of PEG on the nanoparticles allowed lyophilization without aggregation, and without loss of bioactivity for at least 1 month in storage. The clearance of the PEGylated nanoparticles in mice following intravenous administration was slower than unmodified nanoparticles at 15 min, and with higher depositions in kidney and liver. However, no difference was observed at the 1-h time point. Marchal-Heussler, L., P. Maincent, et al. (1990). "[Value of the new drug carriers in ophthalmology: liposomes and nanoparticles]." Journal de Francais de Ophtalmologie 13(11-12): 575-82. Marchal-Heussler, L., D. Sirbat, et al. (1993). "Poly(epsilon-caprolactone) nanocapsules in carteolol ophthalmic delivery." Pharmacetical Research 10(3): 386-90. In order to increase the ocular absorption of carteolol, this antiglaucomatous drug was incorporated into either nanoparticles (NP) or nanocapsules (NC). The polymer used was poly(epsilon-caprolactone) (PCL). The dosage

forms were tested on intraocular hypertensive-induced rabbits. Results are presented as the chronological variations of the intraocular pressure (IOP) in comparison with the commercial aqueous solution (Carteol eye drops). The therapeutic results (decrease in IOP) were much more pronounced with carteolol incorporated into the colloidal carriers than with the commercial eye drops. Further, NC displayed a better effect than NP because the drug was entrapped in the oily core of the carrier, thus more readily available to the eye. The incorporation of the drug into nanocapsules produced a decline in the cardiovascular side effects in comparison with aqueous eye drops, thus showing that the undesired noncorneal absorption was reduced. In conclusion, colloidal suspension made of poly(epsilon-caprolactone) could offer a good opportunity for ophthalmic delivery of drugs. Marine, W., L. Patrone, et al. (2000). "Production of iron-oxide nanoparticles by laser-induced pyrolysis of gaseous precursors." Applied Surface Science 154(155): 353-9. Laser-assisted pyrolysis in a continuous flow reactor has been applied to synthesise iron-oxide nanoparticles. The scope of the present contribution was to investigate the possibility of increasing the reaction yield in order to obtain powder amounts suitable for practical applications. To this aim, a gas mixture containing Fe(CO)/sub 5/ and N/sub 2/O has been submitted to CO/sub 2/ c.w. laser pyrolysis. As a reaction sensitiser gas, SF/sub 6/ has been preferred to C/sub 2/H/sub 4/ to avoid ethylene fragmentation in N/sub 2/O presence and the formation of iron carbides. Due to unexpected SF/sub 6/ dissociation, the synthesis process led to the preferential formation of iron fluoride compounds. Powder samples, submitted to calcining treatment (400 degrees C, 3 h), showed an almost complete transformation to alpha - and gamma -iron oxides retaining the nanostructure feature of the powder. (24 References). Marine, W., L. Patrone, et al. (2000). "Strategy of nanocluster and nanostructure synthesis by conventional pulsed laser ablation." Applied Surface Science 154(155): 345-52. We describe the basic principles of nanoparticle synthesis by conventional pulsed laser ablation. The generalization of the Zeldovich and Raizer theory of condensation has been performed for inhomogeneous laserinduced plume where the rates of nucleation as well as the condensation times are different for different parts of the plume. The theoretical development and analysis of the experimental results are given for condensation, expansion and properties of silicon nanoclusters. (40 References). Markowicz, P., D. Jakubczyk, et al. (2000). "Evolution of size and charge of sodium nanoparticles in an electro-optical trap." Journal of Physics B Atomic Molecular and Optical Physics 33(24): 5513-24. Single and small numbers of sodium nanoparticles were studied in a cold plasma environment of a modified quadrupole trap (optical+low-frequency electrical field). The single nanoparticle radius (mass) was first determined by observing its Brownian motion. Particle size evolution (~90-510 nm) was then determined by applying Mie theory calculations to the intensity of light scattered by a small number of nanoparticles. The trapping potential was determined using a two-nanoparticle system as a probe. As a result, the electrical charge of the nanoparticles and its evolution (~200-1000 elementary charge units) was also found. Strong depolarization of one-nanoparticle scattered light was observed. (24 References). Marsh Jon, N., S. Hall Christopher, et al. (2000). "Kinetic modeling of ultrasonic contrast enhancement by targeted agents using acoustic microscopy." Journal of the American College of Cardiology 35(2 suppl. A): 478A. Martin, J., P. Macchi, et al. (1994). "[The mechanisms of binding of active drugs to polyalkylcyanoacrylate nanoparticles]." Journal de Pharmacie de Belgique 49(6): 498-508. Studies on colloidal carriers such as nanoparticles are generally based on the evaluation of the optimal amount of drug linked to the polymer matrix. This figure is obtained through the mathematical treatment of adsorption/incorporation isotherms. However, results of the literature show an obvious heterogeneity in the isotherms mathematical treatment. A theoretical review of the potential models of the sorption process of drugs will be used to compare the results previously published in the literature. An experimental and systematic approach will be proposed in order to compare more easily the studies from the different research teams and to evaluate the interactions between drugs and colloidal carriers. Martin, J. E., J. P. Wilcoxon, et al. (2000). "Time evolution of enhanced ultrasonic reflection using a fibrin-targeted nanoparticulate contrast agent." Journal of the Acoustical Society of America 108(6): 3049-57. Complex molecular signaling heralds the early stages of pathologies such as angiogenesis, inflammation, unstable atherosclerotic plaques, and areas of remote thrombi. In previous studies, acoustic enhancement of blood clot morphology was demonstrated with the use of a nongaseous, fibrin-targeted acoustic nanoparticle emulsion delivered to areas of thrombosis both in vitro and in vivo. In this study, a system was designed and constructed that allows visualization of the evolution of acoustic contrast enhancement. To evaluate the system, two targets were examined: avidin-complexed nitrocellulose membrane and human plasma clots. The time evolution of enhancement was visualized in 10-min increments for 1 h. A monotonic increase was observed in ultrasonic reflection enhancement from specially treated nitrocellulose membranes for targeted emulsions

containing perfluorooctylbromide (1.30+or-0.3 dB) and for perfluorooctane (2.64+or-0.5 dB) within the first 60 min of imaging. In comparison, the inherently nonechogenic plasma clots showed a substantial increase of 12.0+or0.9 dB when targeted with a perfluoro-octane emulsion. This study demonstrates the concept of molecular imaging and provides the first quantifiable time-evolution report of the binding of a site-targeted ultrasonic contrast agent. Moreover, with the incorporation of specific drug treatments into the nanoparticulate contrast agent, ultrasonic molecular imaging may yield reliable detection and quantification of nascent pathologies and facilitate targeted drug therapy. (31 References). Martins, M. B., A. Supico, et al. (1997). "An analytical methodology to quantify the incorporation of enzymes in polyalkylcyanoacrylate nanoparticles based on size exclusion chromatography." Journal of Pharmaceutical and Biomedical Analysis 15(6): 811-8. The performances of different methods of quantification of protein (methods based on direct spectrophotometric and spectrofluorimetric analysis, chemical reactions and liquid chromatography) to quantify the amount of enzyme incorporated into polyalkylcyanoacrylate nanoparticles, were compared. A methodology based on size exclusion chromatography was selected. The performances of the analytical method to quantify the enzymes Lasparaginase and superoxide dismutase in different polymerization media of poly-isobutilcyanoacrylate, were evaluated. The quantification of superoxide dismutase in the presence of esterase, enzyme used to solubilize nanoparticles, was attempted. An adequate separation between enzyme and the other components of polymerization media was achieved, so the selectivity of the method is adequate to the quantification of an enzyme in polymerization medium, either before or after polymerization. Although lack of selectivity of the column to separate enzymes was observed. The retention time of L-asparaginase and superoxide dismutase in polymerization medium are, respectively, 7.4 and 7.5. Linear correlation between peak area and enzyme concentration were observed for both enzymes in the concentration range from 10 to 80 micrograms ml-1, either before or after polymerization and in different polymerization media. This SE-HPLC analytical methodology is adequate to determine the degree of incorporation of enzymes in polyalkylcyanoacrylate nanoparticles as evidenced by the linear responses of the chromatographic method, the reproductibility of repeated sample injections and the precision of the quantification of enzyme concentration. Marty, J. J., R. C. Oppenheim, et al. (1978). "Nanoparticles--a new colloidal drug delivery system." Pharmaceutica Acta Helvetiae 53(1): 17-23. Maruyama, A., T. Ishihara, et al. (1994). "Preparation of nanoparticles bearing high density carbohydrate chains using carbohydrate-carrying polymers as emulsifier." Biomaterials 15(13): 1035-42. A novel method of preparing nanoparticles bearing high density carbohydrate chains on their surface is described. Carbohydrate-bearing nanoparticles of poly(lactic acid) or polystyrene were prepared by the solvent evaporation method using a carbohydrate-carrying polystyrene derivative which served as both an emulsifier and a surface coating. The diameter of the obtained nanoparticles ranged from 80 to 300 nm depending on the concentration of the polystyrene derivative. As the concentration of the polystyrene derivatives increased the nanoparticle diameter decreased, indicating that the polystyrene derivatives worked as an emulsifier. The obtained particles were specifically aggregated by carbohydrate-specific lectin, showing that the polystyrene derivative was retained on the particle surfaces and expressed carbohydrate residues. The density of carbohydrates on the particle surfaces was determined to be 3-5 molecules per square nanometre. The particles prepared by the present method were stably dispersed and hardly aggregated in aqueous media during storage and centrifugal treatment compared with the post-coated particles that were prepared by adsorbing polystyrene particles with the polystyrene derivative. In vitro study with isolated rat hepatocytes revealed that surface carbohydrate chains were recognized by hepatocytes. Maruyama, A., T. Ishihara, et al. (1997). "Nanoparticle DNA carrier with poly(L-lysine) grafted polysaccharide copolymer and poly(D,L-lactic acid)." Bioconjugate Chemistry 8(5): 735-42. Biodegradable nanoparticles, which contain the sites for both polynucleotide adsorption and targeting ligand on their surfaces, were prepared as a novel carrier for genetic materials. The nanoparticles were obtained from poly(D,L-lactic acid) and poly(L-lysine)-graft-polysaccharide copolymers by using either a solvent evaporation method or a diafiltration method. The size of the particles prepared by the diafiltration method was controlled by varying the initial concentration of the graft copolymer. Nanoparticles as small as 60 nm in diameter were successfully obtained from the graft copolymers with high polysaccharide contents but not from the poly(L-lysine) homopolymer. Polysaccharide moieties on the surface of the nanoparticles were found to interact specifically with a particular lectin as verified by the aggregation assay. The polynucleotide adsorption capacity of the nanoparticles was increased with increasing polysaccharide contents in the graft copolymers, suggesting that the adsorption conformation of poly(L-lysine) moiety in the graft copolymer on the nanoparticle surface is different from that in poly(L-lysine) homopolymer. Moreover, the nanoparticles from the graft copolymer exhibited resistance against self-aggregation and nonspecific adsorption of serum proteins, presumably due to the polymer brush effect and/or exclusion effect from the polysaccharide graft chains. These results suggest that the

nanoparticles prepared from poly(L-lysine)-graft-polysaccharide copolymer and poly(D,L-lactic acid) can serve as a good DNA carrier in vivo. Maruyama, A., A. Ferdous, et al. (1999). "Comb-type copolymers for controlled DNA delivery." Nucleosides Nucleotides 18(6-7): 1681-2. Various comb-type copolymer containing a polycation as a main chain was design to construct delivery systems of DNAs. The comb-type copolymers having cell-specific polysaccharides were proved to be useful to deliver DNA to the target cells in vivo. Of interest, the copolymers with abundant side chains of hydrophilic polymers are capable of stabilizing DNA triplex. Further, injectable nanoparticles for controlled releases of DNAs were fabricated from the copolymer and a biodegradable polymer. Masson, V., F. Maurin, et al. (1997). "Influence of sterilization processes on poly(epsilon-caprolactone) nanospheres." Biomaterials 18(4): 327-35. Polymeric vectors and especially poly(epsilon-caprolactone) nanoparticles have already shown promising results in the optimization of the ophthalmic bioavailability of drugs. Any formulation instilled in the eye must be sterile, and preferentially isotonic. Poly(epsilon-caprolactone) nanospheres were thus formulated with Synperonic PE/F68, Synperonic PE/F127, or Cremophor RH40. A tonicity agent, a preservative and, in some cases, a viscosifiant were then added. The pH was finally adjusted to pH 4 or buffered to pH 7. Different sterilization processes were studied to investigate their influence on the physicochemical characteristics of vectors. Autoclaving did not induce any modification on polymer molecular weight or Synperonic nanospheres diameter, but catalysed some reactions with surfactants and tonicity agents. This method could thus be used if the nanosphere excipients are chosen with care. gamma radiation induced preservative degradation and viscosifiant depolymerization. A cross-linking of poly(epsilon-caprolactone) chains was observed, as reflected by a sharp increase of its molecular weight. However, no variation of the mean particle size was detected. Finally, sterile filtration was the only process which ensured the conservation of physicochemical integrity of nanospheres. This process was successfully applied on non-viscosified vectors with a sufficiently small diameter. Matsumoto, J., Y. Nakada, et al. (1999). "Preparation of nanoparticles consisted of poly(L-lactide)-poly(ethylene glycol)poly(L-lactide) and their evaluation in vitro." International Journal of Pharmacy 185(1): 93-101. This study describes the preparation and the evaluation of biodegradable poly(L-lactide)-poly(ethylene glycol)poly(L-lactide) copolymer (PLA-PEG-PLA) nanoparticles containing progesterone as a model drug. PLA and PLAPEG-PLA copolymers, whose PEG content ranged from 5.2 to 25.8% (w/w), were polymerized in our laboratory. PEG with weight-average molecular weight (Mw) 6600 or 20 000 was introduced as a hydrophilic segment into a hydrophobic PLA homopolymer. A solvent evaporation method was used to prepare the nanoparticles. The drug trapping efficiencies were around 70% and the weight-averaged mean diameters of the nanoparticles were less than 335 nm. The amount of drug released increased as the PEG content and Mw of PLA-PEG-PLA copolymers increased and the total Mw of copolymers of nanoparticles decreased. The initial burst of drug release was reduced by removing the low Mw fraction from the polymer. During the release test, both the extent to which the copolymers were degraded and the size of the nanoparticles were increased slightly by increasing the content of PEG in the polymers. Drug release from the nanoparticles could potentially be controlled by changing the PEG content, PEG Mw and total Mw of the copolymer. The molecular weight distribution (Mw/Mn, Mn: number-average molecular weight) of copolymers was also an important factor for controlled release. Matveev, K. A., L. I. Glazman, et al. (2000). "g-factors of discrete levels in nanoparticles." Physical Review Letters 85(13): 2789-92. Spin-orbit scattering suppresses Zeeman splitting of individual energy levels in small metal particles. This suppression becomes significant when the spin-orbit scattering rate tau(-1)(so) is comparable to the quantum level spacing delta. At small deltatau(so) the g-factor exhibits strong mesoscopic fluctuations. We find the shape of their distribution function using the random matrix theory, and express its parameters in terms of physical characteristics: tau(so), delta, the electron mean free path l, and the particle size L. At deltatau(so)--&gt;0 the average g-factor levels off at a small value g approximately (l/L)(1/2). However, in 2D quantum dots the g-factor is strongly enhanced by spin-orbit coupling. Maxwell, D. J., J. T. Krug, II, et al. (2000). "Optically active nanoparticles for ultrasensitive detection and spectroscopy." Proceedings of SPIE the International Society for Optical Engineering 3913: 112-19. Recent research in the authors' lab has identified a new class of metal nanoparticles that are highly efficient for surface-enhanced optical spectroscopy. By coupling nanoparticles with surface-enhanced Raman scattering (SERS), surface optical processes can be enhanced by 14 to 15 orders of magnitude. This enormous enhancement allows the optical detection of single molecules at room temperature. However, in a standard silver colloid only 1 out of 100 nanoparticles is SERS-active. In this report, a new methodology based on size-selective filtration is demonstrated. This size-selective fractionation procedure yields an enriched colloid that can be used to prepare highly efficient nanoparticle thin films. (15 References).

McCarron, P. A., A. D. Woolfson, et al. (1999). "Response surface methodology as a predictive tool for determining the effects of preparation conditions on the physicochemical properties of poly(isobutylcyanoacrylate) nanoparticles." International Journal of Pharmacy 193(1): 37-47. Preparation conditions of nanoparticles greatly influence their physicochemical characteristics. A factorial design was used to evaluate the influence of these conditions on the particle diameter, zeta potential, polydispersity, percentage recovery, and molecular weight of poly(isobutylcyanoacrylate) nanoparticles. The relationship between these responses and the effects of simultaneously varying three preparation factors (monomer concentration, surfactant concentration, pH of the polymerization medium) were modelled by response-surface methodology. Three levels were chosen for each factor, giving 27 trials. The responses obtained in the experimental design were found to be modelled by either a reduced quadratic or second-order model. Particle diameter was found to be a function of the pH, whereas zeta potential depended on pH and to a lesser extent of the monomer concentration. Polydispersity depended on the pH and an interaction term between pH and the surfactant concentration. The particle recovery was significantly influenced by all three factors, whereas the pH was the primary influence on the molecular weight. Thus, response surface methodology gave detailed information on the predicted physicochemical characteristics found on poly(isobutylcyanoacrylate) nanoparticles prepared using a wide range of experimental conditions. McCarron, P. A., A. D. Woolfson, et al. (2000). "Sustained release of 5-fluorouracil from polymeric nanoparticles." Journal of Pharmacy and Pharmacology 52(12): 1451-9. The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5fluorouracil using three loading concentrations of drug and three different concentrations of added polymer. Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period. It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for transepithelial drug-delivery applications. McClean, S., E. Prosser, et al. (1998). "Binding and uptake of biodegradable poly-DL-lactide micro- and nanoparticles in intestinal epithelia." European Journal of Pharmaceutical Sciences 6(2): 153-63. The use of biodegradable particles as oral delivery vehicles for macromolecular drugs was investigated. We evaluated the binding, uptake and absorption of poly-dl-lactide (PLA) micro- and nanoparticles in Caco-2 monolayers and in ileal tissue and gut associated lymphoid tissue (GALT) of anaesthetised rats and rabbits. Using a range of experimental techniques, we found that approximately 10% of administered micro- and nanoparticles were adsorbed to the apical membranes of each of the five intestinal models. Nanoparticles were found to be absorbed better than microparticles. Overall, little discrimination in uptake patterns was evident between Peyer's patch (PP) and non-PP tissue while rat ileum showed a greater uptake capacity than rabbit. Our results show that uptake of PLA particles was low capacity, size-dependent and predominantly transcellular in all systems. A low proportion of the apically-bound particles was absorbed, with uptake exclusion evident for particles &gt;4microm. The affinity of PLA particles for intestinal epithelia and GALT needs to be greatly enhanced in order to achieve improved oral bioavailability of macromolecules. McCloskey, K. E., J. J. Chalmers, et al. (2000). "Magnetophoretic mobilities correlate to antibody binding capacities." Cytometry 40(4): 307-15. METHODS: A methodology and a mathematical theory have been developed, which allow quantitation of the expression levels of cellular surface antigens using immunomagnetic labels and cell tracking velocimetry (CTV) technology. RESULTS: Quantum Simply Cellular (QSC) microbeads were immunomagnetically labeled with antiCD2 fluorescein isothiocyanate (FITC) antibodies and anti-FITC MACS paramagnetic nanoparticles. Magnetophoretic mobility has been defined as the magnetically induced velocity of the labeled cell or microbead divided by the magnetophoretic driving force, proportional to the magnetic energy density gradient. DISCUSSION: Using computer imaging and processing technology, the mobility measurements were accomplished by microscopically recording and calculating the velocity of immunomagnetically labeled QSC microbeads in a nearly constant magnetic energy gradient. A calibration curve correlating the measured magnetophoretic mobility of the immunomagnetically labeled microbeads to their antibody binding capacities (ABC) has been obtained. CONCLUSION: The results, in agreement with theory, indicate a linear relationship between magnetophoretic mobility and ABC for microbeads with less than 30,000 ABC. The mathematical relationships and QSC

standardization curve obtained allow determination of the number of surface antigens on similarly immunomagnetically labeled cells. McCloskey, K. E., M. Zborowski, et al. (2001). "Measurement of CD2 expression levels of IFN-alpha-treated fibrosarcomas using cell tracking velocimetry." Cytometry 44(2): 137-47. METHODS: A methodology and a mathematical relationship have been developed that allow quantitation of the expression levels of cellular surface antigens, in terms of antibody binding capacities (ABC). This methodology uses immunomagnetically labeled cells and calibration microbeads combined with cell tracking velocimetry (CTV) technology to measure magnetophoretic mobilities corresponding to cellular ABC. The mobility measurements were accomplished by microscopically recording and calculating the velocity of immunomagnetically labeled QSC microbeads and cells in a nearly constant magnetic energy gradient. RESULTS: Transformed fibrosarcoma cells were given controlled treatments of interferon-alpha in order to manipulate CD2 antigen expression levels. These cells were then immunomagnetically labeled with anti-CD2 FITC antibodies and anti-FITC MACS paramagnetic nanoparticles. Measured magnetophoretic mobilities were used to calculate ABC for these cells, corresponding to CD2 expression levels. CONCLUSION: The results from CTV and flow cytometry (FCM) qualitatively verify that these fibrosarcoma cells express elevated levels of CD2 molecules with increasing interferon-alpha treatment from 0 to 24 h. The mean basal CD2 expression level, in terms of ABC, was calculated to be 27,000 from CTV analysis, whereas FCM indicates a comparable ABC value of 33,000. Copyright 2001 Wiley-Liss, Inc. McConnell, W. P., J. P. Novak, et al. (2000). "Sandwich-structured thin film of silicon nanoparticles embedded in Al2O3 matrices." Journal of Physics D Applied Physics 33(21): 2687-90. Silicon nanoparticles embedded in the host matrix of an Al/sub 2/O/sub 3/ thin film, with a thickness of about 260 nm, were prepared by using the pulsed laser deposition method. The laser target consisted of a small silicon wafer glued onto the surface of a circular Al/sub 2/O/sub 3/ plate, which was set to rotate uniformly when laserablating. TEM and EDS results showed that the films consisted of silicon nanoparticles in the form of nanocrystals with diameters of less than 6 nm dispersed in the amorphous Al/sub 2/O/sub 3/ matrices. A secondary ion mass spectroscopy depth profile of the silicon content of the film indicated that the silicon nanoparticles in the Al/sub 2/O/sub 3/ matrices were arranged in fairly well demarcated thin layers sandwiched between layers of the host material, FTIR results evidently suggested that the encapsulating amorphous Al/sub 2/O/sub 3/ material forms a good host for the prevention of atmospheric oxidation of the silicon nanoparticles. However, prolonged annealing can cause the silicon nanoparticle surface interfacing the host material to be oxidized by the oxygen mostly from the Al/sub 2/O/sub 3/ molecules and to be bonded to the Al or O-Al bonds. (18 References). McCullough, J. S., G. M. Hodges, et al. (1995). "A morphological and microanalytical investigation into the uptake of particulate iron across the gastrointestinal tract of rats." Journal of Submicroscopic Cytology and Pathology 27(1): 119-24. The uptake and translocation of particulate iron across the gastrointestinal (GI) mucosa of young adult rats has been investigated using a range of morphological techniques and X-ray microanalysis (XRMA). In animals fed a suspension of iron powder constituted of metallic iron particles ranging in size from 6-9 microns down to 5-30 nm, light microscopic histochemistry has clearly revealed iron deposits within the tissues of the duodenum. Scanning electron microscopy of the duodenal tissue by back-scattered electron imaging has complemented the light microscopic observations and revealed a selective localization of iron in the villi with variation in levels of iron uptake by the mucosal cells. Ultrastructural and XRMA analysis of duodenum has established the presence of metallic iron nanoparticles within the brush border, lateral intercellular spaces of the mucosal cells, mitochondrial cristae and cytoplasm of both mucosal and stromal cells. The observations indicate that metallic iron particles, in the nano-size range, may be taken up by the GI mucosa and that the passage of such particles across the epithelial barrier may take place through both a paracellular as well as a transcytotic process. McEwan, J. F., H. S. Veitch, et al. (1999). "Synthesis and biological activity of ribose-5'-carbamate derivatives of vitamin B(12)." Bioconjugate Chemistry 10(6): 1131-6. Twelve biologically active derivatives of vitamin B(12) (cyanocobalamin) have been synthesized in which spacers were attached to the ribose-5'-hydroxyl group of vitamin B(12). Their potential to act as oral delivery agents for proteins, nanospheres, or immunogens using the vitamin B(12) uptake system was evaluated by determining their affinity for intrinsic factor (IF) and non-IF. The ribose-5'-hydroxyl group of vitamin B(12) was activated through the use of 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyldi(1,2, 4-triazole) (CDT), or di(1-benzotriazolyl) carbonate (DBTC). Subsequent addition of an aminoalkane, diaminoalkane, or alkane diacid dihydrazide gave rise to vitamin B(12) derivatives suitable for attachment to various proteins, peptides, or nanospheres to enable oral delivery utilizing the vitamin B(12) uptake system. The ribose-5'-carbamate derivatives were found to possess similar affinity for intrinsic factor as that of the e-monocarboxylic acid of vitamin B(12). The affinity for non-IF was similar to cyanocobalamin or even higher for some of the smaller derivatives. Polysciences nanoparticles derivatized with vitamin B(12) 5'-carbamate adipic dihydrazide into CaCo-2 cells showed significantly higher levels of transport of the particles, when compared to unmodified particles.

McIntire, G. L., E. R. Bacon, et al. (1998). "Pulmonary delivery of nanoparticles of insoluble, iodinated CT X-ray contrast agents to lung draining lymph nodes in dogs." Journal of Pharmaceutical Sciences 87(11): 1466-70. Lung cancer continues to be a leading cause of death around the world. Staging of this disease is critically dependent upon the involvement or noninvolvement of the lymph nodes which drain the region of lung containing the lesion/tumor. Palpation, unenhanced CT, and lymph node excision (i.e., mediastinectomy) are currently used to ascertain the status of these regional draining lymph nodes. The work reported herein details the first efforts toward the pulmonary instillation of iodinated nanoparticles for contrast-enhanced CT of lung draining lymph nodes. The data reflect the impact of dose, time post instillation, and formulation (surfactant) upon the observed CT enhancement of the tracheobronchial lymph nodes of beagle dogs. In addition, initial safety is discussed with both macroscopic and microscopic observations. The results indicate that pulmonary instillation of small volumes of iodinated nanoparticles could be successfully used to aid staging of lung cancer by CT imaging. McIntire, G. L., E. R. Bacon, et al. (2000). "Time course of nodal enhancement with CT X-ray nanoparticle contrast agents: effect of particle size and chemical structure." Investigative Radiology 35(2): 91-6. RATIONALE AND OBJECTIVES: Levels of CT enhancement in rabbit lymph nodes were followed with time after subcutaneous injection of four iodinated, insoluble nanoparticle contrast agents to provide experimental support for the hypothesis that clearance of these agents is related to the chemical structure of the agent itself. The impact of particle size was also studied. METHODS: Subcutaneous injections (2 x 0.25 mL) were made in the dorsum of rabbit paws with 15% suspensions of four nanoparticle contrast agents. Images were obtained at 4, 10, 24, 48, and 72 hours and 5, 7, and 14 days after injection. Average attenuation (in Hounsfield units [HU]), node volume, and total iodine uptake were estimated from the CT scans for each lymph node at each time point. RESULTS: All the agents provided adequate enhancement of both the popliteal and axillary lymph nodes of the rabbit (ie, > delta100 HU). Lymph node volume appears to be related to the persistence of enhancement, with long-lived agents demonstrating the greatest increase in size. The rate of clearance from the lymph nodes is related to the structure of the agent. CONCLUSIONS: Clearance of insoluble, iodinated nanoparticle contrast agents from lymph nodes can be modulated by changes in the structure of the agent itself. Using the same agent, smaller particles deliver material to the lymph nodes more quickly and clear more quickly. McIntosh Catherine, M., M. Simard Joseph, et al. (2000). "Biomolecular recognition using self-optimizing multivalent nanoparticle receptors." Abstracts of Papers American Chemical Society. 220(Part 2): 253. McLeod, A. D., F. C. Lam, et al. (1988). "Optimized synthesis of polyglutaraldehyde nanoparticles using central composite design." Journal of Pharmaceutical Sciences 77(8): 704-10. A central composite design was applied to the optimization of the synthesis of polyglutaraldehyde nanoparticles (PGNP). The effects of monomer concentration, surfactant concentration, pH, oxygen level, and stirring rate on the particle size, polydispersity, surface carboxyl group concentration, and yield of PGNP were investigated. The optimal conditions for the synthesis of PGNP were found to be: 7% (w/v) glutaraldehyde, 2.5% (w/v) dextran, pH 12, 70% (v/v) oxygen, and a stirring rate of 1080 rpm. Under these conditions, the values of the dependent variables adequately resembled those predicted by the model. The usefulness of these particles in the targeted delivery of cytotoxic drugs is discussed. Mehnert, W. and K. Mader (2001). "Solid lipid nanoparticles. Production, characterization and applications." Advances in Drug Delivery Review 47(2-3): 165-96. Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed. Melinger, J. S., V. D. Kleiman, et al. (2000). "Ultrafast third order nonlinear optical response of germanium nanoparticles embedded in a silica matrix." Nonlinear Optics: Materials, Fundamentals, and Applications. Technical Digest. Postconference Edition. TOPS 46(IEEE Cat. No.00CH37174): 102-4. We study the properties of the third order nonlinear optical response of germanium nanoparticles embedded in a thin film silica matrix. Ultrafast four-wave mixing measurements are performed on samples with different nanoparticle diameters. (5 References). Meltzer, R. S. and K. S. Hong (2000). "Electron-phonon interactions in insulating nanoparticles: Eu2O3." Physical Review B Condensed Matter 61(5): 3396-403.

The temperature and particle size dependencies of the linewidth of spectral holes burned in the /sup 7/F/sub 0/ to /sup 5/D/sub 0/ transition of Eu/sup 3+/ ions in Eu/sub 2/O/sub 3/ are calculated and compared with experiment. The power-low temperature behavior ~T/sup 7/, well-known experimentally and theoretically for the bulk, is observed to be strongly weakened to ~T/sup 3/ for the nanoparticles. A calculation is performed that assumes a two-phonon Raman-scattering mechanism involving the discrete phonon modes of a homogeneous nanoparticle with stress-free boundary conditions. The experimental results are successfully described assuming that the phonon modes broaden with frequency as ~ omega /sup 2/. A quantitative comparison of the calculations with experiment allows the determination of the linewidth of the phonon resonances of the nanoparticles. The calculations predict that the size dependence of the hole linewidth is ~D/sup -2.5/, in close agreement with experiment. (16 References). Menei, P., J. P. Benoit, et al. (1994). "Drug targeting into the central nervous system by stereotactic implantation of biodegradable microspheres." Neurosurgery 34(6): 1058-64; discussion 1064. Controlled drug release in the central nervous system through an implantable polymeric vector has been developed in recent years. For this purpose, different polymeric devices composed primarily of synthetic biocompatible and biodegradable polymers have been investigated. The first polymeric devices developed were macroscopic implants (monolithic devices), which required open surgery for implantation. Microencapsulation methods, however, allow the production of microparticles or nanoparticles loaded with neuroactive drugs. Because of their size, these micro- or nanoparticles may be easily implanted by stereotaxy in discrete, precise, and functional areas of the brain without causing damage to the surrounding tissue. Presently, this method is most frequently applied in the fields of neuro-oncology and neurodegenerative diseases, but neurologically, the potential applications of drug targeting by stereotactic implantation of drug-loaded particles are legion. Merkulova, G., L. Margulies, et al. (2000). "The use of organic templates to develop biomimetic chain structures of magnetic nanoparticles." Journal of Applied Physics 87(9): 1-3. The double-tailed surfactants AOT (bis 2-ethylexyl sodium sulfosuccinate) and lecithin (phosphatidylcholine) selfassemble in the presence of water and a hydrocarbon to form fluid microstructures. The nanostructure of this gel appears to be made up of bicontinuous networked channels of water and the hydrocarbon phase, alpha -Fe nanoparticles are synthesized via reducing the ferrous salt in the aqueous microphase of the gel. Transmission electron microscopy of these particles reveals nanospheres with a uniform size distribution ranging from 15 to 18 nm in diameter. An interesting observation is that these nanoparticles appear to be synthesized in the form of entangled chains reminiscent of magnetic nanoparticles in magnetobacteria. Destruction of the gel phase still leaves the aggregation structure largely intact, implying a clear templating role of the surfactant microstructure. Magnetic properties of these particles were characterized using a SQUID susceptometer. The hysteresis loops at ambient temperature reveals a saturation magnetization of 190 emu/g and a coercivity of 240 G, indicating that the nanoparticles are ferromagnetic. The results indicate the possibility of nanoscale engineering of these materials with biomimetic properties. (9 References). Merodio, M., M. A. Campanero, et al. (2000). "Development of a sensitive method for the determination of ganciclovir by reversed-phase high-performance liquid chromatography." Journal of Chromatography A 870(1-2): 159-67. Ganciclovir is a nucleoside analogue widely used in the treatment of cytomegalovirus infections, which affects mainly immunocompromised patients. Recently, new pharmaceutical dosage forms based on the use of albumin nanoparticles have been developed for improving the efficacy of this drug. The aim of this study was to develop an analytical HPLC method for the determination of ganciclovir in both pharmaceuticals (i.e. albumin nanoparticles) and biological medium samples. The chromatography was performed on a reversed-phase encapped column (LiChrospher Select B C8) with a mobile phase consisting of acetonitrile in 0.05 M ammonium acetate (pH 6.5; 2: 98, v/v). Acyclovir was used as internal standard and the detection wavelength was 254 nm. The limit of quantitation of ganciclovir was 50 ng/ml and the average recoveries over a concentration range of 0.05-10 microg/ml ranged from 98 to 102%. Precision did not exceed 5%. In summary, this assay is a selective, sensitive and reproducible method for the determination of the ganciclovir in albumin nanoparticles. It can be successfully applied to the estimation of the ganciclovir uptake by cultured human corneal fibroblasts. Mezhov-Deglin, L. P., A. A. Levchenko, et al. (2000). "Nanoparticle in a quantum crystal with a narrow vacancy band." Physica B 280: 1-4. Vacancy-assisted diffusion of a neutral probe nanoparticle with a radius R/sub p/ of a few lattice constants in a quantum crystal with a narrow vacancy band is considered. The diffusion coefficient of the probe D/sub p/(T) in such a crystal should fall exponentially near T/sub melt/, and it can go through a maximum at temperatures T/sub tr/, where the transition from thermally activated hopping of localized vacancies to a proper band motion of delocalized vacancions takes place, under the condition that the mean free path of the vacancions l/sub v/(T) at T/sub tr/ is less than R/sub p/ and increases with lowering the temperature quicker than the inverse value of the relative concentration of vacancies X/sub v/(T). Below T/sub tr/, where l/sub v/ is much longer than the probe diameter, the value of D/sub p/ should fall proportionally to X/sub v/(T). (3 References).

Miao, H. H., J. S. Ye, et al. (2000). "Oxidative modification of neurogranin by nitric oxide: an amperometric study." Bioelectrochemistry 51(2): 163-73. Neurogranin (Ng) is a neuron-specific protein kinase C (PKC) substrate, which contains four cysteine (Cys) residues. Recently, it has been shown that Ng is a redox-sensitive protein and is a likely target of nitric oxide (NO) and other oxidants [F.-S. Sheu, C.W. Mahoney, K. Seki, K.-P. Huang, Nitric oxide modification of rat brain neurogranin affects its phosphorylation by protein kinase C and affinity for calmodulin, J. Biol. Chem. 271 (1996) 22407-22413: J. Li, J.H. Pak, F.L. Huang, K.-P. Huang, N-methyl-D-aspartate induces neurogranin/RC3 oxidation in rat brain slices, J. Biol. Chem. 274 (1999) 1294-1300]. In this study, we directly examine the redox reactions between dissolved NO and Cys as well as between NO and bacterial expressed Ng in its reduced form, at concentrations approximate to the physiological levels in phosphate buffer solution (PBS) under aerobic conditions. The reaction kinetics are measured directly by our newly developed electrochemical sensor. Our sensor is based on the chemical modification of electrode with immobilized nanoparticles of transition metal palladium (Pd) which serves as catalytic centers for the electrochemical oxidation of thiol and NO selectively and quantitatively at different potentials. It detects Cys and Ng in a linear range from nano to micromolar concentration at + 450 mV, vs. a saturated calomel reference electrode (SCE), while the detection of NO at the sensor can be optimally achieved at + 700 mV (vs. SCE) with a linear current-to-concentration range of nM to microM. It thus provides a selective control to monitor two reactants independently. With this sensor as a detector, we found that (1) the oxidation of either Cys or Ng by NO is a fast reaction which reaches a near completion within 1-2 min at its physiological concentration; and (2) after the completion of reaction, NO is mostly, if not all, regenerated, an observation consistent with the reaction mechanism involvi ng the formation of S-nitrosothiol as an intermediate. The reaction kinetics of both NO to Cys and NO to Ng implies that NO can achieve local action on cellular proteins in addition to its effect on targets located in neighboring cells via concentration-gradient-dependent diffusion. Miao, B. and G. Wang (2000). "Optical properties of cluster-based nanofilms prepared by Ge-Al co-evaporation." Physica A 8(2): 194-8. Three GeAl thin nanofilms have been prepared by Ge-Al co-evaporation technique. The measurements of transmission electron microscope (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) indicate that the films consist of Ge nanocrystals (NCs) and a-Ge nanoclusters with incorporated Al atoms, and the average size of the nanoclusters are estimated to be ~12, 5 and 3 nm. The XRD also suggests that Ge NCs are preferentially oriented to (110) plane growth due to the stacking faults of Ge atoms during crystallization at low temperatures. The absorption spectra changed drastically. The interband transition absorption in bulk Ge disappeared, and the absorption edge is shifted to high energy. These spectral changes can be qualitatively explained by quantum confinement effect. (10 References). Michaelis, M., J. Matousek, et al. (2000). "Bovine seminal ribonuclease attached to nanoparticles made of polylactic acid kills leukemia and lymphoma cell lines in vitro." Anti Cancer Drugs. [ print] 11(5): 369-376. Bovine seminal ribonuclease (BS-RNase) is a protein with a number of biological effects. It shows antitumoral, aspermatogenic, antiembryonic, immunosuppressive and antiviral properties. The cytotoxic effects appear to be specific for tumor cells as non-malignant cells seem to be unaffected in vitro. Unfortunately, the in vivo application of BS-RNase so far was successful only when it was administered intratumorally. Therefore, the objective of the present investigation was to improve the properties of BS-RNase by attachment to nanoparticles made of polylactic acid (PLA-NP) using an adsorption method. This preparation was tested in vitro against leukemia (MOLT-4) and lymphoma (H9) cell lines sensitive and resistant to cytarabine. No difference between the nanoparticle preparation and pure BS-RNase was found in these tests. To examine the in vivo effects, the preparations were tested for their aspermatogenic and antiembryonal efficacy compared to the pure BS-RNase as a rapid test for antitumoral activity. The aspermatogenic and antiembryonal effects were enhanced by the nanoparticle preparation. Consequently, BS-RNase loaded adsorptively to PLA-NP holds promise for the in vivo use as an antitumoral agent. Further research will investigate the efficacy of this preparations in an in vivo tumor model. Michaelis, M., J. Matousek, et al. (2000). "Bovine seminal ribonuclease attached to nanoparticles made of polylactic acid kills leukemia and lymphoma cell lines in vitro." Anticancer Drugs 11(5): 369-76. Bovine seminal ribonuclease (BS-RNase) is a protein with a number of biological effects. It shows antitumoral, aspermatogenic, antiembryonic, immunosuppressive and antiviral properties. The cytotoxic effects appear to be specific for tumor cells as non-malignant cells seem to be unaffected in vitro. Unfortunately, the in vivo application of BS-RNase so far was successful only when it was administered intratumorally. Therefore, the objective of the present investigation was to improve the properties of BS-RNase by attachment to nanoparticles made of polylactic acid (PLA-NP) using an adsorption method. This preparation was tested in vitro against leukemia (MOLT-4) and lymphoma (H9) cell lines sensitive and resistant to cytarabine. No difference between the nanoparticle preparation and pure BS-RNase was found in these tests. To examine the in vivo effects, the

preparations were tested for their aspermatogenic and antiembryonal efficacy compared to the pure BS-RNase as a rapid test for antitumoral activity. The aspermatogenic and antiembryonal effects were enhanced by the nanoparticle preparation. Consequently, BS-RNase loaded adsorptively to PLA-NP holds promise for the in vivo use as an antitumoral agent. Further research will investigate the efficacy of this preparations in an in vivo tumor model. Minemoto, S., J. Muller, et al. (2000). "Direct observation of the dynamics of electronic excitations in molecules and small clusters." Physical Review Letters 84(16): 3554-7. Femtosecond time-resolved photoelectron spectroscopy is applied to study relaxation paths of excited states of mass-selected negatively charged clusters. As a first example, the lifetime of an excited state of the carbon trimer anion is measured directly. In addition, the mechanism of the decay, i.e., the configurations of the participating electronic states, is determined from the photoelectron spectra. In general, this method can be used to study all kinds of electronic excitation and relaxation processes in mass-selected nanoparticles. Minones, J., E. Yebra-Pimentel, et al. (1995). "Surface pressure-area isotherms of mixed cyclosporinpoly(isobutylcyanoacrylate) monolayers spread at the air/water interface." Journal of Pharmaceutical Sciences 84(4): 50811. The pi-A isotherms of mixed monolayers of cyclosporin and poly(isobutylcyanoacrylate) (PIBCA) show that the molecular areas of cyclosporin and PIBCA are additive regardless of the pH of the substrate or the physical state of the monolayers. All these mixed films collapse at the same surface pressure; therefore, application of the twodimensional phase rule implies that cyclosporin and PIBCA are immiscible at the interface. This conclusion may have important implications with regard to the formulation of PIBCA-cyclosporin nanoparticles for cyclosporin administration, though further research in this direction will require consideration of the role played by the coadjuvants used for PIBCA polymerization during nanoparticle formation. Mintorovitch, J. and K. Shamsi (2000). "Eovist Injection and Resovist Injection: two new liver-specific contrast agents for MRI." Oncology (Huntingt) 14(6 Suppl 3): 37-40. Eovist Injection (gadolinium-EOB-DTPA) is selectively taken up by hepatocytes, which will increase the signal intensity of normal liver parenchyma on T1-weighted images. This results in improved lesion-to-liver contrast because malignant tumors either do not contain hepatocytes or their functioning is hampered. Following intravenous (i.v.) bolus injection, Eovist Injection is excreted by both the renal and biliary routes. Clinical trials have evaluated the safety and efficacy of Eovist Injection up to a dose of 100 mumol/kg body weight. Resovist Injection (SHU-555A) contains iron-oxide nanoparticles coated with carboxydextran and is administered as an intravenous bolus injection at a fixed-volume dose, dependent on body weight. The uptake of Resovist Injection in the reticuloendothelial (RES) cells results in a decrease of the signal intensity of normal liver parenchyma on both T2- and T1-weighted images. Due to the altered phagocytic distribution and activity, the signal intensity in most metastatic tumors is not affected, resulting in improved lesion-to-liver contrast. Both Resovist Injection and Eovist Injection have exhibited acceptable safety profiles in clinical trials, and have the potential to provide additional information regarding lesion detection, classification, and characterization. Mirkin, C. A., R. L. Letsinger, et al. (1996). "A DNA-based method for rationally assembling nanoparticles into macroscopic materials." Nature 382(6592): 607-9. Colloidal particles of metals and semiconductors have potentially useful optical, optoelectronic and material properties that derive from their small (nanoscopic) size. These properties might lead to applications including chemical sensors, spectroscopic enhancers, quantum dot and nanostructure fabrication, and microimaging methods. A great deal of control can now be exercised over the chemical composition, size and polydispersity of colloidal particles, and many methods have been developed for assembling them into useful aggregates and materials. Here we describe a method for assembling colloidal gold nanoparticles rationally and reversibly into macroscopic aggregates. The method involves attaching to the surfaces of two batches of 13-nm gold particles non-complementary DNA oligonucleotides capped with thiol groups, which bind to gold. When we add to the solution an oligonucleotide duplex with 'sticky ends' that are complementary to the two grafted sequences, the nanoparticles self-assemble into aggregates. This assembly process can be reversed by thermal denaturation. This strategy should now make it possible to tailor the optical, electronic and structural properties of the colloidal aggregates by using the specificity of DNA interactions to direct the interactions between particles of different size and composition. Mirkin, C. A. (2000). "Bioinspired two- and three-dimensional nanostructures." Journal of Nanoparticle Research 2: 121122. Moghimi, S. M., L. Illum, et al. (1990). "Physiopathological and physicochemical considerations in targeting of colloids and drug carriers to the bone marrow." Critical Reviews in Therapeutic Drug Carrier Systems 7(3): 187-209. The ability of the bone marrow to remove particulate matters from the circulation, opens up perhaps an

opportunity for the delivery of therapeutic agents by means of colloidal drug carrier systems such as liposomes, emulsions, nanoparticles, etc. for the treatment of diseases and disorders of this multifunctional organ of the body. This article is designed to provide a critical review on fundamentals, problems, current progress, and future prospects of site-specific delivery of intravenously injected colloidal drug carriers to the bone marrow. Moghimi, S. M., A. C. Hunter, et al. (2001). "Long-circulating and target-specific nanoparticles: theory to practice." Pharmacology Review 53(2): 283-318. The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states. Molina, J., J. Urbina, et al. (2001). "Cure of experimental Chagas' disease by the bis-triazole DO870 incorporated into 'stealth' polyethyleneglycol-polylactide nanospheres." Journal of Antimicrobial Chemotherapy 47(1): 101-4. We have incorporated several inhibitors of sterol biosynthesis into long-circulating polyethyleneglycol-polylactide (PEG-PLA) nanospheres in order to improve the bioavailability of these poorly soluble compounds. Mice infected with CL and Y strains of Trypanosoma cruzi and treated for 30 consecutive days with DO870-loaded nanospheres at doses of 3 mg/kg/day, by the intravenous route, showed a significant cure rate (60-90%) for both strains. The activity was dose dependent and significant activity was observed for doses > or = 0.75 mg/kg/day. No cure was observed in mice treated with unloaded nanoparticles. Ketoconazole and itraconazole failed to induce cure against the Y strain even in the entrapped form. Molpeceres, J., M. Guzman, et al. (1996). "Application of central composite designs to the preparation of polycaprolactone nanoparticles by solvent displacement." Journal of Pharmaceutical Sciences 85(2): 206-13. Cyclosporin A (CyA) is a good candidate for incorporation in colloidal carriers such as nanoparticles (NP) that would diminish the adverse effects associated with its use under conventional pharmaceutical dosage forms and improve bioavailability after oral administration. In this study a composite rotational experimental design was used to evaluate the joint influence of five formulation variables: temperature of the aqueous phase, needle gauge, volume of the organic phase, and the amounts of polymer and surfactant on the micromeritic characteristics of the CyA-loaded NP obtained by the method of Fessi et al. The percentage of drug encapsulated in the NP was also evaluated for each formulation, and the yield, which was expressed as the ratio between the experimentally measured quantity of drug in the formulation and the theoretical content, was determined because CyA undergoes surface absorption. Potential variables such as stirring speed (500 rpm), final drug concentration (100 micrograms/mL), or injection rates (GRi = 0.379 mL/s) were maintained constant. The ANOVA corresponding to the experimental design showed that the amounts of polymer and surfactant, and the diameter of the needle used in the preparation of NP, significantly affected the percentage of entrapped drug (I2 = 0.8916). The mean particle size was significantly affected by all the formulation variables tested except for the amount of surfactant dissolved in the external aqueous phase (r2 = 0.9518). Neither the yield (mean value of 99.61%) nor the size distribution parameters (polydispersity and coefficient of variation) presented good correlation coefficients for the equations obtained, although some variables showed statistical significance. A second study was carried out to investigate the effects on the drug-loaded NP characteristics of varying the global injection rates (GRi) for the organic phase into the aqueous medium. The results showed a dramatic decrease in both particle size and drug incorporation in the carrier as the rate of mixing increased. From the results of both the experimental design and the second study, a theoretical model for nanoparticle formation is proposed that considers the most significant variables, and an empirical relationship to predict mean particle size is presented. Thus, particle size can be controlled by the injection rates (GRi), the needle gauge, and the polymer concentration. Molpeceres, J., M. R. Aberturas, et al. (1997). "Stability of cyclosporine-loaded poly-sigma-caprolactone nanoparticles." Journal of Microencapsulation 14(6): 777-87. The aim was to evaluate the long-term stability of cyclosporin A-loaded nanoparticle suspensions, stored at 8 and 25 degrees C. The stability of freeze-dried samples was also investigated. Nanoparticles (NP) of poly-sigmacaprolactone (P sigma CL), a biodegradable polymer, were obtained by a modified nanoprecipitation method. A central composite experimental design was used to investigate the simultaneous effect of technological factors (temperature of the aqueous phase and needle gauge) and formulation variables (volume of acetone and the amount of polymer and surfactant). The effect of these variables on the stability of the 100-220 nm particles

obtained was evaluated. The percentage of cyclosporin A (CyA) encapsulated in the NP suspensions stored at 8 and 25 degrees C for at least 3 months remained unaltered. Moreover, there was no change in the size of NP. After 4 months storage, the physical stability of the preparation was affected. NP aggregates could be observed by light microscopy. Reconstituted freeze-dried preparations showed a mean increase of 1% in the incorporated drug and also a considerable increase in mean size and size distribution. Additional experiments investigated the effect of freezing temperature (-70 and -196 degrees C) and of 5, 10 and 20% (w/v) cryoprotector (mannitol, sorbitol, glucose and threalose) on 100 nm particles. The addition of glucose and threalose at concentrations &gt; 10% permitted adequate reconstitution of the freeze-dried product with conservation of the encapsulated CyA. Molpeceres, J., M. Chacon, et al. (1999). "A polycaprolactone nanoparticle formulation of cyclosporin-A improves the prediction of area under the curve using a limited sampling strategy." International Journal of Pharmacy 187(1): 101-13. Therapeutic monitoring of Cyclosporine (CyA) by using area under the curve (AUC) from abbreviated kinetic profiles is of recent trend in clinical practice due to the potential improvement in transplant and clinical outcome with costs reduction in mind. Several papers describe successful use of the limited sampling strategy to predict AUCs in different transplant populations when treated with Sandimmun or Sandimmun Neoral. However, the same predictive potential is achieved for the latter formulation with lesser effort. The present paper describes the application of the limited sampling strategies to demonstrate the advantages of using CyA incorporated in polymeric nanoparticles (CyA-NP) as compared to two reference Sandimmun formulations which consisted of an emulsion of the oily solution in milk (SIM-EM) and a microemulsion (SIM-Neoral) formerly tried on rats. Two independent data batches were used: group 1 which included 36, 31 and 10 animals receiving SIM-EM, CyA-NP and SIM-Neoral, respectively, and group 2 made of nine and eight rats treated with SIM-EM and CyA-NP. Several limited sampling equations were derived for each formulation from group 1 by stepwise multiple linear regression. Statistical analysis disclosed that CyA concentrations 8 and 32 h after dose administration vouched for 88 and 69% variability in AUC (0-48 h) for CyA-NP and SIM-EM, respectively. When summed up, these two concentrations revealed nearly 97% of AUC (0-48 h) variability. CyA concentrations 8 h post-treatment with SIMNeoral explained 89% variability in AUC (0-48 h). This value raised to 98% when a second CyA concentration (24 h) was introduced. The equations derived from group 1 were then employed to predict AUCs in group 2. CyA blood levels at 8 h post-treatment confirmed AUC for CyA-NP (r(2)=0.98) to be very precise and unbiased (error=1. 46%, interval -16.2 to 21.33%), while the results for SIM-EM obtained with the CyA concentration at 32 h were r(2)=0.93 plus error=5.71%, interval -44.33 to 105.94%. Similar results were obtained when the study period was reduced to 24 h. The use of these limited sampling models manifested the coincidence between CyA-NP and SIM-Neoral as well as the advantages of both formulations over SIM-EM when it comes to CyA monitoring. Molpeceres, J., M. R. Aberturas, et al. (2000). "Biodegradable nanoparticles as a delivery system for cyclosporine: Preparation and characterization." Journal of Microencapsulation. [ print] 17(5): 599-614. Cyclosporine (CyA) was incorporated into polycaprolactone nanoparticles (PCL-NP) in order to increase its oral bioavailability and to control drug distribution, thereby potentially reducing its toxicity. Prior to in vivo studies, the carrier was optimized and characterized by using different techniques. Light scattering (LS) and transmission and scanning electron microscopy (TEM and SEM) indicated the NP were spherical in shape with a mean size of apprx 100 nm. The influence of the solvent evaporation conditions and the polymer and drug amounts on CyA incorporation was established in order to optimize drug loading. When acetone and excess water were removed at constant temperature, no aggregation phenomena were observed. A value of 180 mg PCL was the minimum polymer amount necessary to encapsulate 95% of the drug initially added to the preparation. Under these conditions, HPLC analysis revealed that apprx 130 mug CyA per mg PCL were incorporated for a total CyA concentration of 2.5 mg/ml, being part of the drug adsorbed onto the particle surface. No structural changes or instability of the components during NP preparation were detected by gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). However, GPC studies showed a competition between poloxamer and CyA for adsorption onto the carrier. In addition, DSC results suggested that at least part of the drug associated to NP remained in its crystal form. Therefore, CyA-loaded NP were easily manufactured and characterized and allow for the administration of therapeutic drug doses to experimental animals. Monsky, W. L., D. Fukumura, et al. (1999). "Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor." Cancer Research 59(16): 4129-35. The goal of this investigation was to measure changes in vascular permeability, pore cutoff size, and number of transvascular transport pathways as a function of time and in response to vascular endothelial growth factor (VEGF), placenta growth factor (PIGF-1 and PIGF-2), or basic fibroblast growth factor (bFGF). Two human and two murine tumors were implanted in the dorsal skin chamber or cranial window. Vascular permeability to BSA (approximately 7 nm in diameter) and extravasation of polyethylene glycol-stabilized long-circulating liposomes (100-400 nm) and latex microspheres (approximately 800 nm) were determined by intravital microscopy. Vascular permeability was found to be temporally heterogeneous. VEGF superfusion (100 ng/ml) significantly increased vascular permeability to albumin in normal s.c. vessels, whereas a 30-fold higher dose of VEGF (3000 ng/ml) was required to increase permeability in pial vessels, suggesting that different tissues exhibit different dose thresholds

for VEGF activity. Furthermore, VEGF superfusion (1000 ng/ml) increased vascular permeability to albumin in a hypopermeable human glioma xenograft in cranial window, whereas VEGF superfusion (10-1000 ng/ml) failed to increase permeability in a variety of hyperpermeable tumors grown in dorsal skin chamber. Interestingly, low-dose VEGF treatment (10 ng/ml) doubled the maximum pore size (from 400 to 800 nm) and significantly increased the frequency of large (400 nm) pores in human colon carcinoma xenografts. PIGF-1, PIGF-2, or bFGF did not show any significant effect on permeability or pore size in tumors. These findings suggest that exogenous VEGF may be useful for augmenting the transvascular delivery of larger antineoplastic agents such as gene targeting vectors and encapsulated drug carriers (typical range, 100-300 nm) into tumors. Montasser, I., S. Briancon, et al. (2000). "[Methods of obtaining and formation mechanisms of polymer nanoparticles]." Journal de Pharmacie de Belgique 55(6): 155-67. Severals processes exist today for manufacturing colloidal systems of nanospheres or nanocapsules. These nanoparticles have applications in various industrial fields such as cosmetic, pharmacy, food industry, agrochemicals.... The formation of nanoparticles allows the protection of an active molecule by a polymeric coating and the release of this product following a perfectly defined profile, which depends on the nature of the polymer, the type of particle and the field of use. The purpose of this article is to expose the different methods of preparation of nanoparticular systems. These methods are classified in two mains categories. The first gathers most of the methods which are based on polymerization reactions, the second presents the use of preformed polymers (of natural or synthetic origin). A thorough study is devoted to the mechanisms of formation, in order to find the advantages and the disadvantages of each technique to support the development of manufactoring processes. Monza da Silveira, A., G. Ponchel, et al. (1998). "Combined poly(isobutylcyanoacrylate) and cyclodextrins nanoparticles for enhancing the encapsulation of lipophilic drugs." Pharm Res 15(7): 1051-5. PURPOSE: The aim of this study was to prepare and characterize nanoparticulate systems constituted of poly(isobutylcyanoacrylate) and cyclodextrins and intended for increasing the loading of the particles with lipophilic substances. Progesterone was used as a model substance. METHODS: Nanoparticles were prepared by polymerization of isobutylcyanoacrylate in presence of cyclodextrins or progesterone/ hydroxypropyl-betacyclodextrin complex. Particle size, zeta potential, cyclodextrin and progesterone loading of the particles were determined. RESULTS: Nanoparticles could be easily prepared in presence of cyclodextrins. An increase in hydroxypropyl-beta-cyclodextrin concentration resulted in small nanoparticles (less than 50 nm). It was found that large amounts of cyclodextrins remained associated to the particles, resulting in a 50 fold increase in progesterone loading compared to nanoparticles prepared in absence of cyclodextrins. CONCLUSIONS: The poly(isobutylcyanoacrylate)cyclodextrin nanoparticles were characterized by the presence of many lipophilic sites belonging to the cyclodextrins which were firmly anchored to the structure of the particles. Therefore, this new type of nanoparticles offers probably an opportunity for increasing the loading of nanoparticles with various lipophilic drugs. Moon, H. T., Y. K. Lee, et al. (2001). "A novel formulation for controlled release of heparin-DOCA conjugate dispersed as nanoparticles in polyurethane film." Biomaterials 22(3): 281-9. Heparin is a potent anticoagulant agent that interacts strongly with antithrombin III to prevent the formation of fibrin clot. In this study, we propose a new method for preparing a heparin-releasing system using a simple solvent casting. The heparin-DOCA conjugate, having an amphiphilic property, was homogeneously mixed with polyurethane in the co-solvent of dioxane, propanol and water. After casting the film, heparin-DOCA was homogeneously dispersed as nanoparticles in a polyurethane film. As the loading amount of heparin-DOCA in the film was increased, nanoparticle size, water uptake, and release rate were increased. Moreover, the percentage of released amount of heparin-DOCA was increased with the increase in the loading amount of heparin-DOCA. This was because the size of heparin-DOCA particles increases with the increase in the loading amount of heparin-DOCA, thereby decreasing the distance between particles and the total diffusion length to the surface. The release rate of heparin-DOCA can be controlled by the amount of the drug being loaded and the film thickness. When the heparin-DOCA loaded on the polyurethane films was above 7.5%, the released heparinDOCA prevented the formation of fibrin clot and the platelet adhesion on the film surface. Moore, A., E. Marecos, et al. (2000). "Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model." Radiology 214(2): 568-74. PURPOSE: To investigate the accumulation and cellular uptake of long-circulating dextran-coated iron oxide (LCDIO) particles in malignant neoplasms in vivo. MATERIALS AND METHODS: A gliosarcoma rodent model was established to determine the distribution of a model LCDIO preparation in tumors. LCDIO accumulation in tissue sections was evaluated with multichannel fluorescence microscopy with rhodaminated LCDIO, green fluorescent protein as a tumor marker, and Hoechst 33258 dye as an intravital endothelial stain. Uptake into tumor cells was corroborated with results of immunohistochemical and cell culture uptake experiments. The effect of intratumoral LCDIO uptake on magnetic resonance (MR) imaging signal intensity was evaluated with a 1.5-T

superconducting magnet. RESULTS: Tumoral accumulation of LCDIO was 0.11% +/- 0.06 of the injected dose per gram of tissue in brain tumors and was sufficient for detection at MR imaging. In tumor sections, LCDIO was preferentially localized in tumor cells (49.0% +/- 4.6) but was also taken up by macrophages in tumors (21.0% +/3.1) and by endothelial cells in the areas of active angiogenesis (6.5% +/- 1.4). In cell culture, LCDIO uptake was strongly correlated with growth rate of tumor cell lines. CONCLUSION: Tumoral LCDIO accumulation was not negligible and helped explain MR imaging signal intensity changes observed in clinical trials. Microscopically, LCDIO accumulated predominantly in tumor cells and tumor-associated macrophages. Uptake into tumor cells appeared to be directly proportional to cellular proliferation rates. Morel, S., E. Terreno, et al. (1998). "NMR relaxometric investigations of solid lipid nanoparticles (SLN) containing gadolinium(III) complexes." European Journal of Pharmaceutics and Biopharmaceutics 45(2): 157-63. This work deals with the preparation and relaxometric investigations of solid lipid nanoparticles (SLN) containing [Gd-DTPA(H2O)]2- and [Gd-DOTA(H2O)]-. These paramagnetic chelates are commonly used as contrast agents (CA) for magnetic resonance imaging (MRI) owing to their ability to strongly increase the tissue water proton relaxation rate. The amount of gadolinium(III) (Gd(III)) complex included in the SLN has been evaluated and, on this basis, it has been found that the longitudinal relaxivity of these Gd(III) chelates apparently does not vary, at physiological pH, following their inclusion in SLN. We are unable to establish whether this is due to the free exchange of water from the inner compartment containing the Gd(III) chelate to the bulk water or whether the observed relaxation rate is essentially determined by a fraction of the complex which is close to the surface of the SLN in a region easily accessible to the bulk water. At acidic pH values, the relaxivity of the paramagnetic SLN containing the less thermodynamically and kinetically stable [Gd-DTPA(H2O)]2- markedly increases. This effect may be ascribed to an increased immobilization and/or to an enhanced hydration of the complex on SLN. Moselhy, J., X. Y. Wu, et al. (2000). "In vitro studies of the interaction of poly(NIPAm/MAA) nanoparticles with proteins and cells." Journal of Biomaterials Science Polymer Edition 11(2): 123-47. The pH- and temperature-responsive poly(N-isopropylacrylamide-co-methacrylic acid) (PNIPAm/MAA) nanoparticles are of potential application in targeted drug delivery. Their responsive properties in the presence of human serum albumin were investigated using dynamic light scattering (DLS), protein assay, and electron spin resonance (ESR) spectroscopy. Their interaction with human monocytes and polymorphonuclear leukocytes (PMNLs) was studied using scanning electron microscopy (SEM) and oxygen consumption method. The nanoparticles exhibited a volume phase transition at 35-40 degrees C in Hanks balanced salt solution (HBSS) and in phosphate buffer solution (PBS) of pH 7.4. The diameter of the nanoparticles decreased slightly in the presence of HSA at 25 degrees C at neutral pH, whereas an increase in the diameter in pH 6 PBS at 40 degrees C was revealed. The amount of albumin adsorbed onto the nanoparticles decreased with increasing temperature. The ESR spectra of spin labeled HSA indicated a more restricted environment in the nanoparticles at elevated temperatures. The stimulation of PMNL oxygen consumption by PNIPAm based nanoparticles, an indication of phagocytosis of the particles, was not observed regardless whether the nanoparticles were incubated in plasma or serum. In contrast, the more hydrophobic polystyrene (PSt) particles induced a significant increase in the rate of oxygen consumption after the incubation. PNIPAm/MAA-grafted-PSt particles behaved similarly to the PNIPAm/MAA nanoparticles, suggesting that surface properties dictate the recognition of colloids by PMNLs. Muldoon, L. L., G. Nilaver, et al. (1995). "Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain." American Journal of Pathology 147(6): 1840-51. Delivery of adenovirus, herpes simplex virus (HSV), and paramagnetic monocrystalline iron oxide nanoparticles (MION) to rat brain (n = 64) was assessed after intracerebral inoculation or osmotic disruption of the blood-brain barrier (BBB). After intracerebral inoculation, the area of distribution was 7.93 +/- 0.43 mm2 (n = 9) for MION and 9.17 +/- 1.27 mm2 (n = 9) for replication-defective adenovirus. The replication-compromised HSV RH105 spread to 14.00 +/- 0.87 mm2 (n = 8), but also had a large necrotic center (3.54 +/- 0.47 mm2). No infection was detected when virus was administered intra-arterially without hyperosmotic mannitol. After osmotic BBB disruption, delivery of the viruses and MIONs was detected throughout the disrupted cerebral cortex. Positive staining was found in 4 to 845 cells/100 microns thick coronal brain section (n = 7) after adenovirus administration, and in 13 to 197 cells/section (n = 8) after HSV administration. Cells of glial morphology were more frequently stained after administration of adenovirus, whereas neuronal cells were preferentially stained after delivery of both HSV vectors and MION. In a preliminary test of vector delivery in the feline, MION was detected throughout the white matter tracts after inoculation into normal cat brain. Thus MION may be a tool for use in vivo, to monitor the delivery of virus to the central nervous system. Additionally, BBB disruption may be an effective method to globally deliver recombinant viruses to the CNS. Mulholland, G. W. and B. J. Bauer (2000). "Nanometer calibration particles: What is available and what is needed?" Journal of Nanoparticle Research 2: 5-15.

Mullaney, M., T. Groth, et al. (1999). "Investigation of plasma protein adsorption on functionalized nanoparticles for application in apheresis." Artificial Organs 23(1): 87-97. Particles with specific ligands for the adsorption of plasma proteins can be used in therapeutic or preparative apheresis. The development of these particles may benefit from an improved knowledge of the relationship between protein adsorption and the structure of ligands. Nanoparticles were functionalized with aliphatic diamines of increasing chain length; with the amino acids lysine, tryptophan, histidine, and their corresponding amines; and with tryptophan and histidine spaced with diamines of different length. Suitable protocols were developed for the washing of particles and the subsequent desorption of proteins adsorbed from human plasma. The adsorption pattern, as well as the quantification of the overall adsorption of proteins on these modified particles, was investigated with gel electrophoresis. This was followed by immunoblotting which yielded specific assessments of bound human serum albumin and fibrinogen. The comparison of protein adsorption with surface charge density and measured hydrophobicities yielded no simple correlations although in general more hydrophobic ligands bound higher quantities of protein. The detection of human serum albumin yielded similar results because it was observed for overall protein adsorption while the adsorption of fibrinogen expressed a different pattern. In this case, particular nanoparticles functionalized with aliphatic diamines bound significantly higher amounts of fibrinogen than all other ligands. Muller, R. H., C. Lherm, et al. (1990). "In vitro model for the degradation of alkylcyanoacrylate nanoparticles." Biomaterials 11(8): 590-5. A photometric assay was developed to study the surface erosion of polymeric nanoparticles. The hydrolytic degradation of polyalkylcyanoacrylate particles was studied in different environments (NaOH, buffer, cell culture medium and serum). The influence of particle modification on the degradation rate was assessed. Particularly, the effect of polymer coating for particle targeting and fluorescence labelling was investigated. From the absorption data, a t50% and t100% can be calculated for fast degrading particles and obtained by an extrapolation in case of a slow degradation process. The degradation rate was found to decrease with increasing alkyl chain length from methyl-, ethyl-, isobutyl- to isohexylcyanoacrylate particles. Polymer coating and fluorescent labelling had little effect on the rate of degradation. Muller, R. H., S. Maassen, et al. (1996). "Phagocytic uptake and cytotoxicity of solid lipid nanoparticles (SLN) sterically stabilized with poloxamine 908 and poloxamer 407." Journal of Drug Targeting 4(3): 161-70. Solid lipid nanoparticles (SLN) as alternative intravenous colloidal drug carriers were produced by high pressure homogenisation of melted lipids (glycerolbehenate, cetylpalmitate). Their surface was modified by using hydrophilic poloxamine 908 and poloxamer 407 blockcopolymers in order to reduce the phagocytic uptake by the reticuloendothelial system (RES) after i. v. injection. The phagocytosis reducing effect of the polymers was investigated in vitro in cultures of human granulocytes, uptake was quantified by chemiluminescence. Modification of the SLN with poloxamine 908 and poloxamer 407 reduced the phagocytic uptake to appr. 8-15% compared to the phagocytosis of hydrophobic polystyrene particles. The modified SLN proved more efficient in avoiding phagocytic uptake than polystyrene particles surface-modified with these blockcopolymers (48% and 38%, respectively). Viability determinations revealed the SLN to be 10 fold less cytotoxic than polylactide nanoparticles and 100 fold less than butylcyanoacrylate particles. Muller, B. G., H. Leuenberger, et al. (1996). "Albumin nanospheres as carriers for passive drug targeting: an optimized manufacturing technique." Pharm Res 13(1): 32-7. PURPOSE. The purpose of this study was to develop a new method to produce albumin particles in the sub-200nanometer range with a narrow size distribution and in a controlled and reproducible manner. METHODS. A new emulsion crosslinking method was developed using ultrasound and static mixing as homogenization steps and a central composite design was used to evaluate the influence of different process parameters on particle size, polydispersity and yield. RESULTS. Response surface analysis allowed the location of the most important factors. Of all the factors investigated, only the albumin concentration and the aqueous phase volume showed a significant influence on response parameters. Albumin nanospheres with sizes below 200 nm in diameter and very narrow size distributions were obtained in high yields ( &gt; 80%). CONCLUSIONS. This study describes a new preparation method for albumin nanoparticles which are suitable for future drug targeting studies. Muller, R. H., D. Ruhl, et al. (1997). "Cytotoxicity of solid lipid nanoparticles as a function of the lipid matrix and the surfactant." Pharm Res 14(4): 458-62. PURPOSE: Assessment of the in vitro cytotoxicity of solid lipid nanoparticles (SLNs) as a function of lipid matrix (Dynasan 114, Compritol ATO 888), and stabilizing surfactant (poloxamers, Tween 80, soya lecithin, and sodium dodecyl sulphate). Comparison with other colloidal carriers should determine their potential use in the clinic. METHODS: SLNs were produced by high pressure homogenisation. Cytotoxicity was assessed by measuring the viability of HL60 cells and human granulocytes after incubation with SLNs. Particle internalisation was quantified by chemiluminescence measurements. RESULTS: The nature of the lipid had no effect on viability; distinct differences were found for the surfactants. Binding to the SLN surface reduced markedly the cytotoxic effect of

the surfactants, e.g., up to a factor of 65 for poloxamer 184. The permanent HL60 cell line-differentiated from cells with granulocyte characteristics by retinoic acid treatment-yielded results identical to freshly isolated human granulocytes. In general, the SLNs showed a lower cytotoxicity compared to polyalkylcyanoacrylate and polylactic/glycolic acid (PLA/ GA) nanoparticles. CONCLUSIONS: Because the results are identical when using human granulocytes, differentiated HL60 cells can be used as an easily accessible in vitro test system for i.v. injectable SLN formulations. The SLNs appear suitable as a drug carrier system for potential intravenous use due to their very low cytotoxicity in vitro. Muller, B. and J. Kreuter (1999). "Enhanced transport of nanoparticle associated drugs through natural and artificial membranes--a general phenomenon?" International Journal of Pharmacy 178(1): 23-32. The transport of nanoparticle associated drugs, [75Se]norcholestenol, captopril, methylene blue, hydrocortisone, doxorubicin, and dalargin was determined by permeability measurements in two chamber side by side diffusion cells using cellulose acetate, silicone rubber, pig small intestine, or hairless mice skin as membranes. Solutions of free drugs served as controls. The permeabilities depended on the physico chemical properties of the drugs which governed both, drug interaction with the nanoparticles as well as with the membranes. Consequently, the influence of dilution of the nanoparticle or free drug preparations on permeabilities was complex. With the exception of [75Se]norcholestenol the permeabilities were higher with free drugs than after binding to nanoparticles. The permeabilities of the membranes decreased in the order cellulose acetate, pig small intestine, silicone rubber, and hairless mouse skin. Muller, M., H. Grahl, et al. (2000). "Elastic behavior of nanoparticle chain aggregates: a hypothesis for polymer-filler behavior." Journal of Polymer Science Part B Polymer Physics 38(20): 2658-65. Electron microscopy studies in our laboratory have shown that nanoparticle chain aggregates (NCAs) of inorganic oxides have elastic properties. Measurements were made with titania, alumina, and iron oxide NCAs generated by laser ablation. Primary particles were 5-10 nm in diameter, and the mobility diameters of the NCAs studied were about 0.5 mu m NCA stretching appeared to begin with the rotation and/or sliding of adjacent nanocrystals. This led to a small change in the NCA. Length but allowed for chain straightening. Most of the NCA lengthening resulted from the separation of kinked chain segments held together by weak, probably van der Waals (vdw), forces. NCA strains up to 90% were observed. Calculated values for NCA deformation energies per unit volume were compared with those for conventional polymers; under certain conditions, the two deformation energies were of the same order of magnitude. These results may help explain the remarkable effects that nanoparticle reinforcing fillers such as carbon black and silica have on commercial rubber. It may be possible to improve the properties of composites of molecular polymers and NCAs through the use of NCAs with prescribed primary particle sizes, vdw-bond numbers, chain lengths, and morphological properties. Synthesizing such NCAs will require the use of modern concepts of aerosol aggregate formation. (19 References). Muller, R. H., K. Mader, et al. (2000). "Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art." European Journal of Pharmaceutics and Biopharmaceutics 50(1): 161-77. Solid lipid nanoparticles (SLN) introduced in 1991 represent an alternative carrier system to traditional colloidal carriers, such as emulsions, liposomes and polymeric micro- and nanoparticles. SLN combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews the present state of the art regarding production techniques for SLN, drug incorporation, loading capacity and drug release, especially focusing on drug release mechanisms. Relevant issues for the introduction of SLN to the pharmaceutical market, such as status of excipients, toxicity/tolerability aspects and sterilization and long-term stability including industrial large scale production are also discussed. The potential of SLN to be exploited for the different administration routes is highlighted. References of the most relevant literature published by various research groups around the world are provided. Muller, R. H., C. Jacobs, et al. (2001). "Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future." Advances in Drug Delivery Review 47(1): 3-19. An increasing number of newly developed drugs are poorly soluble; in many cases drugs are poorly soluble in both aqueous and organic media excluding the traditional approaches of overcoming such solubility factors and resulting in bioavailability problems. An alternative and promising approach is the production of drug nanoparticles (i.e. nanosuspensions) to overcome these problems. The major advantages of this technology are its general applicability to most drugs and its simplicity. In this article, the production of nanoparticles on a laboratory scale is presented, special features such as increased saturation solubility and dissolution velocity are discussed, and special applications are highlighted, for example, mucoadhesive nanosuspensions for oral delivery and surfacemodified drug nanoparticles for site-specific delivery to the brain. The possibilities of large scale production -- the prerequisite for the introduction of a delivery system to the market -- are also discussed. Murakami, H., M. Kobayashi, et al. (1999). "Preparation of poly(DL-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method." International Journal of Pharmacy 187(2): 143-52.

PURPOSE: The objectives of this study were to establish a new preparation method for poly(DL-lactide-coglycolide) (PLGA) nanoparticles by modifying the spontaneous emulsification solvent diffusion (SESD) method and to elucidate the mechanism of nanoparticle formation on the basis of the phase separation principle of PLGA and poly(vinyl alcohol) (PVA) in the preparation system. METHODS: PLGA nanoparticles were prepared by the modified-SESD method using various solvent systems consisting of two water-miscible organic solvents, in which one solvent has more affinity to PLGA than to PVA and the other has more affinity to PVA than to PLGA. The yield, particle size, size distribution and PVA content of the PLGA nanoparticles were evaluated, and the phase separation behaviors of the polymers were elucidated. RESULTS: The modified-SESD method provided a good yield of PLGA nanoparticles over a wide range of composition ratios in the binary mixture of organic solvents. Several process parameters, including the fed amount of PLGA, PLGA concentration and PVA concentration were examined to achieve the optimum preparation conditions. The discrete powder of PLGA nanoparticles was obtained by freeze-drying. No change in the PVA content of PLGA nanoparticles was observed even after several times of washing treatment by ultrafiltration, suggesting a strong surface adsorption. It was found that the appropriate selections of binary solvent mixtures and polymeric concentrations in both organic and aqueous phases could provide excellent yield and favorable physical properties of PLGA nanoparticles. CONCLUSION: The proposed modified-SESD method can be used to provide PLGA nanoparticles of satisfactory quality at an acceptable yield for industrial purposes. Murakami, H., M. Kobayashi, et al. (2000). "Utilization of poly(DL-lactide-co-glycolide) nanoparticles for preparation of mini-depot tablets by direct compression." Journal of Controlled Release 67(1): 29-36. PURPOSE: The objectives of this study were to prepare the long-acting matrix tablets by direct compression of the mixture of drug and poly(DL-lactide-co-glycolide) (PLGA) nanoparticles and to clarify the effects of such factors as polymer species, mixing ratio of nanoparticles with different molecular weights, and the tablet weight on the drug release and to discuss the mechanism of drug release from matrix tablets. In addition, mini-matrix tablets were prepared to investigate the possibility of application as an implantable dosage form. METHODS: PLGA nanoparticles were prepared by the modified spontaneous emulsion solvent diffusion method. The matrix tablets were prepared by direct compression of mixtures of drug and nanoparticles, and then the release properties, swelling properties and changes in molecular weight of PLGA during the release test were evaluated. RESULTS: The drug showed the biphasic release patterns from all matrix tablets; i.e. a portion of the drug was released rapidly (the initial release phase), the release stopped for a long period (the lag time), and then the residual drug was released (the second release phase). Matrix tablets with various biphasic release patterns could be prepared by altering the molecular weight or copolymer ratio of PLGA. The addition of nanoparticles of low molecular weight PLGA to those of high molecular weight reduced the release rate at the initial release phase, but that at the second release phase was almost entirely unaffected by mixing ratio. Also, the release patterns could be changed by altering the tablet weight and size, but the amounts released per unit of surface area were the same. Hydration analysis suggested that the initial release rates were correlated well with the swelling properties of tablets. CONCLUSION: This system had advantages in terms of simplicity in design and predictability of drug release rate and may be useful as an implantable dosage form. Mustafa, E. A. A. (2000). "Ca-PSZ prepared via polymeric sol-gel route." Ceramics International 26(2): 215-20. Microstructural control of 10 mol% Ca-PSZ through doping and heat treatment was studied after firing at 1300, 1400 and 1500 degrees C/2 h using SEM. Tetragonal precipitate was developed under a condition of metastability and transformed partially to monoclinic in the presence of stresses developed through nucleation and growth when the particle size became above the critical grain size. The volume of critically metastable tprecipitate was maximized to more than 90% through controlling transformation between 1300 and 1400 degrees C/2 h. The average grain size of the major phase is related to the precipitation conditions, where t-ZrO/sub 2/ precipitate prevents abnormal grain growth and swallows pores. Combined with submicron size microstructure, closed packing without any signs of pores exists without applied stress at 1400 degrees C/2 h. Controlled chemical preparation via polymerization reaction of urea with formaldehyde forming polyamide resin was utilized for preparation of very fine nanomaterials with narrow particle size distribution. Metal cations are homogeneously distributed through the structure of the resin. The conditions achieved lead to the precipitation of tetragonal zirconia without grain growth or crack formation. (17 References). Na, K., K. H. Park, et al. (2000). "Self-assembled hydrogel nanoparticles from curdlan derivatives: characterization, anticancer drug release and interaction with a hepatoma cell line (HepG2)." Journal of Controlled Release 69(2): 225-36. Self-assembled hydrogel nanoparticles were synthesized from carboxymethylated (CM)-curdlan, substituted with a sulfonylurea (SU) as a hydrophobic moiety for self-assembly. The degree of SU substitution was 2.4, 5.6, or 7.2 SU groups per hundred anhydroglucose units of curdlan. The physicochemical properties of the self-assembled hydrogel nanoparticles (DS 2.4, DS 5.6, and DS 7.2) in aqueous media were characterized by dynamic light scattering, transmission electron microscopy, and fluorescence spectroscopy. The mean diameter of all samples was less than 300 nm with a unimodal size distribution. The critical aggregation concentrations (CAC) of selfassembled hydrogel nanoparticles in distilled water were 4.2 x 10(-2), 3.1 x 10(-2) and 1.9 x 10(-2) mg/ml for DS

2.4, 5.6 and 7.2, respectively. The loading and release of all-trans retinoic acid (ATRA) was studied. The ATRA loading efficiencies and loading contents of CM-curdlan/SU nanoparticles increased as the degree of SU substitution increased. The ATRA release rate was controlled by the degree of substitution and drug-loading. For specific interaction with a hepatic carcinoma cell line (HepG2), CM-curdlan was additionally conjugated with lactobionic acid (LBA; galactose moiety) (5.5 LBA molecules per hundred glucose units). HepG2 was strongly luminated by ligand-receptor interactions with fluorescence-labeled LBA/CM-curdlan/SU hydrogel nanoparticles. The luminescence was not observed for other control cases. It is concluded that LBA/CM-curdlan/SU hydrogel nanoparticles are a useful drug carrier for the treatment of liver cancer, because of the potential immunological enhancement activities of CM-curdlan in the body, the ligand-receptor mediated specific interactions, and the controlled release of the anti-cancer drug. Nah, J. W., Y. W. Paek, et al. (1998). "Clonazepam release from poly(DL-lactide-co-glycolide) nanoparticles prepared by dialysis method." Archives of Pharmacal Research 21(4): 418-22. Aim of this work is to prepare poly(DL-lactide-co-glycolide) (PLGA) nanoparticles by dialysis method without surfactant and to investigate drug loading capacity and drug release. The size of PLGA nanoparticles was 269.9 +/- 118.7 nm in intensity average and the morphology of PLGA nanoparticles was spherical shape from the observation of SEM and TEM. In the effect of drug loading contents on the particle size distribution, PLGA nanoparticles were monomodal pattern with narrow size distribution in the empty and lower drug loading nanoparticles whereas bi- or trimodal pattern was showed in the higher drug loading ones. Release of clonazepam from PLGA nanoparticles with higher drug loading contents was slower than that with lower loading contents. Nakada, Y., E. Fattal, et al. (1996). "Pharmacokinetics and biodistribution of oligonucleotide adsorbed onto poly(isobutylcyanoacrylate) nanoparticles after intravenous administration in mice." Pharmacetical Research 13(1): 38-43. PURPOSE. The goal of this study was to evaluate the ability of nanoparticles to be used as a targeted delivery system for oligonucleotides. METHODS. Pharmacokinetic and tissue distribution were carried out in mice by measuring radioactivity associated to the model oligothymidylate 33P-pdT16 loaded to poly(isobutylcyanoacryate) (PIBCA) nanoparticles. In addition, we have used a TLC linear analyzer to measure quantitatively on a polyacrylamide gel electrophoresis, the amount of non degraded pdT16. RESULTS. Organ distribution study has shown that nanoparticles deliver 33P-pdT16 specifically to the liver reducing its distribution in the kidney and in the bone marrow. Nanoparticles could partially protect pdT16 against degradation in the plasma and in the liver 5 min after administration, whereas free oligonucleotide was totally degraded at the same time. CONCLUSIONS. Nanoparticles protect oligonucleotides in vivo against degradation and deliver them to the liver. Nakyama, T., T. A. Yamamoto, et al. (2000). "Structure and magnetic properties of iron oxide dispersed silver based nanocluster composite." Journal of Materials Science 35(15): 3857-61. Magnetic nanocomposites composed of iron oxide and silver were fabricated by an inert gas condensation (IGC) method combined with co-evaporation, in situ oxidation, and in situ compaction techniques. The particle sizes of composite powder were controlled by varying helium gas pressure between 1 and 10 Torr, with the smallest one being about 10 nm at 1.0 Torr. The nanostructure of the composites was characterized by TEM. The magnetization behaviors were analyzed taking into account both the paramagnetic (PM) and ferromagnetic (FM) contributions to investigate the correlation between the nanostructure and the magnetic properties. It was found that some composites exhibit the superparamagnetism evidencing magnetically isolated grains as a single domain. TEM observation assisted with EDX revealed that iron nanocluster of a few nanometers size were surrounded by silver grains. Variation of the magnetic property of the nanocluster composites was also related to nanocluster size and heat treatment in an oxygen atmosphere. (7 References). Nayral, C., E. Viala, et al. (2000). "Synthesis of tin and tin oxide nanoparticles of low size dispersity for application in gas sensing." Chemistry 6(22): 4082-90. Nanocomposite core-shell particles that consist of a Sn0 core surrounded by a thin layer of tin oxides have been prepared by thermolysis of [(Sn(NMe2)2)2] in anisole that contains small, controlled amounts of water. The particles were characterized by means of electronic microscopies (TEM, HRTEM, SEM), X-ray diffraction (XRD) studies, photoelectron spectroscopy (XPS), and Mossbauer spectroscopy. The TEM micrographs show spherical nanoparticles, the size and size distribution of which depends on the initial experimental conditions of temperature, time, water concentration, and tin precursor concentration. Nanoparticles of 19 nm median size and displaying a narrow size distribution have been obtained with excellent yield in the optimized conditions. HRTEM, XPS, XRD and Mossbauer studies indicate the composite nature of the particles that consist of a well-crystallized tin beta core of approximately equals 11 nm covered with a layer of approximately equals 4 nm of amorphous tin dioxide and which also contain quadratic tin monoxide crystallites. The thermal oxidation of this nanocomposite yields well-crystallized nanoparticles of SnO2* without coalescence or size change. XRD patterns show that the powder consists of a mixture of two phases: the tetragonal cassiterite phase, which is the most abundant, and an orthorhombic phase. In agreement with the small SnO2 particle size, the relative intensity of the adsorbed

dioxygen peak observed on the XPS spectrum is remarkable, when compared with that observed in the case of larger SnO2 particles. This is consistent with electrical conductivity measurements, which demonstrate that this material is highly sensitive to the presence of a reducing gas such as carbon monoxide. Nefzger, M., J. Kreuter, et al. (1984). "Distribution and elimination of polymethyl methacrylate nanoparticles after peroral administration to rats." Journal of Pharmaceutical Sciences 73(9): 1309-11. Polymethyl [1-14C]methacrylate nanoparticles were administered orally to bile cannulated rats. Ten to fifteen percent of the administered radioactivity was absorbed and found in the bile and urine. Within 48 h, 94-97% of the absorbed radioactivity had been eliminated from the body. After 8 d, the highest residual radioactivity was found in the bone marrow, fatty renal tissue, stomach, liver, and lymph nodes. Neimark, A. V., P. I. Ravikovitch, et al. (2000). "Adsorption hysteresis in nanopores." Physical Review E. Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics 62(2 Pt A): R1493-6. Capillary condensation hysteresis in nanopores is studied by Monte Carlo simulations and the nonlocal density functional theory. Comparing the theoretical results with the experimental data on low temperature sorption of nitrogen and argon in cylindrical channels of mesoporous siliceous molecular sieves of MCM-41 type, we have revealed four qualitatively different sorption regimes depending on the temperature and pore size. As the pore size increases at a given temperature, or as the temperature decreases at a given pore size, the following regimes are consequently observed: volume filling without phase separation, reversible stepwise capillary condensation, irreversible capillary condensation with developing hysteresis, and capillary condensation with developed hysteresis. We show that, in the regime of developed hysteresis (pores wider than 5 nm in the case of nitrogen sorption at 77 K), condensation occurs spontaneously at the vaporlike spinodal while desorption takes place at the equilibrium. A quantitative agreement is found between the modeling results and the experimental hysteresis loops formed by the adsorption-desorption isotherms. The results obtained provide a better understanding of the general behavior of confined fluids and the specifics of sorption and phase transitions in nanomaterials. Nemeth, J. and I. Dekany (2000). "The effect of nanoparticle growth on rheological properties of silica and silicate dispersions." Colloid and Polymer Science 278(3): 211-19. CdS and ZnS nanoparticles were prepared in the solid-liquid interfacial adsorption layer as a nanophase reactor. The substrates were hydrophilic and hydrophobic aerosils and hydrophilic layer silicates dispersed in ethanolcyclohexane mixtures. The growth of particles at various surface concentration of precursor ions was monitored by absorption spectroscopy, band-gap-energy measurements and particle diameter measurements. Also, the rheological properties of nanoparticle-support composites in organic and aqueous dispersions were measured. The energy of separation between the nanoparticles depended on the particle diameter. The intercalation of nanoparticles in the layered silicates yielded a nano-structured two-phase system. The presence of semiconductive subcolloids was proven by transmission electron microscopy measurements, which offer an excellent possibility for the determination of the particle size distribution. (32 References). Nery, G. A., A. Mahfoud, et al. (2000). "Study of the luminescence of Eu-doped nanocrystalline Si/SiO2 systems prepared by RF co-sputtering." Nanophase and Nanocomposite Materials III. Symposium 581: 647-52. We prepared Eu-doped films of Si nanoparticles embedded in SiO/sub 2/ using pellets of Eu/sub 2/O/sub 3/ by sputtering. We studied their photoemission, transmission and fluorescence to obtain data about their composition and particle size and the Eu interaction characteristics. We were able to incorporate Eu(III) into the Si nanoparticle/SiO/sub 2/ host. We also found we obtained Eu(II) in the process. We found a lowering of photoluminescence intensity with lowering of temperature. An as yet unanswered question is the reason for the intense whitish luminescence found in some regions of the samples. Some involvement with Eu(II) is suspected. Eu(III) related peaks were only observed where the size distribution peak of the nanoparticles was lower than 1.3 nm. Whitish luminescence was related to peak sizes ranging from 1.1 nm to 1.4 nm. Annealing the samples had clear effects upon their photoluminescence, but did not necessarily involve changes in particle sizes, nor were these size changes necessary to increase luminescence. The Eu doping has a tendency to halt the annealing effects on size and, when changes did occur, the particles generally became smaller. (13 References). Nesheva, D. and H. Hofmeister (2000). "Formation of CdSe nanoclusters in SiOx thin films." Solid State Communications 114(10): 511-14. CdSe nanoclusters embedded in silicon oxide layers are produced by sequential physical vapor deposition of SiO/sub x/ (x approximately= 1.5) and CdSe on crystalline silicon substrates at room temperature. High-resolution electron microscopy is used to prove the formation of CdSe nanoclusters as well as to study their shape, size and structure. Cross-sectional electron micrographs of the as-deposited samples reveal clusters with nearly spherical shapes, which are not arranged in a plane. The spatial distribution of the CdSe clusters follows the surface morphology of the SiO/sub x/ films. The average size of the nanoclusters is about two times greater than the nominal thickness of the CdSe layers deposited. Upon annealing the samples at 670 K for 80 min, a slight size

increase is observed accompanied by some improvement in crystallinity of the CdSe nanoclusters. The sigma /a ratio (a: average size of nanocrystals, sigma : half-width at half-maximum of size distribution) found for 1-nm CdSe deposited on 20-nm SiO/sub x/ is 0.13-0.14, while for 2-nm CdSe deposited on 40-nm SiO/sub x/ it is 0.19. (15 References). Ngo, A. T. and M. P. Pileni (2000). "Nanoparticles of cobalt ferrite: influence of the applied field on the organization of the nanocrystals on a substrate and on their magnetic properties." Advanced Materials 12(4): 276-9. Ferrite nanocrystals have been synthesized by use of functionalized surfactants to give nanoparticles doped with 3.5% in mass of cobalt ions. These nanoparticles can be aligned on a substrate on a very large scale when the particles are deposited in the presence of a magnetic field. In the absence of an applied field, the particles selfassemble into large spheres. (36 References). Nichols, W. T., G. Malyavanatham, et al. (2000). "Synthesis of nanostructured WC films by supersonic impaction of nanoparticle aerosols." Nanophase and Nanocomposite Materials III. Symposium 581: 193-8. Tungsten carbide (WC) coatings were prepared using supersonic impaction of nanoparticles produced by pulsed laser ablation of microparticle aerosols. The influence of experimental parameters such as, carrier gas type and impaction velocity on the structure, composition and physical properties of the resultant particles and films were studied. It was found that stoichiometric, crystalline films could be grown. These films pass both the adhesive lift off and scratch tests. TEM investigations indicate that the laser ablation forms individual particles with mean size of 7+or-3 nm. At the highest aerosol pressures small aggregates were also observed, and adjustment of the gas pressure in the laser interaction cell was found to control the degree of aggregation. Upon impaction, the separate particles form dense, self sintering nanocrystalline films, with helium forming the most dense as determined from SEM images. (13 References). Nichols, W. T., G. Malyavanatham, et al. (2000). "Hetero-colloidal metal particle multilayer films grown using electrostatic interactions at the air-water interface." Journal of Nanoparticle Research 2(2): 183-90. The formation of nanoparticle multilayer films by electrostatic immobilization of surface-modified colloidal particles at the air-water interface has been recently demonstrated by us. In this paper, we extend our study to show that multilayer assemblies consisting of metal particles of different chemical nature (hetero-colloidal particle superlattices) and size can be deposited by the versatile Langmuir-Blodgett technique. Multilayer films consisting of a different number of bilayers of gold and silver colloidal particles have been deposited and characterized using quartz crystal microgravimetry and UV-visible spectroscopy measurements. It is observed that while layer-bylayer deposition of the different colloidal particle assemblies is possible by this technique without a detectable variation in the cluster density in the different layers, a degree of post-deposition reorganization of the clusters occurs in the film. In addition to this aging behavior, the effect of different organic solvents on the reorganization process has also been studied. (35 References). Nichols, W. T., G. Malyavanatham, et al. (2000). "Gas and pressure dependence for the mean size of nanoparticles produced by laser ablation of flowing aerosols." Journal of Nanoparticle Research 2: 141-145. Nicoli, S., P. Santi, et al. (2001). "Design of triptorelin loaded nanospheres for transdermal iontophoretic administration." International Journal of Pharmacology 214(1-2): 31-5. Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for the treatment of sex-hormones dependents diseases. The aim of this work was to prepare triptorelin-loaded nanospheres useful for transdermal iontophoretic administration. Nanospheres were prepared with the double emulsion/solvent evaporation technique. The effect of three parameters on the encapsulation efficiency has been determined: the role of the pH of the internal and external aqueous phases, the nature of the organic solvent and the effect of three different poly(lactide-co-glycolide) (PLGA) co-polymers. Particle size, zeta potential and release kinetics were also determined. The encapsulation efficiency varied from 4 to 83% reaching the maximum value when both the internal and the external water phases were brought to pH 7 (isoelectric point of the peptide), methylene chloride was used as solvent of the copolymers and PLGA rich in free carboxylic groups was employed. The release profiles obtained with this co-polymer were characterized by the absence of burst effect. This behavior as well as the high encapsulation efficiency was explained by an ionic interaction occurring between the peptide and the co-polymer. This supports the already expressed theory that the release of peptides and proteins from PLGA nanospheres is also governed by the affinity of the encapsulated molecule versus the polymer. The obtained nanoparticles, regarding their size, amount encapsulated and zeta potential, were shown to be suitable for transdermal iontophoretic administration. Nie, S. and S. R. Emory (1997). "Probing single molecules and single nanoparticles by surface-enhanced Raman scattering." Science 275(5303): 1102-6. Optical detection and spectroscopy of single molecules and single nanoparticles have been achieved at room temperature with the use of surface-enhanced Raman scattering. Individual silver colloidal nanoparticles were

screened from a large heterogeneous population for special size-dependent properties and were then used to amplify the spectroscopic signatures of adsorbed molecules. For single rhodamine 6G molecules adsorbed on the selected nanoparticles, the intrinsic Raman enhancement factors were on the order of 10(14) to 10(15), much larger than the ensemble-averaged values derived from conventional measurements. This enormous enhancement leads to vibrational Raman signals that are more intense and more stable than single-molecule fluorescence. Nilsson, K. G. (1989). "Preparation of nanoparticles conjugated with enzyme and antibody and their use in heterogeneous enzyme immunoassays." Journal of Immunological Methods 122(2): 273-7. Enzyme conjugates suitable for enzyme-linked immunosorbent assays can be conveniently prepared by binding enzyme and antibody to nanoparticles. Peroxidase and antitransferrin or anti-alpha-fetoprotein were coimmobilized to tresyl activated 40 nm silica particles and the particle conjugates used in heterogeneous enzyme immunoassays for the evaluation of transferrin and alpha-fetoprotein within the concentration range 0.25-1000 ng/ml. Niu, Y., L. K. Yeung, et al. (2001). "Size-selective hydrogenation of olefins by dendrimer-encapsulated palladium nanoparticles." Journal of the American Chemical Society 123(28): 6840-6. Nearly monodisperse (1.7 +/- 0.2 nm) palladium nanoparticles were prepared within the interiors of three different generations of hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers. These dendrimer-encapsulated catalysts (DECs) were used to hydrogenate allyl alcohol and four alpha-substituted derivatives in a 4:1 methanol/water mixture. The results indicate that steric crowding on the dendrimer periphery, which increases with dendrimer generation, can act as an adjustable-mesh nanofilter. That is, by controlling the packing density on the dendrimer periphery, it is possible to control access of substrates to the encapsulated catalytic nanoparticle. In general, higher-generation DECs or larger substrates resulted in lower turnover frequencies (although some interesting exceptions were noted). Although the main products of the olefin hydrogenation reactions were the corresponding alkanes, ketones were also obtained when monosubstituted alpha-olefins were used as substrates. NMR spectroscopy was used to measure the size selectivity of DECs for the competitive hydrogenation of allyl alcohol and 3-methyl-1-penten-3-ol. The effect on catalytic rate as a function of nanoparticle size is also briefly discussed. Nugent, J., A. L. Po, et al. (1998). "Design and delivery of non-parenteral vaccines." Journal of Clinical Pharmacy and Therapeutics 23(4): 257-85. Non-parenteral delivery of vaccines is reviewed focusing on the delivery systems that have been used for various mucosal routes of administration. Systems considered include biodegradable micro- and nanoparticles, liposomes, live bacterial and viral vectors and mucosal adjuvants. New approaches to mucosal vaccine formulation using: (i) gene fusion technology to create non-toxic derivatives of mucosal adjuvants, (ii) genetically inactivated antigens with a deletion in an essential gene, (iii) coexpression of an antigen and a specific cytokine that is important in the modulation and control of a mucosal immune response, and (iv) genetic material itself that would allow DNA or RNA uptake and its endogenous expression in the host cell are described. O'Hagan, D. T. (1996). "The intestinal uptake of particles and the implications for drug and antigen delivery." Journal of Anatomy 189(Pt 3)(6): 477-82. A number of researchers from different scientific disciplines have independently described the uptake of a variety of particulates across the gastrointestinal tract in animal models. The reports of particle uptake are briefly reviewed and the alternative mechanisms and proposed sites of uptake are discussed. Following these observations, some researchers have exploited the phenomenon of particulate uptake by using microparticles and nanoparticles as oral delivery systems for active agents, such as drugs and vaccines. The potential use of particulate carrier systems as drug and vaccine delivery systems is also briefly discussed. Odijk, T. (2000). "Remarks on the depletion interaction between nanoparticles and flexible polymers." Physica A 278: 3-4. The depletion interaction between nanoparticles and flexible polymers is discussed when the suspensions are nondilute. It is argued that a mean-field approximation is often useful. It is shown that the capacitance is a variable of interest for a nanoparticle immersed in a semidilute polymer solution. We also investigate the contraction of a polymer chain in a fixed array of nanosized obstacles. The contraction of a chain in a semidilute suspension of proteins is viewed as a problem of osmotic equilibrium. (52 References). Ogawa, K., T. Vogt, et al. (2000). "Elastic properties of nanoparticle chain aggregates of TiO2, Al2O3, and Fe2O3 generated by laser ablation." Journal of Applied Physics 87(1): 63-73. Previous studies have shown that nanoparticle chain aggregates (NCA) of titania are elastic S.K. Friedlander, H.D. Jang and K.H. Ryu, Appl. Phys. Lett. 72, 1 (1998). The NCA were a few tenths of a micron long and composed of (approximately) 7 nm primary particles. They were produced by thermal decomposition of titanium tetraisopropoxide vapor in nitrogen. The goal of this study was to see whether the elastic behavior depends on (a)

the material properties, (b) primary particle size, and (c) method of NCA formation. For this purpose, titania, alumina, and iron oxide NCA were generated by laser ablation. Rotating metal foil targets were mounted in a small cylindrical chamber and exposed to an excimer laser beam. The resulting aerosol was swept out by an oxygen stream. The generator was operated to produce NCA with similar mobility diameter and primary particle size. The NCA were deposited on the carbon or formvar films of an electron micrograph grid. Under the electron beam a hole develops in the carbon film in the neighborhood of the deposited NCA. The NCA then stretch and contract as described in our earlier study S.K. Friedlander, H.D. Jang and K.H. Ryu, Appl. Phys. Lett. 72, 1 (1998). The titania, alumina, and iron oxide NCA generated by laser ablation all showed elastic behavior for primary particles smaller than about 10 nm. However, titania NCA composed of 36 nm primary particles did not exhibit elastic behavior indicating that very small primary nanoparticles are needed for this phenomenon to occur. The small scale stretching and contraction of chain segments were studied by measuring changes in the bond angles between adjoining particles and in the lengths of the segments studied. The elastic behavior is probably associated with local folding of chain segments due to van der Waals forces. Under tension, folded chains straighten but when the tension is relaxed, folds tend to reform but not reversibly. Rotation and sliding probably occur at the boundaries between particles during stretching. We hypothesize that elastic behavior is a general property of NCA composed of transition metal oxides with primary particles smaller than 10-15 nm; the phenomenon has now been observed for NCA produced in two ways, thermal decomposition and laser ablation. These phenomena may play a role in the action of nanoparticle additives such as fumed silica and carbon black used to improve the properties of rubber. NCA elasticity may also contribute to the ductile properties of nanoparticle compacts. (24 References). Oh, I., K. Lee, et al. (1999). "Release of adriamycin from poly(gamma-benzyl-L-glutamate)/poly(ethylene oxide) nanoparticles." International Journal of Pharmacy 181(1): 107-15. Prolonged circulation of anticancer agent in blood is expected to decrease the host toxicity and enhance the anticancer activity. The purpose of this study is to develop and characterize the prolonged and sustained release formulation of anticancer agent using biodegradable poly(gamma-benzyl-L-glutamate)/poly(ethylene oxide) (PBLG/PEO) polymer nanoparticles. PBLG/PEO polymer is a hydrophilic/hydrophobic block copolymer and forms a micelle-like structure in solution. Spherical nanoparticles incorporating adriamycin were prepared by a dialysis method. The fluorescence intensity of adriamycin in the nanoparticles was increased when sodium dodecylsulfate was added. It is one of the evidences of entrapment of adriamycin in the polymer nanoparticles. Only 20% of entrapped drug was released in 24 h at 37 degrees C a and the release was dependent on the molecular weight of hydrophobic polymer. The endothermic peak of adriamycin at 197 degrees C disappeared in the nanoparticles system, suggesting the inhibition of a crystallization of adriamycin by polymer adsorption during the precipitation process. The mean residence time of adriamycin from the nanoparticles was more than threefold that from a free adriamycin. These results suggest usefulness of PBLG/PEO nanoparticles as a sustained and prolonged release carrier for adriamycin. Ohara, P. C., D. V. Leff, et al. (1995). "Crystallization of opals from polydisperse nanoparticles." Physical Review Letters 75(19): 3466-3469. Okada, T., J. Muramoto, et al. (2000). "Particle dynamics during nanoparticle synthesis by laser ablation." Review of Laser Engineering 28(6): 333-7. The particle dynamics during the synthesis process of nanoparticles by laser ablation in the background gas is described, based on the recent results of laser spectroscopic imaging studies. The nanoparticle synthesis processes in the silicon and YBa/sub 2/Cu/sub 3/O/sub x/ ablation plume have been visualized using laserinduced fluorescence (LIF), Rayleigh scattering and a newly developed decomposition-assisted LIF. Influences of the synthesis conditions on the particle dynamics are presented. (29 References). Okon, E., D. Pouliquen, et al. (1994). "Biodegradation of magnetite dextran nanoparticles in the rat. A histologic and biophysical study." Laboratory Investigation 71(6): 895-903. BACKGROUND: Superparamagnetic iron oxide particles represent a new class of contrast agents that increase the detectability of hepatic and splenic tumors by magnetic resonance imaging (MRI). Magnetite dextran nanoparticles, a preparation with a small mean particle diameter in solution and null zeta potential present high safety margin and efficacy. The purpose of this investigation was to define the main steps of the metabolism of the iron oxide crystals. EXPERIMENTAL DESIGN: Rats were intravenously administered a single small dose of 59Fe-labeled MD3 (3 mg Fe/kg), and the biodistribution of 59Fe was investigated in the different organs from 2 hours to 25 days postinjection. Magnetic susceptibility studies were conducted in parallel to light microscopy and immunohistochemistry from day 1 to day 14 after administration. RESULTS: Most of the dose accumulated in the carcass (45%), liver (7%), and spleen (7%) in the first 2 hours. In the spleen, a continuously iron uptake was observed up to 48 hours (44%), then decreased to 25 days (22%). The splenic magnetic susceptibility dropped sharply during the first days and then more slightly until day 14. In the liver and blood, the 59Fe-level decreased at 24 hours and then increased until day 25 (11% and 27%, respectively). Histochemistry features essentially

confirmed the radiotracer data and showed that iron oxide cores were accumulated into the Kupffer cells and the macrophages of the splenic marginal zone. With time, the number of the granules was decreased whereas the fine iron granules appeared in the cytoplasm. Immunopositive staining for ferritin was markedly increased in the liver hepatocytes to 3 days after injection, and in the splenic marginal zone macrophages to 14 days after injection. CONCLUSIONS: The data point to the early biodegradation of the iron oxide crystals. MD3 thus appear as an interesting biodegradable new contrast agent first devoted to magnetic resonance imaging of liver and spleen diseases that could be further extended to heart, kidneys, and other organs. Okon, E. E., D. Pulikan, et al. (2000). "[Toxicity of magnetite-dextran particles: morphological study]." Tsitologiia 42(4): 358-66. Females of OFI mice were given single repeated intravenous injections of magnetite-dextran nanoparticles (MD3), the total partical diameter being 49 nm, with the magnetic core diameter equal to 10-15 nm. MD3 is a superparamagnetic preparation commonly used for magnetic resonance imaging (MRI). The liver, spleen, heart, kidney, and lung microstructures of these mice were determined after MD3 administration. Both dose- and timedependent changes in the examined organs were compared after single and repeated MD3 doses. MD3 induces an increse in ferritine and iron levels in all the organs, the appearance of small aggregates of lymphoid cells in the liver, the appearance of iron-containing cell formations in hepatic sinusoids, presumably composed of the Kupffer cells and portal macrophages, splenomegaly, and hemostasis of spleen blood vessels. The pronounced morphological alterations have been revealed primarily in the liver and spleen after a single administration of high MD3 doses and after repeated MD3 injections. The results of The present investigation seem to narrow somewhat the safety limits of superparamagnetic iron oxide particles. Nevertheless, the degree of morphological changes in the liver and spleen in our experiments appeared to be rather low even after a single MD3 dose that exceeds approximately by 200 times a dose necessary for diagnostics in MRI. Olbrich, C. and R. H. Muller (1999). "Enzymatic degradation of SLN-effect of surfactant and surfactant mixtures." International Journal of Pharmacy 180(1): 31-9. Solid lipid nanoparticles (SLN) show different degradation velocities by the lipolytic enzyme pancreatic lipase as a function of their composition (lipid matrix, stabilizing surfactant). In combination with pancreatic colipase a degradation assay has been developed for studying the degradation behavior. As a measure to follow the degradation the formed free fatty acids have been analyzed using an enzymatic test. In the studies SLN degradation showed dependencies in relation to the length of the fatty acid chains in the triglycerides and the surfactants used for SLN production. The longer the fatty acid chains in the glycerides, the slower the degradation. The influence of surfactants can be degradation accelerating (e.g. cholic acid sodium salt) or a hindering, degradation slowing down effect due to steric stabilization (e.g. Poloxamer 407). As a second steric stabilizer, Tween 80 has been used and the results showed a less pronounced effect on hindering the degradation process than for Poloxamer 407. This result seems to be correlated to the number of ethyleneoxide chains in the molecule. The longer the ethyleneoxide chains are in the molecule, the more hindered is the anchoring of the lipase/colipase complex and consequently the degradation of the SLN. The result can be used to adjust degradation of SLN and consequently drug release in a controlled way. Olivier, J. C., M. Taverna, et al. (1994). "Capillary electrophoresis monitoring of the competitive adsorption of albumin onto the orosomucoid-coated polyisobutylcyanoacrylate nanoparticles." Electrophoresis 15(2): 234-9. The simultaneous and rapid quantitation of a glycoprotein, human orosomucoid, and a protein, human serum albumin (HSA), by micellar electrokinetic capillary electrophoresis was developed and optimized (pH and sodium dodecyl sulfate concentration) in order to study the competitive adsorption of HSA onto orosomucoid-coated nanoparticles of polyisobutylcyanoacrylate. This method provided satisfactory repeatability and the response was linear for concentrations of orosomucoid and HSA ranging from 0.025 to 0.500 mg/mL (r &gt; 0.994 for both proteins). To study the competitive adsorption of HSA, the amounts of free orosomucoid and free HSA were determined in the supernatant obtained after centrifugation of the orosomucoid-coated nanoparticle suspension incubated with HSA. Furthermore, the quantities of both orosomucoid and HSA absorbed onto nanoparticles were also determined after desorption of these molecules from the nanoparticle surface, using sodium dodecyl sulfate. No analytical interference was observed with this surfactant. The results showed that HSA did not at all absorb onto the orosomucoid-coated nanoparticles and, thus, that this protein did not displace the layer of absorbed orosomucoid from the nanoparticle surface. Olivier, J. C., L. Fenart, et al. (1999). "Indirect evidence that drug brain targeting using polysorbate 80-coated polybutylcyanoacrylate nanoparticles is related to toxicity." Pharmacetical Research 16(12): 1836-42. PURPOSE: To investigate the mechanism underlying the entry of the analgesic peptide dalargin into brain using biodegradable polybutylcyanoacrylate (PBCA) nanoparticles (NP) overcoated with polysorbate 80. METHODS: The investigations were carried out with PBCA NP and with non biodegradable polystyrene (PS) NP (200 nm diameter). Dalargin adsorption was assessed by HPLC. Its entry into the CNS in mice was evaluated using the tail-flick procedure. Locomotor activity measurements were performed to compare NP toxicities. BBB

permeabilization by PBCA NP was studied in vitro using a coculture of bovine brain capillary endothelial cells and rat astrocytes. RESULTS: Dalargin loading was 11.7 microg/mg on PBCA NP and 16.5 microg/ mg on PS NP. Adding polysorbate 80 to NP led to a complete desorption. Nevertheless, dalargin associated with PBCA NP and polysorbate 80 induced a potent and prolonged analgesia, which could not be obtained using PS NP in place of PBCA NP. Locomotor activity dramatically decreased in mice dosed with PBCA NP, but not with PS NP. PBCA NP also caused occasional mortality. In vitro, PBCA NP (10 microg/ml) induced a permeabilization of the BBB model. CONCLUSIONS: A non specific permeabilization of the BBB, probably related to the toxicity of the carrier, may account for the CNS penetration of dalargin associated with PBCA NP and polysorbate 80. Oswald, P., O. Clement, et al. (1997). "Liver positive enhancement after injection of superparamagnetic nanoparticles: respective role of circulating and uptaken particles." Magnetic Resonance Imaging 15(9): 1025-31. Superparamagnetic nanoparticles have both high r1 and r2 relaxivities responsible for positive or negative enhancement properties. The aim of this study was to investigate to what extent perfusion (circulating particles) and uptake (clustered particles) mechanisms contribute to liver positive or negative enhancement using two different particles, superparamagnetic iron oxides (ferumoxides, AMI 25) and ultrasmall superparamagnetic iron oxides (ferumoxtran, AMI-227). Uptake kinetics were studied after intravenous injection of 20 micromol Fe/kg ferumoxtran on a washout liver model. Livers of 82 rats were surgically isolated and washed with saline infusion. Imaging was performed ex vivo at 0.5T with T1- and T2-weighted sequences. Enhancement kinetics of the liver were studied in vivo using MRI up to 180 min post injection of 20 micromol Fe/kg ferumoxtran (time response study) or 10, 20, 40 micromol Fe/kg ferumoxtran and 20 micromol Fe/kg ferumoxides (dose response study.) Particle uptake occurred early and resulted in a negative enhancement of the washed livers 15 min after injection of both T1 and T2 sequences. In vivo, a positive enhancement was only seen during the first five min with the lowest dose of ultrasmall superparamagnetic iron oxides and the T1 sequence. Uptake and clustering of the particles induced a negative liver enhancement. During the first minutes after injection, when uptake has not significantly occurred, perfusion imaging of the liver at a dose of 10 micromol Fe/kg results in a positive enhancement with T1-weighted sequences. Otten, F., L. B. Kish, et al. (2000). "Self-capacitance of a Thomas-Fermi nanosphere." Applied Physics Letters 77(23): 3797-9. We calculate the self-capacitance and charging energy of a spherical nanoparticle in the Thomas-Fermi approximation. The result is C/sub TF/=C/sub 0/1-p/sup -1/ tanh p/1-(1- epsilon /sup -1/)p/sup -1/ tanh p, with C/sub TF/>or=C/sub 0/. Here C/sub 0/=4 pi epsilon /sub 0/R is the classical geometrical value, p=R/l is the ratio of the particle radius R to the Thomas-Fermi screening length l, and epsilon is the material dielectric constant. The addition of surface localized states drives C toward C/sub 0/. These results should be relevant to tunneling spectroscopy studies of giant carbon onions and "large" semiconductor nanocrystals that do not require a full quantum treatment. (15 References). Page-Clisson, M. E., H. Pinto-Alphandary, et al. (1998). "Development of ciprofloxacin-loaded nanoparticles: physicochemical study of the drug carrier." Journal of Controlled Release 56(1-3): 23-32. This paper describes the optimization of the preparation of ciprofloxacin-loaded polyethylbutylcyanoacrylate (PEBCA) nanoparticles. The association of ciprofloxacin with nanoparticles was performed by emulsion polymerization, but successful entrapment was only obtained in the presence of acetone in the polymerization medium. This preparation process led to a stable ciprofloxacin nanoparticle suspension, with a mean size value twice as high as that obtained in the absence of drug, and an association efficiency of 82%. Moreover, the molecular weight value of ciprofloxacin nanoparticles was shown to be reduced as compared with unloaded nanoparticles. Drug release from the colloidal carrier in medium containing esterase was found to be very slow (a maximum of 51.5% after 48 h), suggesting that this release resulted from bioerosion of the polymer matrix. Interestingly, it was observed that 30.5% of the initial amount of ciprofloxacin was not detectable by HPLC analysis after nanoparticle preparation and corresponded either to ciprofloxacin covalently bound to PEBCA or to ciprofloxacin chemically degraded during the polymerization process. 19F-NMR analysis demonstrated that ciprofloxacin entrapped into nanoparticles was only in its neutral form. The measurements of molecular weight suggest the participation of the antibiotic as an anionic polymerization initiator, leading to the formation of a chemical bond between some of the drug and the polymer. These data allowed us to propose a model describing the association of ciprofloxacin with PEBCA nanoparticles obtained by emulsion polymerization. Page-Clisson, M. E., H. Pinto-Alphandary, et al. (1998). "Drug targeting by polyalkylcyanoacrylate nanoparticles is not efficient against persistent Salmonella." Pharmacetical Research 15(4): 544-9. PURPOSE: We have investigated the efficacy of colistin and ciprofloxacin, free or bound to polyalkylcyanoacrylate nanoparticles, for the targeting and eradication of Salmonella persisting in the organs of the mononuclear phagocyte system. METHODS: A model of persistent S. typhimurium infection was developed in C57BL/6 mice using i.v. inoculation of the plasmid-cured strain C53. RESULTS: In vivo and ex vivo experiments showed that the persisting bacteria seem to evolve to a nongrowing state during experimental salmonellosis. In

vivo treatment with free or nanoparticle-bound colistin did not significantly reduce the number of viable Salmonella C53, either in the liver or the spleen of infected mice. In contrast, in vivo treatment with ciprofloxacin led to a significant decrease of bacterial counts in the liver whatever the stage of infection and the form used. However, none of the treatments were able to sterilize the spleen or the liver. In ex vivo experiments, colistin was only active against bacteria recovered during the early phase of infection, whereas ciprofloxacin exerted its activity at all times postinfection. CONCLUSIONS: We suggest that the micro-environment in which the bacterial cells persist in vivo probably causes dramatic changes in their susceptibility to antimicrobial agents. Palla, B. J., D. O. Shah, et al. (1999). "Preparation of nanoparticles of barium ferrite from precipitation in microemulsions." Journal of Nanoparticle Research 1: 215-221. Panagi, Z., A. Beletsi, et al. (2001). "Effect of dose on the biodistribution and pharmacokinetics of PLGA and PLGA-mPEG nanoparticles." International Journal of Pharmacology 221(1-2): 143-52. The effect of nanoparticle dose on the biodistribution and pharmacokinetics of conventional PLGA and stealth poly(Lactide-co-glycolide)-monomethoxypoly(ethyleneglycol) (PLGA-mPEG) nanoparticles was investigated. The precipitation-solvent diffusion method was used to prepare PLGA and PLGA-mPEG nanoparticles labeled with 125I-cholesterylaniline. These were administered intravenously (i.v.) in mice and at predetermined time intervals the animals were sacrificed and their tissues were excised and assayed for radioactivity. Within the dose range applied in this study, blood clearance and mononuclear phagocyte system (MPS) uptake of the PLGA nanoparticles depended on dose whereas they were independent of dose in the case of the PLGA-mPEG nanoparticles. Increasing the dose, decreased the rates of blood clearance and MPS uptake of the PLGA nanoparticles, indicating a certain degree of MPS saturation at higher doses of PLGA nanoparticles. The dose affected the distribution of PLGA nanoparticles between blood and MPS (liver) but it did not affect the nanoparticle levels in the other tissues. Within the range of doses applied here, the PLGA nanoparticles followed non-linear and dose-dependent pharmacokinetics whereas the PLGA-mPEG nanoparticles followed linear and dose-independent pharmacokinetics. In addition to the prolonged blood residence, the dosage-independence of the pharmacokinetics of the PLGA-mPEG nanoparticles would provide further advantages for their application in controlled drug delivery and in drug targeting. Papatheofanis, F. J. and R. Barmada (1991). "Polymorphonuclear leukocyte degranulation with exposure to polymethylmethacrylate nanoparticles." Journal of Biomedical Materials Research 25(6): 761-71. Polymethylmethacrylate (PMMA) is clinically employed in a wide range of orthopaedic procedures. The etiology of the inflammatory reaction of recipient tissues to PMMA remains unresolved. Classically, polymorphonuclear leukocytes (PMNs) release cytoplasmic lysosomal granules when exposed to a variety of proinflammatory stimuli. Such degranulation contributes, and partially defines, the local tissue reaction to this foreign material. In the present investigation, PMMA particles (50-60 nm) were mixed with human PMNs, and the amount of lactate dehydrogenase, lysozyme, and beta-glucuronidase released from the cells was quantitated. In all cases, a dosedependent increase in degranulation followed the addition of increasing amounts of PMMA to the PMNs. In addition, the migration of PMNs was diminished in a dose-dependent manner with exposure to increasing amounts of the cement. These results suggested that PMMA stimulates the release of leukocyte lysosomal contents and alters the migration characteristics of these cells in a manner that is consistent with the local inflammatory reaction to this cement. Park, J. I. and J. Cheon (2001). "Synthesis of "solid solution" and "core-shell" type cobalt-platinum magnetic nanoparticles via transmetalation reactions." Journal of the American Chemical Society 123(24): 5743-6. In this article, we report the synthesis of "solid solution" and "core-shell" types of well-defined Co-Pt nanoalloys smaller than 10 nm. The formation of these alloys is driven by redox transmetalation reactions between the reagents without the need for any additional reductants. Also the reaction proceeds selectively as long as the redox potential between the two metals is favorable. The reaction between Co(2)(CO)(8) and Pt(hfac)(2) (hfac = hexafluoroacetylacetonate) results in the formation of "solid solution" type alloys such as CoPt(3) nanoparticles. On the other hand, the reaction of Co nanoparticles with Pt(hfac)(2) in solution results in "Co(core)Pt(shell)" type nanoalloys. Nanoparticles synthesized by both reactions are moderately monodispersed (sigma < 10%) without any further size selection processes. The composition of the alloys can also be tuned by adjusting the ratio of reactants. The magnetic and structural properties of the obtained nanoparticles and reaction byproducts are characterized by TEM, SQUID, UV/vis, IR, EDAX, and XRD. Passirani, C., G. Barratt, et al. (1998). "Long-circulating nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate)." Pharmacetical Research 15(7): 1046-50. PURPOSE: In a biomimetic approach to the development of drug carriers escaping early capture by phagocytes, nanoparticles made of amphiphilic copolymers of either heparin or dextran and methyl methacrylate were evaluated relative to their in vivo blood circulation time. They were compared to bare PMMA nanoparticles. METHODS: Owing to the fluorescent properties of the covalently attached N-vinyl carbazole, the particles could

be detected directly in mouse plasma. Samples were drawn at different time intervals and fluorescence was recorded. RESULTS: After an initial phase of elimination from the blood with a half-life of 5 h, the remaining heparin nanoparticles circulated for more than 48 h and were still detectable in the plasma at 72 h. Dextran nanoparticles were also eliminated very slowly over 48 h. Bare poly (methyl methacrylate) nanoparticles were found to have a half-life of only 3 min. CONCLUSIONS: Both types of nanoparticles proved to be long-circulating. The potent capacity for opsonisation of the poly(methyl methacrylate) core were hidden by the protective effect of either polysaccharide, probably due to a dense brush-like structure. In the case of heparin nanoparticles, the &quot;stealth&quot; effect was probably increased by its inhibiting properties against complement activation. Passirani, C., G. Barratt, et al. (1998). "Interactions of nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate) with the complement system." Life Sciences 62(8): 775-85. The efficient uptake of injected nanoparticles by cells of the mononuclear phagocyte system (MPS) limits the development of long-circulating colloidal drug carriers. The complement system plays a major role in the opsonization and recognition processes of foreign materials. Since heparin is an inhibitor of complement activation, nanoparticles bearing heparin covalently bound to poly(methyl methacrylate) (PMMA) have been prepared and their interactions with complement evaluated. The particles retained the complement-inhibiting properties of soluble heparin. Nanoparticles bearing covalently bound dextran instead of heparin were weak activators of complement as compared with crosslinked dextran (Sephadex) or bare PMMA nanoparticles. In addition to the specific activity of bound heparin, the protective effect of both polysaccharides is hypothesized to be due to the presence of a dense brush-like layer on the surface of the particles. Such properties are expected to reduce the uptake by MPS in vivo. Passirani, C., L. Ferrarini, et al. (1999). "Preparation and characterization of nanoparticles bearing heparin or dextran covalently-linked to poly(methyl methacrylate)." Journal of Biomaterials Science Polymer Edition 10(1): 47-62. Nanoparticles have been obtained directly in aqueous media, from amphiphilic copolymers synthesized by radical polymerization of methyl methacrylate (MMA) initiated by Ce(IV) ions in the presence of heparin or dextran. The reaction conditions under which the copolymers spontaneously formed nanoparticles depended on the type of polysaccharide and on the concentrations of the reagents. Fluorescent nanoparticles containing N-vinyl carbazole (NVC), covalently linked to PMMA, were also prepared by random copolymerization of MMA and NVC in similar polymerization systems. The non-fluorescent nanoparticle suspensions were stable for several months without using surfactant. The fluorescent particles were larger and less stable then the unlabelled ones. Since all the particles are monodisperse, and in the submicron range, they can be used as models of drug carriers; the covalently-linked fluorescent species allowing them to be followed in vivo. The average molecular weights of the PMMA blocks of the copolymers and of oxidized heparin and dextran were determined by viscometry and/or gel permeation chromatography. The antithrombic activity of oxidized heparin was measured. The results show that the polysaccharide chains were cleaved by Ce(IV) in aqueous nitric acid, resulting in formation of block copolymers made of one or two blocks of PMMA linked to the ends of one polysaccharide block. Taken together, the results suggest that the particles were organized with the polysaccharidic moieties on the surface of the particles and the more hydrophobic PMMA or P(MMA-co-NVC) in the core, in a brush-like structure. This should confer 'stealth' properties to such particles. Paszti, Z., G. Peto, et al. (2000). "Laser ablation induced formation of nanoparticles and nanocrystal networks." Applied Surface Science 168(15): 114-17. Using experimental data on morphology of nanophase materials prepared by pulsed laser ablation in an inert gas atmosphere, we present a phenomenological description of their condensation process. According to our idea, in high-enough background pressure a shock wave is initiated by collisions between gas and target atoms, which slows down and spatially confines the plume, while it is effectively cooled by further collisions. Thus, the plume becomes highly supersaturated and the condensed phase of the target material starts to develop via homogeneous nucleation. Later on, still in a very limited volume, nanoparticles grow via complete or incomplete coalescence forming compact objects or large networks. The pressure threshold for gas phase condensation is intimately related to the collisional energy loss characteristics of the particular gas-target combination as well as to the thermophysical properties of the target. (14 References). Patil, V. and M. Sastry (2000). "Formation of close-packed silver nanoparticle multilayers from electrostatically grown octadecylamine/colloid nanocomposite precursors." Langmuir 16(5): 2207-12. The formation of close-packed silver nanoparticle thin films via a two-stage self-assembly approach is described. In the first step, surface-modified silver colloidal particles are extracted from aqueous solution via electrostatic interactions into thermally evaporated fatty amine films. Thereafter, the excess fatty amine molecules in the organic matrix are removed by dissolution in a range of organic solvents of varying dielectric properties. Thermogravimetric and quartz crystal microgravimetric studies indicate that, irrespective of whether the dissolution medium is polar or nonpolar, except for a monolayer of amine molecules in direct contact with the colloidal particle surface, almost complete fatty amine dissolution occurs leading to a considerable increase in the

packing density of the silver colloidal particles. While UV-vis spectroscopy measurements of the films after amine removal suggest subtle differences in the final structure of the films prepared from the different solvents, atomic force microscopy studies show fairly aggregated colloidal particle structures in all cases. (21 References). Patrone, L., D. Nelson, et al. (2000). "Photoluminescence of silicon nanoclusters with reduced size dispersion produced by laser ablation." Journal of Applied Physics 87(8): 3829-37. We report a photoluminescence study of silicon nanoclusters produced by laser ablation. It was found that by varying the preparation parameters it was possible to change the mean cluster size in the range 1-5 nm. Within this size variation, the photoluminescence band shifts in a wide spectral region from near ultraviolet to near infrared. This size-dependent photoluminescence of Si nanoclusters is consistent with a quantum confinement effect. The observed influence of cluster oxidation on the luminescence properties also supports the quantum confinement interpretation. We proposed a discrete size model which supposes that the spectral position of the luminescence band is essentially determined by the volume of clusters with a complete outer atomic layer. In the framework of this model, we were able to deconvolute the observed luminescence bands into a set of fixed Gaussian bands. The model is supported by the observation of a size selective doping of Si nanoclusters whose effect was well explained by Auger recombination. Finally, our model allowed us to obtain a dependence of the optical gap on the cluster size which is in good agreement with existing calculations of Si nanocrystal electronic structure. (48 References). Pattabi, M. and J. Uchil (2000). "Synthesis of cadmium sulphide nanoparticles." Solar Energy Materials and Solar Cells 63(4): 309-14. Nanoparticles form a link between molecular and bulk state of matter and exhibit size dependent physical and chemical properties. A novel technique of synthesizing nanoparticle films on biological membrane substrates is presented here. Cadmium Sulphide (CdS) nanoparticles were prepared by the chemical reaction of aqueous solutions of Cadmium Acetate and Thiourea. The reacting solutions were allowed to diffuse across the membrane for different periods to control the deposition time. The optical absorption spectra of the membrane after the reaction were recorded with bare membrane as reference. The optical absorption spectra show a clear shift in the absorption edge for films with different deposition times at a fixed concentration. The band gaps calculated from the absorption spectra for films with smaller deposition time were higher than that for the bulk CdS. The particle size, estimated from the band gaps, lie in the nanometer range showing that the particle size and band gap can be tailored by controlling the deposition time and concentration of the precursors. (9 References). Paul, M., R. Durand, et al. (1998). "Physicochemical characteristics of pentamidine-loaded polymethacrylate nanoparticles: implication in the intracellular drug release in Leishmania major infected mice." Journal of Drug Targeting 5(6): 481-90. This work describes the preparation, the physicochemical properties, the tolerance and the intracellular trafficking of pentamidine loaded nanoparticles. Pentamidine was bound to the polymer by ionic interaction. This interaction involved the carboxylic acid functions of methacrylic acid (10% of the polymer) and the amine groups of the drug. Pentamidine fixation and release were pH dependent. An acidic pH led to a decrease of fixation or a release. At pH 5, which is the pH value of lysosomes and parasitophorous vacuoles, the release reached up to 50%. At this pH value, pentamidine is ionized and therefore can not traverse the biological membranes. Unloaded nanoparticles and pentamidine-loaded nanoparticles were tested in vitro on U937 cells and no cytotoxicity was observed. In vivo, in Leishmania infected mice, no significant weight loss was found. Ultrastructural studies showed the different steps of drug loaded nanoparticles trafficking inside Leismania-infected Kupffer cells. The nanoparticle uptake by macrophagic cells led to the location of nanoparticles inside phagocytosis vacuoles which fused with primary lysosomes to form secondary lysosomes. Ultimate fusion of secondary lysosomes containing nanoparticles with parasitophorous vacuoles was also observed. Nanoparticles were identified close to amastigotes but internalization by the parasite was not observed. Pecora, R. (2000). "Dynamic light scattering measurement of nanometer particles in liquids." Journal of Nanoparticle Research 2: 123-131. Pepin, X., L. Attali, et al. (1997). "On the use of ion-pair chromatography to elucidate doxorubicin release mechanism from polyalkylcyanoacrylate nanoparticles at the cellular level." Journal of Chromatography B Biomedical Sciences and Applications 702(1-2): 181-91. The major hypothesis underlying the remarkable efficiency of polyalkylcyanoacrylate particles loaded with doxorubicin against multidrug resistant tumor cells in vitro, is based on the ion-pair association of doxorubicin with soluble hydrolysis products of polyalkylcyanoacrylate. In an attempt to demonstrate the validity of this hypothesis, we have used ion-pair reversed-phase high-performance liquid chromatography and a laboratory-synthetized compound, i.e., the 2-cyano-2-butylhexanoic acid, as a model for polyalkylcyanoacrylate highly polydispersed degradation products. It is shown that, compared to a counter-ion, like heptane sulfonic acid, 2-cyano-2butylhexanoic acid exhibits an effective ion-pairing effect at different pH values and organic mobile phase

conditions. Moreover, at pH close to physiological conditions and at low mobile phase organic modifier percentage, this effect is experimentally observed, which strongly supports the initial hypothesis. Peracchia, M. T., C. Vauthier, et al. (1997). "Development of sterically stabilized poly(isobutyl 2-cyanoacrylate) nanoparticles by chemical coupling of poly(ethylene glycol)." Journal of Biomedical Materials Research 34(3): 317-26. To develop rapidly biodegradable &quot;stealth&quot; nanoparticles, a physicochemical investigation was done on the formation of PEG-coated poly(isobutyl 2-cyanoacrylate) (PIBCA) nanoparticles. In particular, this study focused on the effect of polymerization conditions on particle size and surface properties, such as charge and hydrophilicity. Among the parameters involved, the pH of the polymerization medium was found to be a key to control the preparation of PEG-coated nanoparticles. Currently, poly(alkylcyanoacrylate) (PACA) nanoparticles are prepared in H2O at pH 2.5, the most appropriate for producing nanoparticles with a mean diameter of 200 nm and an unimodal size distribution. The presence of PEG in the polymerization medium was shown to affect particles formation: only a pH value &lt; 1.5 led to the formation of colloidal nanoparticles, and slight pH variations dramatically affected particle size and PEG association. Polymer chemistry investigations and chemical determination of PEG strongly suggest that PEG associated with nanoparticles was well copolymerized with PIBCA. Peracchia, M. T., C. Vauthier, et al. (1997). "Complement consumption by poly(ethylene glycol) in different conformations chemically coupled to poly(isobutyl 2-cyanoacrylate) nanoparticles." Life Sciences 61(7): 749-61. There is an increasing interest to develop injectable drug polymeric carriers not recognizable by the body as foreign particles and eliminated very quickly from the bloodstream. A polyethylene glycol (PEG)-coating onto injectable particles showed to reduce either protein adsorption and complement consumption, as a function of the PEG density. In this work we compared the complement rejecting ability of PEG in different conformations coupled to polyisobutylcyanoacrylate (PIBCA) nanoparticles, through the analysis of the residual hemolytic capacity of the human serum after contact with the particles. Nanoparticles were formed by chemical coupling of PEG during emulsion/polymerization of isobutylcyanoacrylate (IBCA). Nanoparticles characterization included an investigation of their surface properties, such as hydrophilicity and conformational mobility of the PEG chains grafted on the nanoparticles surface, and PEG total content. The polymerization kinetics of IBCA in presence of PEG or MePEG were also studied. Complement consumption was observed to be very sensitive to the number of particles in contact with human serum, as well as to the PEG conformation, suggesting PEG configuration could affect the particle exposed surface. Peracchia, M. T., C. Vauthier, et al. (1998). "Pegylated nanoparticles from a novel methoxypolyethylene glycol cyanoacrylate-hexadecyl cyanoacrylate amphiphilic copolymer." Pharmacetical Research 15(4): 550-6. PURPOSE: The aim of this work was to develop PEGylated poly(alkylcyanoacrylate) nanoparticles from a novel methoxypolyethyleneglycol cyanoacrylate-co-hexadecyl cyanoacrylate copolymer. METHODS: PEGylated and non-PEGylated nanoparticles were formed by nanoprecipitation or by emulsion/solvent evaporation. Nanoparticles size, zeta potential and surface hydrophobicity were investigated. Surface chemical composition was determined by X-ray photoelectron spectroscopy. Nanoparticle morphology was investigated by transmission electron microscopy after freeze-fracture. Nanoparticles cytotoxicity was assayed in vitro, onto mouse peritoneal macrophages. Cell viability was determined through cell mitochondrial activity, by a tetrazolium-based colorimetric method (MTT test). Finally, the degradation of PEGylated and non-PEGylated poly(hexadecyl cyanoacrylate) nanoparticles was followed spectrophotometrically during incubation of nanoparticles in fetal calf serum. RESULTS: Monodisperse nanoparticles with a mean diameter ranging between 100 and 200 nm were obtained using nanoprecipitation or emulsion/solvent evaporation as preparation procedures. A complete physico-chemical characterization, including surface chemical analysis, allowed to confirm the formation of PEG-coated nanoparticles. The PEGylation of the cyanoacrylate polymer showed reduced cytotoxicity towards mouse peritoneal macrophages. Furthermore, the presence of the PEG segment increased the degradability of the poly(hexadecyl cyanoacrylate) polymer in presence of calf serum. CONCLUSIONS: We succeeded to prepare PEGylated nanoparticles from a novel poly(methoxypolyethyleneglycol cyanoacrylate-co-hexadecyl cyanoacrylate) by two different techniques. Physico-chemical characterization showed the formation of a PEG coating layer. Low cytotoxicity and enhanced degradation were also shown. Peracchia, M. T., S. Harnisch, et al. (1999). "Visualization of in vitro protein-rejecting properties of PEGylated stealth polycyanoacrylate nanoparticles." Biomaterials 20(14): 1269-75. The in vitro protein-rejecting properties of PEG-coated polyalkylcyanoacrylate (PACA) nanoparticles were for the first time visualized after freeze-fracture of the nanoparticles pre-incubated with fibrinogen as a model blood protein. The reduced protein association to the nanoparticles was evidenced also by two-dimensional PAGE after incubation of the nanoparticles with human plasma. In vivo experiments showed the 'stealth' long-circulating properties of the PEGylated nanoparticles after intravenous administration to mice. Thus, the images obtained after nanoparticle-protein incubation were predictive of the behavior observed in vivo. In conclusion, freezefracture analysis represents a novel and original qualitative approach to investigate the interactions between

proteins and particulate systems. Peracchia, M. T., E. Fattal, et al. (1999). "Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting." Journal of Controlled Release 60(1): 121-8. The aim of the present work was to investigate the biodistribution characteristics of PEG-coated polycyanoacrylate nanoparticles prepared by the nanoprecipitation/solvent diffusion method using the previously synthesized poly(MePEGcyanoacrylate-hexadecylcyanoacrylate) copolymer. It was observed that [14C]radiolabeled PEGylated nanoparticles remained for a longer time in the blood circulation after intravenous administration to mice, compared to the non-PEGylated poly(hexadecylcyanoacrylate) (PHDCA) nanoparticles. Furthermore, hepatic accumulation was dramatically reduced, whereas a highly increased spleen uptake was shown. The PEGylation degree of the polymer seemed not to affect the in vivo behavior of the nanoparticles, whereas previously obtained in vitro data have shown a modification of plasma protein adsorption depending on the density of PEG at the surface of the particles. Moreover, the study of the in vitro cytotoxicity of the nanoparticles revealed that the PEGylation of the cyanoacrylate polymer reduced its toxicity. These results open up interesting perspectives for the targeting of drugs to other tissues than the liver. Perez, C., A. Sanchez, et al. (2001). "Poly(lactic acid)-poly(ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA." Journal of Control Release 75(1-2): 211-24. The purpose of the present work was to produce and characterize poly(lactic acid)-poly(ethylene glycol) (PLAPEG) nanoparticles (size lower than 300 nm) containing a high loading of plasmid DNA in a free form or coencapsulated with either poly(vinyl alcohol) (PVA) or poly(vinylpyrrolidone) (PVP). The plasmid alone or with PVA or PVP was encapsulated by two different techniques: an optimized w/o/w emulsion-solvent evaporation technique as well as by a new w/o emulsion-solvent diffusion technique. Particle size, zeta potential, plasmid DNA loading and in vitro release were determined for the three plasmid-loaded formulations. The influence of the initial plasmid loadings (5, 10, 20 &mgr;g plasmid DNA/mg PLA-PEG) on those parameters was also investigated. The plasmid loaded into the nanoparticles and released in vitro was quantified by fluorimetry and the different molecular forms were identified by gel electrophoresis. PLA-PEG nanoparticles containing plasmid DNA in a free form or co-encapsulated with PVA or PVP were obtained in the range size of 150-300 nm and with a negative zeta potential, both parameters being affected by the preparation technique. Encapsulation efficiencies were high irrespective of the presence of PVA or PVP (60-90%) and were slightly affected by the preparation technique and by the initial loading. The final plasmid DNA loading in the nanoparticles was up to 10-12 &mgr;g plasmid DNA/mg polymer. Plasmid DNA release kinetics varied depending on the plasmid incorporation technique: nanoparticles prepared by the w/o diffusion technique released their content rapidly whereas those obtained by the w/o/w showed an initial burst followed by a slow release for at least 28 days. No significant influence of the plasmid DNA loading and of the co-encapsulation of PVP or PVA on the in vitro release rate was observed. In all cases the conversion of the supercoiled form to the open circular and linear forms was detected. In conclusion, plasmid DNA can be very efficiently encapsulated, either in a free form or in combination with PVP and PVA, into PLA-PEG nanoparticles. Additionally, depending on the processing conditions, these nanoparticles release plasmid DNA either very rapidly or in a controlled manner. Perner, M., S. Gresillon, et al. (2000). "Observation of hot-electron pressure in the vibration dynamics of metal nanoparticles." Physical Review Letters 85(4): 792-5. We investigate the vibration dynamics of ellipsoidal silver nanoparticles, using time-resolved optical pump-probe spectroscopy. When excited with femtosecond laser pulses, the particles execute anisotropic shape oscillations. We show that these vibrations are triggered by the thermal expansion of the optically heated particles. The time dependence of the vibrations indicates that this expansion is caused by two mechanisms: The lattice anharmonicity and the extremely large pressure of the hot conduction electrons. Perrin, A., A. Theretz, et al. (1999). "Immunomagnetic concentration of antigens and detection based on a scanning force microscopic immunoassay." Journal of Immunological Methods 224(1-2): 77-87. Scanning Force Microscopy has already been shown to be a convenient and rapid method for sensitive antigen detection and quantification. Here, we describe different improvement steps brought to a TSH Scanning Force Microscopic ImmunoAssay (SFMIA), each of them aiming to solve a previous limitation of the solid phase test format and leading to a significant sensitivity enhancement. First, superparamagnetic nanoparticles conjugated to monoclonal anti alphaTSH antibodies were used for the specific TSH capture step. Their magnetic properties allowed easy separation of the complexes obtained from relatively large reaction volumes by application of a High Gradient Magnetic Field System. As a consequence, complex formation could proceed in a stirred solution, which greatly enhances binding rates compared to previous 'static' conditions of solid-phase reactions. It was established that, despite their small size, magnetic complexes could be moved over short distances by a NdFeB magnet magnetic field. This property was exploited to overcome diffusion barrier and boundary layer constraints and to drive magnetic complexes through the liquid, towards anti-betaTSH antibodies immobilized on silica wafers. Finally, we significantly increased the complex number/surface area by a stepwise reduction of the

biospecific solid phase area. The proposed steps permitted a 3-fold improvement in the TSH SFMIA dynamic range. Moreover, as little as 0.02 pg/ml (0.1 nIU/ml or 0.8 amol/ml) of TSH could be detected using 1 ml sample volumes. This is over 100 times more sensitive than the current performance of commercialized automated systems. Persans, P. D., L. B. Lurio, et al. (2000). "Combining X-ray and optical spectroscopies in the study of dilute semiconductor nanoparticle composites." Journal of Applied Physics 87(8): 3850-7. We discuss a methodology for the cooperative analysis of optical and X-ray spectroscopies to deduce the thermophysical properties of dilute suspensions of semiconductor nanoparticles in a wide band gap host. X-ray spectroscopy is used to determine concentration and bonding of selected elements. Resonant Raman spectroscopy establishes limits on composition and strain in particles. Analysis of optical absorption, with constraints provided by X-ray and Raman measurements, yields the particle size distribution and concentration. As an example of this approach, we study borosilicate glasses doped with ~0.1 wt% CdS and heat treated to produce nanoparticles. (64 References). Petit, C. and M. P. Pileni (2000). "Physical properties of self-assembled nanosized cobalt particles." Applied Surface Science 162(163): 519-28. Fabrication, structural, magnetic and local electronic properties of cobalt metallic nanocrystals are reported. Nanosized cobalt particles are synthesized in colloidal assemblies. After surface passivation and extraction of the nanocrystals from the micellar media, cobalt nanoparticles with a narrow size distribution are obtained. The particles are then stable under air. Deposited on a surface, the nanoparticles form a 2D hexagonal network spontaneously. The magnetic properties are strongly dependent on the self-organization of cobalt nanocrystals. In 2D self-assemblies, collective properties originated from the dipolar magnetic interaction between adjacent particles are observed. Isolated particles are studied by scanning tunneling microscopy at room temperature under air. The spectroscopy experiments performed at 77 K show well-resolved Coulomb gap and Coulomb staircase features. (30 References). Petta, J. R., D. G. Salinas, et al. (2000). "Measurements of discrete electronic states in a gold nanoparticle using tunnel junctions formed from self-assembled monolayers." Applied Physics Letters 77(26): 4419-21. We present results from nanometer-scale tunnel junctions fabricated using organic self-assembled monolayers (SAMs) as tunnel barriers. Single junctions have resistances consistent with tunneling through a single layer of molecules. In several devices, a gold nanoparticle nucleated within the SAM barrier. Such samples allow a sensitive test of mechanical stability-some are sufficiently stable to permit the observation of electron tunneling through individual electron-in-a-box states at low voltages and mK temperatures. We also observe anomalous transport characteristics at larger voltages, which may be due to the motion of the gold nanoparticle within the monolayer. (16 References). Peyser, L. A., A. E. Vinson, et al. (2001). "Photoactivated fluorescence from individual silver nanoclusters." Science 291(5501): 103-6. Fluorescence microscopy of nanoscale silver oxide (Ag2O) reveals strong photoactivated emission for excitation wavelengths shorter than 520 nanometers. Although blinking and characteristic emission patterns demonstrate single-nanoparticle observation, large-scale dynamic color changes were also observed, even from the same nanoparticle. Identical behavior was observed in oxidized thin silver films that enable Ag2O particles to grow at high density from silver islands. Data were readily written to these films with blue excitation; stored data could be nondestructively read with the strong red fluorescence resulting from green (wavelengths longer than 520 nanometers) excitation. The individual luminescent species are thought to be silver nanoclusters that are photochemically generated from the oxide. Phely-Bobin, T. S., R. J. Muisener, et al. (2000). "Preferential self-assembly of surface-modified Si/SiO x nanoparticles on UV/ozone micropatterned poly(dimethylsiloxane) films." Advanced Materials 12(17): 1257-61. The specific self-assembly of Si/SiO/sub x/ core-shell nanoparticles onto UV/ozone micropatterned poly(dimethylsiloxane) (PDMS) films is reported here. Auger and Raman spectroscopic mapping document the preferential Si/SiO/sub x/ nanoparticle adsorption within PDMS domains. These nanoparticles display a high refractive index, which renders them potentially important for photonic band-gap applications. (37 References). Pimienta, C., V. Lenaerts, et al. (1990). "Mucoadhesion of hydroxypropylmethacrylate nanoparticles to rat intestinal ileal segments in vitro." Pharmacetical Research 7(1): 49-53. The purpose of this study was to evaluate the adhesion of HPMA nanoparticles to mucus using a perfused rat ileum test system. Radiolabeled nanoparticles were prepared and deposited onto rat ileal segments in vitro. The segments were perfused and the perfusate was collected in fractions and assayed for radioactivity. Between 10 and 50% of the radioactivity was eliminated over the first 120-sec perfusion, whereas the remaining activity was firmly attached to the ileum. Among the variables tested, the time interval between nanoparticle deposition and

perfusion played the major role, indicating that the mucus-nanoparticle interaction is likely to result from the diffusion of polymers into the mucus and of mucin into the polymeric matrix. Pinto-Alphandary, H., O. Balland, et al. (1994). "Intracellular visualization of ampicillin-loaded nanoparticles in peritoneal macrophages infected in vitro with Salmonella typhimurium." Pharm Res 11(1): 38-46. Intracellular targeting of ampicillin by means of polyisohexylcyanoacrylate (PIHCA) nanoparticles was studied in murine peritoneal macrophages infected with Salmonella typhimurium. The intracellular distribution of actively endocytosed nanoparticles was visualized by transmission electron microscopy and confocal microscopy. Nanoparticles were either isolated or closely associated with bacteria within phagosomes or phagolysosomes. Thus the potential of ampicillin-loaded nanoparticles in targeting of intracellular bacteria is demonstrated. Consequently, ampicillin, which usually penetrates into cells at a low level, is directly carried in, when loaded on nanoparticles, and brought into contact with intracellular bacteria. Pinto-Alphandary, H., O. Balland, et al. (1995). "A new method to isolate polyalkylcyanoacrylate nanoparticle preparations." Journal of Drug Targeting 3(2): 167-9. A simple method for the separation of polyalkylcyanoacrylate nanoparticles was developed using polyisohexylcyanoacrylate (PIHCA) as a model. Fluorescein isothiocyanate dextran 70 was used to label the nanoparticles. Ultracentrifugation onto a performed sucrose gradient allowed the easy elimination of the dextran and of the free molecules remaining in the upper phase. After such treatment, the physicochemical characteristics of the PIHCA nanoparticles were not modified. This method could be usefully extended to other types of nanoparticles. Pinto-Alphandary, H., A. Andremont, et al. (2000). "Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications." International Journal of Antimicrobial Agents 13(3): 155-68. This review examines current technologies for increasing the bioavailability of antibiotics by means of liposomes or nanoparticles. The main focus is on liposomes. These carriers were preferentially developed because their composition is compatible with biological constituents. Biodegradable polymers in the form of colloidal particles have also been used and show promise for future applications in antimicrobial chemotherapy. The in vivo behaviour of both types of carriers and consequently their therapeutic potential, are determined by their route of administration. Conventional carrier strategies permit the mononuclear phagocyte system to be targeted by intravenous injection of antibiotics. Stealthy strategies avoid major uptake by these cells and extend the systemic presence of these carriers. The purpose of this review is to provide background information in antibiotic targeting gathered from papers published over the last twenty years. It seems clear that such drug carriers (liposomes, nanoparticles) allow increased drug concentration at infected sites but reduce drug toxicity. Poizot, P., S. Laruelle, et al. (2000). "Nano-sized transition-metal oxides as negative-electrode materials for lithium-ion batteries." Nature 407(6803): 496-9. Rechargeable solid-state batteries have long been considered an attractive power source for a wide variety of applications, and in particular, lithium-ion batteries are emerging as the technology of choice for portable electronics. One of the main challenges in the design of these batteries is to ensure that the electrodes maintain their integrity over many discharge-recharge cycles. Although promising electrode systems have recently been proposed, their lifespans are limited by Li-alloying agglomeration or the growth of passivation layers, which prevent the fully reversible insertion of Li ions into the negative electrodes. Here we report that electrodes made of nanoparticles of transition-metal oxides (MO, where M is Co, Ni, Cu or Fe) demonstrate electrochemical capacities of 700 mA h g(-1), with 100% capacity retention for up to 100 cycles and high recharging rates. The mechanism of Li reactivity differs from the classical Li insertion/deinsertion or Li-alloying processes, and involves the formation and decomposition of Li2O, accompanying the reduction and oxidation of metal nanoparticles (in the range 1-5 nanometres) respectively. We expect that the use of transition-metal nanoparticles to enhance surface electrochemical reactivity will lead to further improvements in the performance of lithium-ion batteries. Pokutnyi, S. I. and V. V. Kovalchuk (2000). "Theoretical investigation of light absorption and scattering by nanoparticles." Semiconductor Physics Quantum Electronics and Optoelectronics 3(1): 69-76. In the framework of the dipole approximation we predict theoretically high magnitudes of: (1) oscillator strength transitions, and (2) the resonance light scattering ( sigma /sub ss/( omega , a)) and absorption ( sigma /sub abs/( omega , a)) cross-sections. We suggest that these peculiarities can be observed experimentally. We discuss the dependence of sigma /sub obs/( omega , a) and sigma /sub ss/( omega , a)) on light frequency omega and radius a of the nanoparticle at different physical conditions. (31 References). Polakovic, M., T. Gorner, et al. (1999). "Lidocaine loaded biodegradable nanospheres. II. Modelling of drug release." Journal of Controlled Release 60(2-3): 169-77. The mechanism of the release of encapsulated lidocaine from spherical nanoparticles based on poly(D,L-lactic acid) polymer carrier (PLA) was studied through mathematical modelling. The drug was incorporated in the PLA

matrix with particle sizes from approximately 250 to 820 nm and corresponding loadings varying from about 7 to 32% (w/w). The rate of release correlated with the particle drug loading and was fastest at small particles with a low drug content. It was about four times slower at large particles with a high loading when the process of release took up to 100 h. Two simple models, diffusion and dissolution, were applied for the description of the experimental data of lidocaine release and for the identification of the release mechanisms for the nanoparticles of different drug loading. The modelling results showed that in the case of high drug loadings (about 30% w/w), where the whole drug or a large part of it was in the crystallised form, the crystal dissolution could be the step determining the release rate. On the other hand, the drug release was diffusion-controlled at low loadings (less than 10% w/w) where the solid drug was randomly dispersed in the matrix. The estimated values of the diffusion coefficient of lidocaine in these particles were in the range of 5-7x10(-20) m(2)/s. A significant influence of both crystal dissolution and drug diffusion on the overall rate of release was assumed at PLA nanoparticles with medium lidocaine loadings. Ponchel, G. and J. Irache (1998). "Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract." Advanced Drug Delivery Reviews 34(2-3): 191-219. The oral route constitutes the preferred route for drug delivery. However, numerous drugs remain poorly available when administered by this route. In order to circumvent this problem, it has been proposed, successfully for several of them, to associate drugs to polymeric nanoparticulate systems (or small particles in the range of the micrometre in size) because of their propensity to interact with the mucosal surface. The present review focuses on the gastrointestinal bioadhesion of micro- and nanoparticles. Bioadhesion can be obtained by the building of either non-specific interactions with the mucosal surface, which are driven by the physicochemical properties of the particles and the surfaces, or specific interactions when a ligand attached to the particle is used for the recognition and attachment to a specific site at the mucosal surface. The relative merits of those systems are discussed. Their fate in the gastrointestinal tract, including at least three different pathways: (i) bioadhesion, (ii) translocation through the mucosa and (iii) transit and direct faecal elimination, is also presented. Portet, D., B. Denizot, et al. (2001). "Nonpolymeric coatings of iron oxide colloids for biological use as magnetic resonance imaging contrast agents." Journal of Colloid and Interface Science 238(1): 37-42. Iron oxide nanoparticles are used in vivo as contrast agents in magnetic resonance imaging. Their widely used polymer coatings are directly involved in their biocompatibility and avoid magnetic aggregation. As these polymer brushes also limit their tissular diffusion due to important hydrodynamic sizes, this work looks to obtain particles coated with thin layers of organic biocompatible molecules. Coating molecules were chosen depending on their fixation site on iron cores; carboxylates, sulfonates, phosphates, and phosphonates, and, among them, analogs of the phosphorylcholine. Two coating procedures (dialysis and exchange resins purification) were evaluated for hydrodynamic size, total iron concentration, electrophoretic mobility, and colloidal stability. Furthermore, a complementary test on stainless steel plates evaluated the contamination by competition of phosphonates as a rough estimation of the biocompatibility of the particles. Coating with bisphosphonates, the more interesting fixation moiety, leads to small (less than 15 nm) and stable objects in a wide range of pH including the neutrality. From stability data, the coating density was evaluated at around 1.6 molecules per nm(2). Including a quaternary ammonium salt to the coating molecule lowers their electrophoretic mobility. Moreover, this type of coating protects steel plates against contamination without significant desorption. All these properties allow further developments of these nanoparticles for biomedical applications. Copyright 2001 Academic Press. Pouliquen, D., R. Perdrisot, et al. (1989). "Superparamagnetic iron oxide nanoparticles as a liver MRI contrast agent: contribution of microencapsulation to improved biodistribution." Magnetic Resonance Imaging 7(6): 619-27. We have developed a new method of synthetizing superparamagnetic iron oxide nanoparticles, consisting in the modifications of Molday's method, which ensures high relaxivity (2.4 10(5) s-1.M-1.L), good chemical stability, singular biodistribution and a considerable safety margin. The ED (Efficace Dose) to LD50 ratio is 1/2400 instead of 1/50 for Gd-DTPA. In order to develop a magnetite-delivery system to the liver we have incorporated the nanoparticles into biodegradable synthetic microcapsules. Encapsulated 59Fe oxide nanoparticles are injected into rats; in these conditions the sequestration is 9-fold greater in liver and 6 and 5 times lower in blood and carcase, respectively. This modification of the biodistribution enables the use of magnetite containing microcapsules at only 0.3 mg/kg iron to obtain an improved contrast in liver. Pouliquen, D., J. J. Le Jeune, et al. (1991). "Iron oxide nanoparticles for use as an MRI contrast agent: pharmacokinetics and metabolism." Magnetic Resonance Imaging 9(3): 275-83. The pharmacokinetics and metabolism of a new preparation of superparamagnetic iron oxide nanoparticles were evaluated by 59Fe radiotracer studies and histologic examination of mice liver and spleen tissues (light and transmission electron microscopy). In the first 30 min following IV injection of the product half of the dose injected remains in the blood, the other part being sequestered mainly by the mononuclear phagocyte system (MPS). In the first five days following IV administration of the nanoparticles, early metabolization of the iron oxide cores occurs, revealed by modification of their aspect in the lysosomes of Kupffer cells and macrophages of the splenic

red pulp. The incorporation of 59Fe is then observed in RBC of the mice. These results are discussed in relation with the physicochemical properties of this new preparation of nanoparticles, and compared with current pharmacokinetic data concerning injectable particle systems. Pouliquen, D., H. Perroud, et al. (1992). "Investigation of the magnetic properties of iron oxide nanoparticles used as contrast agent for MRI." Magn Reson Med 24(1): 75-84. Superparamagnetic iron oxide particles, a new class of contrast agents for MRI, are extremely good enhancers of proton relaxation. However, the development of such particle systems has resulted in a wide range of preparations whose physico-chemical properties differ greatly. We have conducted a set of physical experiments: X ray diffraction analysis, relaxivity measurements, susceptibility determinations, and thermomagnetic cycling on different preparations of superparamagnetic particles. Our results demonstrate a good correlation between susceptibilities measured in liquid samples at room temperature and the R2/R1 ratio. Susceptibility measurements between liquid nitrogen temperature and room temperature show three different types of behavior dependent on the size of iron oxide crystals. Comparison of heating and cooling curves from strong field thermomagnetic cycles provides information about the maghemite/magnetite crystal content. The information on magnetic properties reported in this study may help to characterize and to select these materials for use as MRI contrast agents. Pouliquen, D., I. Lucet, et al. (1993). "Liver-directed superparamagnetic iron oxide: quantitation of T2 relaxation effects." Magn Reson Imaging 11(2): 219-28. A new liver-directed superparamagnetic iron oxide nanoparticle preparation, MDL, is described. MDL is derived from previously developed MD particles only by modification of the characteristics of the coating:chemical structure and charge. The biodistribution, pharmacokinetics, and intratissular localization of both 59Fe-labeled MD and MDL particles were analyzed. R2 relaxivities determined in aqueous solution are compared to measurements in liver tissue and to R2 of nanoparticles incorporated into synthetic microcapsules, which represent a simplified cell pattern. T2 relaxation effects of both preparations in liver tissue are discussed relative to physical parameters such as iron oxide core dimension, total particle size, and charge, and pharmacological properties such as biodistribution, pharmacokinetics, and extra/intracellular localization. Puglisi, G., G. Giammona, et al. (1993). "Evaluation of polyalkylcyanoacrylate nanoparticles as a potential drug carrier: preparation, morphological characterization and loading capacity." Journal of Microencapsulation 10(3): 353-66. Some physicochemical behaviours were investigated of polyethyl- (PECA) and polyisobutylcyanoacrylate (PICA), which, in recent years, have been proposed as nanoparticle colloidal systems for drug carrying. We observed the influence of preparation conditions, such as pH value and surfactant concentration, on parameters such as particle size and polymer molecular weight. Lower operating pH values (0-2) resulted in smaller nanoparticles than those prepared at pH 5.5. The polymer molecular weight was also a function of pH: low molecular weight at low pH and vice-versa. The surfactant concentration positively influenced main particle size and polymer molecular weight. These trends were independent of type of monomer; in fact, both ethyl- (ECA) and isobutyl-2cyanoacrylate (ICA) showed the same behaviour. Loading capacity, as well as release profile, of the two polymers were evaluated using fluorescein as a model drug. Whereas both polymers showed almost the same release profile, there was a difference in the amount of encapsulated probe: higher aliquots for PICA than for PECA. Storage effects on such physicochemical parameters were also tested. Pui, D.-R. C. a. D. Y. H. (1999). "A high efficiency, high throughout unipolar aerosol charger for nanoparticles." Journal of Nanoparticle Research 1: 115-126. Pui, D. Y. H. (2000). "Focus on instrumentation." Journal of Nanoparticle Research 2: 3-4. Pui, D. Y. H., J. R. Brock, et al. (2000). "Instrumentation and measurement issues for nanometer particles: Workshop summary." Journal of Nanoparticle Research 2: 103-112. Putnam, D. A. (1996). "Antisense strategies and therapeutic applications." American Journal of Health System Pharmacy 53(2): 151-60; quiz 182-3. The concepts underlying the antisense approach to disease therapy are discussed, and potential applications are examined. Antisense therapeutic agents bind to DNA or RNA sequences, blocking the synthesis of cellular proteins with unparalleled specificity. Transcription and translation are the two processes with which the agents interfere. There are three major classes of antisense agents: antisense sequences, commonly called antisense oligonucleotides; antigene sequences; and ribozymes. Antisense sequences are derivatives of nucleic acids that hybridize cytosolic messenger RNA (mRNA) sense strands through hydrogen bonding to complementary nucleic acid bases. Antigene sequences hybridize double-stranded DNA in the nucleus, forming triple helixes. Ribozymes, rather than inhibiting protein synthesis simply by binding to a single targeted mRNA, combine enzymatic processes with the specificity of antisense base pairing, creating a molecule that can incapacitate

multiple targeted mRNAs. Antisense therapeutic agents are being investigated in vitro and in vivo for use in treating human immunodeficiency virus infection, hepatitis B virus infection, herpes simplex virus infection, papillomavirus infection, cancer, restenosis, rheumatoid arthritis, and allergic disorders. Although many results are preliminary, some are promising and have led to clinical trials. A major goal in developing methods of delivering antisense agents is to reduce their susceptibility to nucleases while retaining their ability to bind to targeted sites. Modification of the phosphodiester linkages in oligonucleotides can lend the sequences enzymatic stability without affecting their binding capacities. Carrier systems designed to protect the antisense structure and improve passage through the cell membrane include liposomes, water-soluble polymers, and nanoparticles. The pharmacokinetics of antisense agents are under investigation. Antisense therapeutic agents have the potential to become an integral part of medicinal regimens. Quintanar-Guerrero, D., E. Allemann, et al. (1998). "Preparation techniques and mechanisms of formation of biodegradable nanoparticles from preformed polymers." Drug Development and Industrial Pharmacy 24(12): 1113-28. The techniques available to prepare biodegradable nanoparticles (nanospheres and nanocapsules) from preformed polymers are reviewed. Although there is abundant literature on this topic, only a few focus on the thorough analysis of preparative procedures. In particular, four techniques are discussed in terms of their technological advantages and drawbacks: emulsification evaporation, solvent displacement, salting-out, and emulsification diffusion. The proposed mechanism of nanoparticle formation for each technique is described from a physicochemical perspective. The effects of preparative variables on nanoparticle size and drug-entrapment efficiency are also discussed. Quintanar-Guerrero, D., E. Allemann, et al. (1998). "Preparation and characterization of nanocapsules from preformed polymers by a new process based on emulsification-diffusion technique." Pharm Res 15(7): 1056-62. PURPOSE: The aim of this study was to investigate whether biodegradable nanocapsules could be obtained by the emulsification-diffusion technique. METHODS: This technique consists of emulsifying an organic solution containing an oil, a polymer, and a drug in an aqueous solution of a stabilizing agent. The subsequent addition of water to the system induces solvent diffusion into the external phase, resulting in the formation of colloidal particles. Nanoparticles obtained in this way were characterized by their particle size, zeta potential, isopycnic density and drug entrapment. The shape, surface and structure of the nanocapsules were evaluated by freeze fracture scanning electron microscopy (SEM) and by atomic force microscopy (AFM). RESULTS: Density gradient centrifugation confirmed the formation of nanocapsules. The density was found to be intermediate between those of nanoemulsions and nanospheres. The existence of a unique density band indicated high yields. Nanocapsule density was a function of the original oil/polymer ratio, revealing that the polymer content and, consequently, the wall thickness, can be controlled by this method. SEM and AFM showed the presence of capsular structures with smooth homogeneous walls. The versatility and effectiveness of the method were demonstrated using different lipophilic drug/oil core/wall polymer/partially water-miscible solvent systems. The mechanism of nanocapsule formation was explained as a chemical instability (diffusion stranding) generated during diffusion. CONCLUSIONS: This study demonstrated that the emulsification-diffusion technique enables the preparation of nanocapsules in a simple, efficient, reproducible and versatile manner. Quintanar-Guerrero, D., A. Ganem-Quintanar, et al. (1998). "Influence of the stabilizer coating layer on the purification and freeze-drying of poly(D,L-lactic acid) nanoparticles prepared by an emulsion-diffusion technique." Journal of Microencapsulation 15(1): 107-19. In this study, the purification by cross-flow filtration (CFF) and freeze drying of poly(D,L-lactic acid) (PLA) nanoparticles prepared by an emulsion-diffusion technique using poly(vinyl alcohol) (PVAL) or poloxamer 188 (P188) were investigated. The stability of the suspensions was correlated to the affinity of the stabilizers for the nanoparticle surface, the resistance of the coating layer to continuous filtration and to freeze-thawing procedures. The results indicated a clear difference between the two stabilizers, suggesting that the nature of the coating layer has a very important role during CFF and freeze-drying. Nanoparticles prepared with PVAL were filtered and freeze-dried without nanoparticle fusion. This behaviour was attributed to the formation of a stable thick layer (similar to that found for polystyrene latex). In contrast, aggregation of nanoparticles was observed during CFF for the batches prepared with P-188, indicating that the polypropylene oxide blocks present in the copolymer have little affinity for the PLA surface. However, these suspensions were successfully recovered when using stabilizer solutions as diafiltration media, suggesting a dynamic exchange between the P-188-adsorbed chains and those of the identical polymer remaining in the bulk solution. The presence of P-188 did not prevent nanoparticle aggregation after freeze-drying. Therefore, the use of cryoprotectants was necessary. Aggregation may have been due to an increase in the solubility of P-188 in the bulk solution, which provokes a destabilization of the suspension by desorption and partial coverage of the surface. The best cryoprotectants were found to be sugars containing glucose units. The cryoprotective effect was related to the hydrogen bonding capability of these sugars, which prevented aggregation by dehydration of P-188 forcing it to the PLA surface. Quintanar-Guerrero, D., E. Allemann, et al. (1999). "Pseudolatex preparation using a novel emulsion-diffusion process

involving direct displacement of partially water-miscible solvents by distillation." International Journal of Pharmacy 188(2): 155-64. Pseudolatexes were obtained by a new process based on an emulsification-diffusion technique involving partially water-miscible solvents. The preparation method consisted of emulsifying an organic solution of polymer (saturated with water) in an aqueous solution of a stabilizing agent (saturated with solvent) using conventional stirrers, followed by direct solvent distillation. The technique relies on the rapid displacement of the solvent from the internal into the external phase which thereby provokes polymer aggregation. Nanoparticle formation is believed to occur because rapid solvent diffusion produces regions of local supersaturation near the interface, and nanoparticles are formed due to the ensuing interfacial phase transformations and polymer aggregation that occur in these interfacial domains. Using this method, it was possible to prepare pseudolatexes of biodegradable and non-biodegradable polymers such as poly(D,L-lactic acid) and poly(varepsilon-caprolactone), Eudragit E, cellulose acetate phthalate, cellulose acetate trimellitate using ethyl acetate or 2-butanone as partially watermiscible solvents and poly(vinyl alcohol) or poloxamer 407 as stabilizing agent. A transition from nano- to microparticles was observed at high polymer concentrations. At concentrations above 30% w/v of Eudragit E in ethyl acetate or cellulose acetate phthalate in 2-butanone only microparticles were obtained. This behaviour was attributed to decreased transport of polymer molecules into the aqueous phase. Radwan, M. A., I. Y. Zaghloul, et al. (1999). "In vivo performance of parenteral theophylline-loaded polyisobutylcyanoacrylate nanoparticles in rats." European Journal of Pharmaceutical Sciences 8(2): 95-8. Theophylline-loaded polyisobutylcyanoacrylate (PICA) nanoparticles were prepared by emulsifier-free polymerization in aqueous media at ambient conditions. PICA nanoparticles were shown (in vitro) to be a promising controlled delivery system for theophylline. Therefore, this study was conducted to investigate the feasibility of PICA nanoparticles as a parenteral controlled drug delivery system in rats. Wistar rats were given intraperitoneal (i.p.) injections of theophylline solution (4 mg/kg) and theophylline nanospheres suspension (8 mg/kg) on two different occasions. Theophylline serum concentrations were measured by an HPLC assay. The drug solution was rapidly absorbed, distributed, and eliminated. The peak concentration (Cmax), 5.34+/-1.9 mg/l, was achieved 20 min following administration. The mean residence time was 2.94 h, and the apparent clearance was 0.31 (l/h)/kg. After nanospheres administration the mean Cmax, 2.53+/-1.1 mg/l, was attained at 3 h. The drug was successfully maintained around this elevated serum drug concentration up to 11 h in rats. The drug concentration was only reduced to 1.43+/-0.98 mg/l (i.e. reduced by 43.5%) after 20 h of administration. This present study provides evidence that the sorption of theophylline to PICA nanoparticles could control the drug release in rats. Raghuvanshi, R. S., O. Singh, et al. (2001). "Formulation and characterization of immunoreactive tetanus toxoid biodegradable polymer particles." Drug Delivery 8(2): 99-106. Poly lactide-co-glycolide and polylactide polymer particles entrapping immunoreactive tetanus toxoid (TT) were prepared with a view to developing a single shot controlled release vaccine formulation. Denaturation of TT by dichloromethane (DCM) during primary emulsification stage of particle formulation was minimized by incorporation of an optimal amount of rat serum albumin (RSA) in the internal aqueous phase. Incorporation of RSA as a stabilizer during the primary emulsification stage of polymer particle formulation protected the immunoreactivity of TT, enhanced its encapsulation efficiency and also led to uniform polymer particle formation. Use of sonication, both during primary and secondary emulsification processes, resulted in formation of nanoparticles whereas microparticles were formed when the secondary emulsion was carried out by homogenization. Immunoreactive TT particles made from different polymers incorporating stabilizers released antigen continuously for more than four months in vitro. Single injection of both type of particles encapsulating stabilized TT elicited anti-TT antibody titers in rats for more than five months, which was higher than that obtained with TT injected in saline. Anti-TT antibody titers in vivo were in accordance with the in vitro release characteristics of immunoreactive TT from the particles. Immune responses with hydrophobic polymer particles were better than those made using hydrophilic polymers. These results indicate the importance of protecting the immunoreactivity of TT during formation of polymer particles for sustained and improved antibody response. Raikher, Y. L., V. V. Rusakov, et al. (2001). "Dynamic susceptibilities of an assembly of dipolar particles in an elastic environment." Physical Review E. Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics 63(3 Pt 1): 031402. Theoretical model to describe magnetodynamics of a ferrogel, i.e., an assembly of ferromagnetic nanoparticles embedded in a gel, is proposed. The reorientations of the particles are determined by the influence of the elastic matrix and the rotational Brownian motion. Due to the interplay between these two factors, the main parameter characterizing the static magnetic susceptibility of the system is the ratio of the elastic modulus of the matrix times particle volume to the thermal energy. It is shown that the main components of the dynamic magneticsusceptibility tensor are determined by the combinations of the reference rates of several processes inherent to the system, namely, the elastic restoration of the particle orientation, Brownian rotary diffusion, and viscous relaxation of the particle angular momentum. In the framework of the model, absorption of the energy of an

alternating external field by a ferrogel is studied. With allowance for the ever present interaction of elastic and Brownian forces, the effective relaxation times for the longitudinal and transverse components of the ferrogel magnetization are evaluated. Rainov, N. G., C. Zimmer, et al. (1995). "Selective uptake of viral and monocrystalline particles delivered intra-arterially to experimental brain neoplasms." Human Gene Therapy 6(12): 1543-52. In this study we investigated the intra-arterial delivery of viral and nonviral particles to experimental brain tumors. A herpes simplex virus (HSV) vector and monocrystalline iron oxide nanoparticles (MION) were injected into the internal carotid artery of Fisher 344 rats harboring intracerebral 9L gliosarcomas, using bradykinin to disrupt the blood-tumor barrier. Brain and internal organs were stained both for virus-mediated gene expression and for iron. Quantitative comparisons of gene expression and MION uptake with and without blood-tumor barrier disruption were performed in the center and at the periphery of the tumor mass, as well as in normal brain. In addition, MION distribution was traced in vivo by MR imaging. Delivery of HSV into 9L gliosarcoma cells was greatly enhanced by intra-carotid bradykinin infusion. Virus-mediated expression of the HSV-thymidine kinase (TK) and beta-galactosidase gene products was highest at the tumor periphery as compared to the tumor center. Selective HSV infection of multiple tumor foci was achieved in both hemispheres without affecting normal brain. MION uptake was high at the tumor periphery even without blood-tumor barrier disruption. Bradykinin increased MION uptake predominantly in the center of the tumor with virtually no effect at the periphery. These findings show that selective blood-tumor barrier disruption by bradykinin can be used to enhance HSV-mediated gene delivery to tumor cells in the periphery of brain tumors. A crucial aspect in the treatment of malignant brain tumors is the eradication of tumor cells infiltrating the brain; bradykinin may facilitate access of vectors to these areas by selective disruption of their neovasculature. Rajaonarivony, M., C. Vauthier, et al. (1993). "Development of a new drug carrier made from alginate." Journal of Pharmaceutical Sciences 82(9): 912-7. A new approach for the preparation of nanoparticles is presented. The method is based on control of the gelification phenomenon of alginate by calcium ions, and it leads to small particles of a wide range of very welldefined sizes (250-850 nm) depending on the alignate concentration. The particles are formed in a sodium alginate solution by addition of calcium chloride and then poly-L-lysine. The concentrations of sodium alginate and of calcium chloride were lower than those required for gel formation and corresponded to the formation of a pregel state. The size of the particles formed is greatly dependent on the order of addition of calcium and poly-L-lysine to the sodium alginate solution. This phenomenon can be attributed to the difference in the nature of the interactions between calcium and alginate and between poly-L-lysine and alginate. Furthermore, the data indicate that the formation of the particles probably occurs during the addition of the first component to the sodium alginate solution. Evaluation of the drug-loading capacity was done with doxorubicin as a drug model. The results indicate that alginate nanoparticles are interesting carriers because the drug-loading capacity could be &gt; 50 mg of doxorubicin per 100 mg of alginate. Ramakrishnan, S. and C. F. Zukoski (2000). "Characterizing nanoparticle interactions: Linking models to experiments." Journal of Chemical Physics 113(3): 1237-48. Self-assembly of nanoparticles involves manipulating particle interactions such that attractions are on the order of the average thermal energy in the system. If the self-assembly is to result in an ordered packing, an understanding of their phase behavior is necessary. Here we test the ability of simple pair potentials to characterize the interactions and phase behavior of silico tungstic acid (STA), a 1.2 nm particle. The strength of interaction is controlled by dispersing STA in different background salt concentrations. The experimental variables used in characterizing the interactions are the osmotic compressibility (d Pi /d rho ), the second virial coefficient (B/sub 2/), relative solution viscosity ( eta / eta /sub c/), and the solubility ( rho sigma /sup 3/)/sub sat/. Various techniques are then developed to extract the parameters of square well, the adhesive hard sphere (AHS), and the Yukawa pair potentials that best describe the experimental data. The AHS model describes the solution thermodynamic behavior only where the system is weakly attractive but, as would be expected, fails when long range repulsions or nonmonotonic pair potentials become important. Model free representations are presented which offer the opportunity to extract pair potential parameters. (43 References). Ramge, P., J. Kreuter, et al. (1999). "Circadian phase-dependent antinociceptive reaction in mice determined by the hotplate test and the tail-flick test after intravenous injection of dalargin-loaded nanoparticles." Chronobiology International 16(6): 767-77. Peptides normally do not cross the blood-brain barrier (BBB). Previously, it has been shown that the hexapeptide enkephalin analogue dalargin with polysorbate-80-coated nanoparticles (DAL/NP) can be transported across the BBB and is able to exhibit an antinociceptive effect in mice. In the present study, the circadian time and dose dependencies of the antinociceptive effect of different dalargin preparations were investigated. The active preparation (DAL/NP, 5 mg/kg, 10 mg/kg), as well as a dalargin solution in phosphate buffered saline (DAL/SOL, 10 mg/kg) were injected intravenously to groups of 10-12 inbred DBA/2 mice at 12 different circadian times; mice

were synchronized to a light-dark (LD) 12:12 regimen. The antinociceptive effect was determined 15 minutes postinjection by the hot-plate test. Experiments with DAL/NP were repeated using the tail-flick test system at two selected times (08:00 and 20:00) to test for dose dependency (2.5, 5, 7.5, 10 mg/kg). Hot-plate latencies were rhythmic under baseline and after DAL/SOL, with acrophases in the dark phase; DAL/SOL did not influence latency time. In contrast, DAL/NP significantly increased reaction time dose dependently; the maximal possible effect was rhythmic with the 10 mg/kg preparation, with a peak effect in the early light phase. Results were confirmed by the tail-flick test. The experiments demonstrate that an enkephalin analogue coated with nanoparticles can easily cross the BBB and is able to display a dose- and time-dependent antinociceptive effect. Ramge, P., R. E. Unger, et al. (2000). "Polysorbate-80 coating enhances uptake of polybutylcyanoacrylate (PBCA)nanoparticles by human and bovine primary brain capillary endothelial cells." European Journal of Neuroscience 12(6): 1931-40. Certain drugs such as dalargin, loperamide or tubocurarine are not transported across the blood-brain barrier (BBB) and therefore exhibit no effects on the central nervous system. However, effects on the central nervous system can be observed when these drugs are loaded onto polybutylcyanoacrylate (PBCA)-nanoparticles and coated with polysorbate 80. The mechanism by which these complexed nanoparticles cross the BBB and exhibit their effects has not been elucidated. Cultured microvessel brain endothelial cells of human and bovine origin were used as an in vitro model for the BBB to gain further insight into the mechanism of uptake of nanoparticles. With cells from these species we were able to show that polysorbate 80-coated nanoparticles were taken up by brain endothelial cells much more rapidly and in significantly higher amounts (20-fold) than uncoated nanoparticles. The process of uptake was followed by fluorescence and confocal laser scanning microscopy. The results demonstrate that the nanoparticles are taken up by cells and that this uptake occurs via an endocytotic mechanism. Rand, S. C. (2000). "Size effect on the freezing temperature of lead particles." Journal of Materials Science Letters 19(21): 1893-5. A model, free of any adjustable parameters, for the size-dependent solidification of Pb nanoparticles is developed according to the classic nucleation theory and our model for the size-dependent melting. The model, supported by experimental evidence, is utilized to interpret the size-dependent freezing temperature of liquid and sizedependent undercooling. It is found that the freezing temperature and the solid-liquid interfacial energy are dependent on the size of the particles. As the nanoparticle size reaches a critical size, the melting temperature and freezing temperature are the same. (15 References). Rasa, L. V. M. and D. Bica (2000). "Magnetic nanoparticle properties and microstructure formation in liquid dispersions." IEEE 2(00TH8486): 495-8. The physical properties and microstructures of magnetite and cobalt ferrite nanoparticles, dispersed in liquid matrices, are studied. Qualitative and quantitative analyses of static magnetization curves were performed. Magneto-granulometric results were obtained and interactions and agglomerations were evidenced, as a function of the preparation techniques as well as carrier liquids and surfactants used. (15 References). Ray, J. C., R. K. Pati, et al. (2000). "Chemical synthesis and structural characterization of nanocrystalline powders of pure zirconia and yttria stabilized zirconia (YSZ)." Journal of the European Ceramic Society 20(9): 1289-95. Nanocrystals of pure zirconia and yttria stabilized zirconia (YSZ) are obtained by a simple chemical synthesis route using sucrose, polyvinyl alcohol (PVA) and metal nitrates. The reaction mixture on pyrolysis and calcination gives nanocrystals. These are characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD). The size of the nanocrystallites for pure zirconia is in the range of about 7.0-45.0 nm and for yttria stabilized zirconia, is in the range of about 5.0-24.0 nm at 200 degrees C and above, according to the preparative condition. At 200 degrees C, pure zirconia forms cubic phase and this cubic phase is stable up to 600 degrees C and then slowly transformed into monoclinic form. For yttria stabilized zirconia, the crystals are tetragonal in the temperature range from 200 to 1200 degrees C. (21 References). Redhead, H. M., S. S. Davis, et al. (2001). "Drug delivery in poly(lactide-co-glycolide) nanoparticles surface modified with poloxamer 407 and poloxamine 908: in vitro characterisation and in vivo evaluation." Journal of Control Release 70(3): 353-63. Poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles of 150-nm mean size were produced by an interfacial deposition method. The polar model drug Rose Bengal was successfully loaded into the nanoparticles during production and the surface of these particles was subsequently modified with poloxamer 407 and poloxamine 908 in order to create a steric stabilising layer of PEG on the surface. Drug loading was low (`1%) which can be attributed to the polar nature of the drug and the small size of the nanoparticles. Drug release was biphasic with 50% release measured within 30 min in serum. After intravenous injection in rats, the drug loaded nanoparticles substantially avoided capture by the Kupffer cells of the liver as compared to free drug. The half-life of Rose Bengal in the blood stream when administered in the nanoparticles was greatly extended with approximately 30%

remaining after 1 h as compared to only 8% of Rose Bengal left 5 min after administration in solution. These surface modified nanoparticles would have potential as carriers for drugs to specific sites within the body or for slow release of drug within the circulation. Reese, T., B. Bjelke, et al. (2000). "Regional brain activation by bicuculline visualized by functional magnetic resonance imaging. Time-resolved assessment of bicuculline-induced changes in local cerebral blood volume using an intravascular contrast agent." NMR in Biomedicine 13(1): 43-9. Functional magnetic resonance imaging (fMRI) has been applied to study rat focal brain activation induced by intravenous administration of the GABA(A) antagonist bicuculline. Using magnetite nanoparticles as a blood pool contrast agent, local changes in cerebral blood volume (CBV) were assessed with high temporal (10 s) and spatial (0.35 x 0.6 mm(2)) resolutions. Upon infusion of the bicuculline region-specific increases in CBV have been observed, suggesting CBV to reflect brain activity. During the first 2 min, the signal increases were predominant in the cortex, followed by increases in other brain areas, such as the caudate putamen, thalamus and cerebellum. Ten minutes after the start of infusion, a dominant response was observed in the thalamus, while in the caudate putamen a biphasic response pattern was seen. The magnitude of the signal responses in all brain regions was dependent on the dose of bicuculline and, in general, matched the known distribution of GABA(A) binding sites. This study suggests that pharmacological fMRI, displaying brain function at the highly specific level of drug-receptor interaction, should foster our understanding of normal and pathological brain function. Reetz, M. T., M. Winter, et al. (2001). "Size-selective electrochemical preparation of surfactant-stabilized Pd-, Ni- and Pt/Pd colloids." Chemistry 7(5): 1084-94. A detailed study concerning the size-selective electrochemical preparation of R4N+Br- -stabilized palladium colloids is presented. Such colloids are readily accessible using a simple electrolysis cell in which the sacrificial anode is a commercially available Pd sheet, the surfactant serving as the electrolyte and stabilizer. It is shown that such parameters as solvent polarity, current density, charge flow, distance between electrodes and temperature can be used to control the size of the Pd nanoparticles in the range 1.2-5 nm. Characterization of the Pd colloids has been performed using transmission electron microscopy (TEM), small angle X-ray scattering (SAXS) and X-ray powder diffractometry (XRD) evaluated by Debye-function-analysis (DFA). Possible mechanisms of particle growth are discussed. Experiments directed towards the size-selective electrochemical fabrication of (n-C6H13)4N+Br- -stabilized nickel colloids are likewise described. Finally, a new strategy for preparing bimetallic colloids (e.g., Pt/Pd nanoparticles) electrochemically is presented, based on the use of a preformed colloid (e.g., (n-C8H17)4N+Br- -stabilized Pt particles) and a sacrificial anode (e.g., Pd sheet). Reichert, J., A. Csaki, et al. (2000). "Chip-based optical detection of DNA hybridization by means of nanobead labeling." Analytical Chemistry 72(24): 6025-9. A new scheme for the detection of molecular interactions based on optical readout of nanoparticle labels has been developed. Capture DNA probes were arrayed on a glass chip and incubated with nanoparticle-labeled target DNA probes, containing a complementary sequence. Binding events were monitored by optical means, using reflected and transmitted light for the detection of surface-bound nanoparticles. Control experiments exclude significant influence of nonspecific binding on the observed contrast. Scanning force microscopy revealed the distribution of nanoparticles on the chip surface. Remsen, L. G., C. I. McCormick, et al. (1996). "MR of carcinoma-specific monoclonal antibody conjugated to monocrystalline iron oxide nanoparticles: the potential for noninvasive diagnosis." American Journal of Neuroradiology 17(3): 411-8. PURPOSE: To determine if tumor-specific monoclonal antibodies conjugated to superparamagnetic monocrystalline iron oxide nanoparticles can be used to yield specific diagnoses with the use of MR imaging. METHODS: Monoclonal antibodies conjugated to monocrystalline iron oxide nanoparticles were given to nude rats with intracranial tumors either by intravenous injection, intraarterial injection with osmotic blood-brain barrier disruption, or direct intratumoral inoculation. Either L6, a tumor-specific antibody, or P-1.17, a control isotypematched antibody, was used. Coronal T1-weighted, T2-weighted, and spoiled gradient-recalled acquisition in the steady state images were obtained before, 30 minutes after, 6 hours after, and 24 hours after injection. RESULTS: Intravenous injection of greater than 2 mg of the tumor-specific antibody showed a specific pattern of enhancement of the tumors with the largest concentration of antibody in the area with the greatest density of tumor cells. The control antibody showed nonspecific changes. After intraarterial injection with barrier disruption to increase delivery globally or direct inoculation to increase delivery focally, no specific enhancement pattern was seen. CONCLUSION: Monoclonal antibodies conjugated with monocrystalline iron oxide particles may provide a method to obtain specific diagnoses with the use of MR imaging. Requicha, A. A. G. (1999). "Nanoparticle patterns." Journal of Nanoparticle Research 1: 321-323. Resch, R., D. Lewis, et al. (2000). "Manipulation of gold nanoparticles in liquid environments using scanning force

microscopy." Ultramicroscopy 82(1-4): 135-9. Precise and controlled manipulation of individual gold nanoparticles (deposited on a Si/SiO2 surface) in liquid environments using the tip of a scanning force microscope is reported for the first time. Experiments were performed in deionized water and in ethanol as a prototype for an organic solvent. Analysis of the amplitude signal of the cantilever before and during manipulation reveals that the particles are pushed across the surface, similar to the manipulation of nanoparticles in air. Reszka, R., P. Beck, et al. (1997). "Body distribution of free, liposomal and nanoparticle-associated mitoxantrone in B16melanoma-bearing mice." Journal of Pharmacology and Expimental Therapeutics 280(1): 232-7. B16-melanoma-bearing mice were treated with four different formulations containing equivalent doses of the highly effective antineoplastic drug mitoxantrone. The formulations were: A mitoxantrone solution, a negatively charged liposome preparation (small unilamellar vesicles), a 14C-labeled polybutylcyanoacrylate- (PBCA) nanoparticle suspension, and a suspension of poloxamine 1508-coated 14C-PBCA-nanoparticles. After 1, 4 and 24 hr, three animals of each group were killed and the mitoxantrone concentrations in the blood, tumor, liver, spleen, heart and bone marrow were determined using an high performance liquid chromatography technique. Additionally, the concentrations of PBCA particles in the same tissues were measured by scintillation counting to compare the mitoxantrone distribution with the corresponding PBCA nanoparticle distribution. Each formulation led to a different body distribution profile of the drug. Liposomes drastically increased the blood level of mitoxantrone even after 24 hr, although free drug was cleared quickly. Liposomes also raised the concentration in the liver and spleen, but not the drug level in the tumor. PBCA-nanoparticles considerably increased the mitoxantrone concentrations in tumor, heart and spleen. However, the increase in tumor concentrations was not statistically significant due to the high variability. Nevertheless, the tumor growth was reduced significantly (P &lt; .05) compared to both, the liposome and the solution preparation. The nanoparticle polymer concentrations did not completely mirror those of the drug concentrations. Especially in the heart, where no nanoparticle polymer radioactivity was found, the particle concentration did not completely correspond to the mitoxantrone concentration, revealing that a part of the drug was lost from the particles. These pharmacokinetic results correspond to parallel therapeutic effects obtained with mitoxantrone-loaded nanoparticles and liposomes in the B16 melanoma. Rety, F., O. Clement, et al. (2000). "MR lymphography using iron oxide nanoparticles in rats: pharmacokinetics in the lymphatic system after intravenous injection." Journal of Magnetic Resonance Imaging 12(5): 734-9. The objective of the study was to quantify the kinetics of the superparamagnetic nanoparticle ferumoxtran (AMI 227, Sinerem(R), Combidex(R)) in the efferent lymph of the subdiaphragmatic lymph nodes and in various node groups of the rat to elucidate the uptake mechanism. The thoracic lymph duct was catheterized in 24 rats after an IV injection of 40 micromol Fe/kg ferumoxtran. Three rats were studied at several time points between 1.5 and 24 hours. At each time point, 0.3 ml of lymph were collected over 45 minutes. Lymph nodes were differentiated into five groups. The iron concentration in the samples and in plasma was measured by relaxometry at 0.47 T and atomic absorption spectrometry. Cytology was performed on the lymph. High concentrations of nanoparticles were found in the thoracic lymph soon after injection (90 minutes). No particle was found in the lymph cells, indicating that ferumoxtran was extracellular in the lymph fluid. The maximum concentration was reached later in all node groups, at 12 hours, and then plateaued. The transcapillary pathway and subsequent lymph drainage of the particles seem to play a major role in the delivery to the lymph nodes. Reynaud, C., O. Guillois, et al. (2001). "Optical properties of synthetic carbon nanoparticles as model of cosmic dust." Spectrochimica Acta A Molecular Biomolecular and Spectroscopy 57(4): 797-814. Carbon nanoparticles synthesised by laser pyrolysis of small hydrocarbons are deposited at low energy on a silicon substrate. Infrared spectroscopy of the as-formed films are studied as a function of the synthesis parameters and post-treatments, such as annealing and heavy ion irradiation. Correlation between infrared spectroscopy and multiscale organisation of the samples is made through transmission electron microscopy, including image analysis. Changes in infrared spectra are analysed in terms of the carbon network building. The relevance of the results to model the structure and spectroscopy of carbon dust in the carbon-rich circumstellar media is discussed. Ribeiro, S. J. L., Y. Messaddeq, et al. (2000). "Self-capacitance of a Thomas-Fermi nanosphere." Applied Physics Letters 77(23): 3797-9. We calculate the self-capacitance and charging energy of a spherical nanoparticle in the Thomas-Fermi approximation. The result is C/sub TF/=C/sub 0/1-p/sup -1/ tanh p/1-(1- epsilon /sup -1/)p/sup -1/ tanh p, with C/sub TF/>or=C/sub 0/. Here C/sub 0/=4 pi epsilon /sub 0/R is the classical geometrical value, p=R/l is the ratio of the particle radius R to the Thomas-Fermi screening length l, and epsilon is the material dielectric constant. The addition of surface localized states drives C toward C/sub 0/. These results should be relevant to tunneling spectroscopy studies of giant carbon onions and "large" semiconductor nanocrystals that do not require a full quantum treatment. (15 References).

Ridley, B. A., B. Nivi, et al. (2000). "Solution-processed inorganic transistors and sub-micron non-lithographic patterning using nanoparticle inks." Nanophase and Nanocomposite Materials III. Symposium 581: 115-20. Pyridine solutions of CdSe nanocrystals were solution-deposited in the fabrication of thin film transistors (TFTs). A peak mobility of 1 cm/sup 2/ V/sup -1/ s/sup -1/ and an ON/OFF ratio of 3*10/sup 4/ were observed for TFTs processed at 350 degrees C. The nanocrystals acted as a precursor to the bulk material, coalescing to form a semiconductor thin film when heated at plastic-compatible temperatures. Single crystalline regions several hundred times the size of the original semiconductor nanocrystals were observed for films processed at 350 degrees C. We also report a process for direct liquid phase deposition and patterning of nanoparticle inks at submicron resolutions by elastomeric embossing and AFM nanospotting. These results suggest that microelectronic devices produced from nanoparticle-based inks can enjoy the processing advantages usually associated with organic materials while retaining the performance advantages typically associated with inorganic materials. (19 References). Roan, J. R. (2001). "Attraction between nanoparticles induced by end-grafted homopolymers in good solvent." Physical Review Letters 86(6): 1027-30. The interactions between nanoparticles coated by end-grafted homopolymers of comparable size are studied using Edwards' self-consistent field (SCF) theory. The equilibrium monomer density distribution is obtained by solving the SCF equations in bispherical coordinates. It is shown that, because of the spherical geometry and redistribution of monomer density, end-grafted homopolymers in good solvent environment can induce attractive interactions. This result suggests that steric stabilization of nanoparticles requires new working principles and that the equilibrium distance between nanoparticles may be tuned by end-grafted polymers. Rodrigues, J. M., S. L. Croft, et al. (1994). "The activity and ultrastructural localization of primaquine-loaded poly (D,Llactide) nanoparticles in Leishmania donovani infected mice." Tropical Medicine and Parasitology 45(3): 223-8. The activity of primaquine (PQ) was compared to that of PQ-loaded Poly (D,L-Lactide) (PLA) nanoparticles against Leishmania donovani. The association of PQ with PLA nanoparticles increased the antileishmanial in vitro and in vivo effects of intravenously administered drug while its toxicity was reduced. The effectiveness of PQloaded PLA nanoparticles was 3.3 times as high as that of free drug in the suppression of amastigotes in the liver of BALB/c mice. A total dose of 30 mg PQ bound/kg (600 mg PLA/kg) was well tolerated and no sign of acute toxicity was observed. A similar dose of free drug resulted in 15% weight loss. No significant leishmanicidal activity was observed for unloaded PLA nanoparticles. Ultrastructural studies showed the uptake of drug-loaded nanoparticles by Leishmania-infected Kupffer cells. Nanoparticles were identified closed to amastigotes. Rodrigues, J. M., C. Bories, et al. (1995). "Development of an injectable formulation of albendazole and in vivo evaluation of its efficacy against Echinococcus multilocularis metacestode." International Journal of Parasitology 25(12): 1437-41. The loading of poly (D, L-lactide) nanoparticles with ABZ has led us to evaluate the potential of this new colloidal drug delivery system against E. multilocularis, using a murine model of hepatic alveolar echinococcosis. ABZloaded nanoparticles had a monodisperse size distribution between 100 and 150 nm. The efficiency of drug loading to nanoparticles was over 97%. In vitro, at an ABZ concentration of 1.0 microgram ml-1, the formulation had no toxicity for peritoneal macrophages harvested from uninfected mice. In vivo, the ABZ-loaded nanoparticles exhibited no signs of toxicity at any of the doses tested. Intravenous injections of 6 mg kg-1 of bound ABZ to infected mice had an equivalent antiparasitic effect on the metacestode growth to that of a treatment with 1500 mg kg-1 of orally administered free ABZ. The parasite hepatic superficial size as well as the peritoneal metastatic burden was significantly reduced by these 2 courses of treatment, as compared to those of untreated mice. Our results should encourage further study in order to explain the absence of dose-dependent efficacy of ABZ-loaded nanoparticles demonstrated in the present study. Rogers, J. A. (1982). "Recent developments in drug delivery." Canadian Journal of Hospital Pharmacy 35(6): 170-4, 196. Some recent innovative approaches to drug delivery have demonstrated that the administration of drugs can be more rigidly controlled with respect to the rate and amount of drug delivered to sites of action than from the conventional dosage forms. One category of controlled release referred to as programmed drug delivery primarily involves the application of polymers of defined specifications to release agents from either non-bioerodible membrane-controlled systems or bioerodible and non-bioerodible matrices. Also included here are the pro-drugs, inactive derivatives of drugs which are transformed into the active form in vivo but possess improved solubility, stability and disposition properties, yielding more efficient action and fewer side effects. Thus, exploitation of several routes of administration have resulted in products which are inserted ophtalmically, rectally or vaginally, implanted subcutaneously, taken orally or applied topically to achieve transdermal delivery of drugs to the systemic circulation. In several cases, release is designed to follow zero-order kinetics to achieve control of therapeutic plasma concentrations for prolonged time periods. Targeting of drugs by carrier is another form of controlled release technology. Normally administered intravenously, carriers such as liposomes, nanoparticles, microspheres, human cells and linear macromolecules are finding application in treating disease states with drugs

which previously were unavailable to treatment. Rolland, A., G. Merdrignac, et al. (1987). "Flow cytometric quantitative evaluation of phagocytosis by human mononuclear and polymorphonuclear cells using fluorescent nanoparticles." Journal of Immunological Methods 96(2): 185-93. The use of fluorescent polymethacrylic nanoparticles (0.3 micron) as a flow cytometric reagent in the quantitative evaluation of phagocytosis by human mononuclear and polymorphonuclear cells is described. The preparation of the nanoparticles, by emulsion copolymerization of methacrylic monomers, and their physicochemical properties are briefly summarized. Nanoparticles coupled with a fluorescent agent (ethidium bromide) were used in a flow cytometric assay to study opsonin-independent phagocytosis by human polymorphonuclear cells and by human monocytes. The phagocytosis of nanospheres by monocytes was determined by flow cytometry from the fluorescence distribution and ingestion was visualized by scanning and transmission electron microscopy. One possible application of the fluorescent nanoparticles is the simultaneous analysis of cell surface antigens and cell phagocytic activity. Rolland, A., B. Collet, et al. (1989). "Blood clearance and organ distribution of intravenously administered polymethacrylic nanoparticles in mice." Journal of Pharmaceutical Sciences 78(6): 481-4. Polymethacrylic nanospheres (mean diameter 0.25-0.30 microns), prepared by aqueous emulsion copolymerization, were developed as a new site-specific drug delivery system. The nanoparticles were labeled either with indium-111 or iodine-125, and after a single iv injection of labeled particles into mice, their blood clearance and organ distribution were analyzed. A rapid clearance of 111In-labeled nanoparticles from the blood circulation to the mononuclear phagocyte system (MPS) was visualized using external scintigraphic imaging. From 10 to 60 min, radioactivity measurements in blood and organs (liver, spleen, kidneys, lungs, heart) showed that the 125I-labeled nanospheres were rapidly removed from the bloodstream (distribution half-life approximately 3-5 min) and mainly deposited in the liver (60% of the administered dose, 10 min after administration). Up to 1 h, radioactivity in heart and lungs remained insignificant, while in the kidneys, radioactivity levels increased from 8 to 11%. Rollot, J. M., P. Couvreur, et al. (1986). "Physicochemical and morphological characterization of polyisobutyl cyanoacrylate nanocapsules." Journal of Pharmaceutical Sciences 75(4): 361-4. Two different polymerization mechanisms of alkyl cyanoacrylates were compared with regard to their morphological and physico-chemical characteristics. Cyanoacrylates were polymerized by simple emulsification into an aqueous medium or by interfacial polymerization in an o/w type emulsion. Suspensions of particles obtained by these two mechanisms show dramatic differences when studied for their turbidity, refractive index, and stability following centrifugation. These observations are consistent with the fact that nanoparticles obtained by emulsion polymerization are known to be formed by a full polymer core, while nanocapsules obtained by interfacial polymerization were thought to consist of an internal oil droplet surrounded by a polymeric wall. This theory was further confirmed by an electron microscopic examination of the internal structures of the two types of polymeric aggregates. Roman-Velazquez, C. E., C. Noguez, et al. (2000). "Optical characterization of a spheroidal nanoparticle on a substrate." Nanophase and Nanocomposite Materials III. Symposium 581: 485-90. With the help of a spectral formalism recently formulated, we study the effects in the optical response of the material properties of a nanoparticle lying over a substrate. A spectral representation was formulated to calculate the optical response of spheroidal nanoparticles including multipolar effects. We present our results in terms of Differential Reflectance spectra that can be compared directly with measurements. We have found that multipolar contributions depend in the shape of the particle and type of substrate. (14 References). Ropert, C., Z. Mishal, et al. (1996). "Retrovirus budding may constitute a port of entry for drug carriers." Biochimica et Biophysica Acta 1310(1): 53-9. This paper investigates the relation between viral infection and cell uptake of liposomes and nanoparticles. A defective virus was used to infect two types of cells: cells allowing virus budding (psi2neo cells) and cells bereft of a virus exit process (NIH 3T3 cells). This study has revealed that cell uptake of pH-sensitive-liposomes is highly dependent on the virus exit process, since it ensued only when virus budding occurred. This preferential uptake of pH-sensitive liposomes by infected cells was not carrier-specific because similar uptake was observed with nonbiodegradable fluorescent nanoparticles using confocal microscopy. Also, inhibition of neo gene expression by oligonucleotide pH-sensitive-liposomes was only observed in the cell system (psi2neo) endowed with a virus exit process. Finally, increased membrane fluidity was noted in the infected cells, possibly reflecting membrane perturbation due to virus budding. We suggest that this membrane perturbation may be the key to the uptake of the different colloidal carriers. Infected cells could, thus, constitute a natural target for particulate drug carriers. Rosen, B. R. and T. J. Brady (1993). "Future uses of MR imaging agents." Journal of Computer Assisted Tomography 17(Suppl 1(1)): S36-42.

Existing paramagnetic agents and novel superparamagnetic pharmaceuticals under development promise to advance substantially the frontiers of MR imaging. Used in conjunction with ultrafast MR techniques, such as echoplanar imaging and turboFLASH (fast low-angle shot), relaxivity agents (e.g., dysprosium, gadolinium), which alter T1 characteristics of tissue protons they act on, can be used to generate quantitative maps of dynamic blood-brain barrier permeability as well as regional hemodynamic profiles of diseased heart and other organs. In addition, the magnetic susceptibility (T2*)-altering effects of gadolinium can be exploited to map regional cerebral blood volume during task-activated and pathologic brain states. Magnetic susceptibility agents, such as monocrystalline iron oxide nanoparticles (MIONs), allow the advantages of scintigraphy to be joined with the high spatial resolution of MR imaging. Not only can these magnetopharmaceutical preparations serve as hemodynamic markers, they have already enabled function-specific imaging at the cellular level under diverse pathologic conditions. Roser, M., D. Fischer, et al. (1998). "Surface-modified biodegradable albumin nano- and microspheres. II: effect of surface charges on in vitro phagocytosis and biodistribution in rats." European Journal of Pharmaceutics and Biopharmaceutics 46(3): 255-63. The surface charges on biodegradable albumin nanoparticles were introduced by covalent coupling different primary amines to examine their influence on phagocytosis by macrophages under in vitro conditions. Albumin particles with a zeta potential close to zero showed a reduced phagocytic uptake in comparison with charged particles, especially nanoparticles with a positive zeta potential. The phagocytic uptake in the present study was examined using an established cell culture model based on primary mouse peritoneal macrophages and a human hematopoietic monocytic cell line (U-937) treated with phorbol-12-myristic-13-acetate to induce cell differentiation. The influence of opsonins on in vitro phagocytosis experiments was characterized using carriers pre-treated with human serum. In the presence of human serum the phagocytic activity of U-937 cells was found to be similar to primary mouse macrophages without serum. In contrast to peritoneal macrophages, U-937 cells showed no phagocytic activity in the absence of serum. In particular, only the C3b- complement deposition on the particle surface seems to promote the phagocytic process. The in vivo distribution of albumin carriers in rats was investigated using magnetic resonance imaging (MRI). No differences in blood circulation times and organ accumulation between different nanoparticle preparations with positive, neutral and negative surface charges could be observed in rats, suggesting that the in vivo fate of albumin nanoparticles is significantly influenced by factors not reflected in the in vitro cell culture models. Rosner, Y. X. a. D. E. (1999). "Prediction of spherule size in gas phase nanoparticle synthesis." Journal of Nanoparticle Research 1: 277-291. Rossler, B., J. Kreuter, et al. (1995). "Collagen microparticles: preparation and properties." Journal of Microencapsulation 12(1): 49-57. Collagen microparticles (CMPs) of diameters ranging from about 3 to 40 microns were prepared by the method of emulsifying and cross-linking native collagen. The particle size was mainly controlled by the molecular weight of the collagen used: an increase in denaturation of the collagen resulted in smaller particle sizes. Consequently, controlled denaturation is the best method to control the size of CMPs. Total denaturation results in the degradation product gelatin and subsequently yields very small nanoparticles with a minimum diameter of about 0.1 micron. Collagen microparticles can be used as carriers for lipophilic drugs e.g. retinol, tretinoin, or tetracaine and lidocaine in free base form. Another feature of the biodegradable CMPs is their thermal stability, thus their sterilization can be readily achieved. Rothlisberger, U., W. Andreoni, et al. (1994). "Structure of nanoscale silicon clusters." Physical Review Letters 72(5): 665668. Rousseau, V., B. Denizot, et al. (1997). "Investigation of blood-brain barrier permeability to magnetite-dextran nanoparticles (MD3) after osmotic disruption in rats." Magma 5(3): 213-22. The permeability of experimentally disrupted blood-brain barrier (BBB) to superparamagnetic nanoparticles (MD3) was studied in rats. BBB opening was induced by intracarotid injection of mannitol. One hundred eighty rats were used for the study. Rats were examined at two time points, 30 minutes and 12 hours after intracarotid mannitol injection. Different preparations intravenously injected 30 minutes before rat sacrifice were used for characterization of BBB disruption. BBB integrity was determined with 99mTc-diethylenetriamine pentaacetic acid (DTPA) and 99mTc-albumin. Iron oxide-glucose particles (12-nm mean diameter), 99mTc-labeled lecithincholesterol liposomes of three different sizes (50, 100, and 200 nm), and polyethylene glycol (PEG)-coated 99mTc liposomes (50 nm) were used for investigations of the dependence of BBB permeability on particle system size or surface. Magnetite-dextran nanoparticles (MD3) were evaluated as superparamagnetic contrast agent to monitor with magnetic resonance imaging (MRI) the BBB breakdown. In vitro T1 and T2 relaxation times of the brain tissue were measured at 40 MHz and 37 degrees C, and T2-weighted MR images were acquired at 0.5 T. After intracarotid mannitol infusion, as expected, the BBB breakdown was immediate and temporary as judged by

soluble molecule diffusion. MD3 nanoparticles crossed the BBB 12 hours after intravenous mannitol injection, at a time when brain permeability for molecules or small particles returns to normal. Magnetite crystals were found in cytoplasmic vesicles of glial cells. On MRI, signal intensity decreased after injection of MD3, even 12 hours after mannitol injection. This particularity could be useful in the study of focal pathological lesions accompanied by BBB permeability modifications. In such conditions, superparamagnetic particle contrast agents could be caught by the BBB, allowing the observation of impaired BBB areas without detectable cellular lesions. Rousseau, V., D. Pouliquen, et al. (1998). "NMR investigation of experimental chemical induced brain tumors in rats, potential of a superparamagnetic contrast agent (MD3) to improve diagnosis." Magma 6(1): 13-21. The different steps of development of chemically induced brain tumors were investigated in rats by MRI using a superparamagnetic contrast agent, magnetite-dextran nanoparticles (MD3). Sprague Dawley strain pregnant female rats were injected intravenously with ethylnitrosourea solution at the end of pregnancy. Offspring whelped by the inoculated mother were followed. MRI examinations were performed at 0.5 T. MD3 nanoparticles were injected intravenously at a dose of 5 mg Fe kg(-1) body weight 30 min before rat sacrifice. After sacrifice, histological slices were stained with hematoxylin-eosin. Relaxation times were measured at 40 MHz and 37 degrees C. MD3 nanoparticles act differently according to the step of the tumor development. Before tumor appearance, at a step characterized by the presence of abnormal cell clusters, relaxation time T2 increased significantly. The T2-weighted image showed a small increase in signal intensity in the lesion. Image contrast was improved by MD3 nanoparticles injection because of the decrease in healthy tissue signal intensity. The T1weighted image did not provide any additional information. In presence of a minute tumor, relaxation times decreased in tumor but increased in surrounding tissue. The T1-weighted image showed a hypersignal on the border of an hyposignal. T2-weighted image showed a hypersignal in the same area. Signal intensity was not modified after MD3 nanoparticles injection. When new vascular capillaries developed in the tumor, MD3 nanoparticles cross into the cerebral parenchyma. Transmission electron microscopy showed magnetite crystals in this specific area on cytoplasm vesicles of glial cells and in tumor-specific membrane arrangements. On T2weighted image, the hypersignal consisted of a well defined part and a second more fuzzy part, its signal being extinguished after MD3 nanoparticles injection. Necrotic areas and edema can be discriminated. The use of such a superparamagnetic contrast agent would be helpful in early detection of tumor development and in improving distinction of tumor mass from its vascular environment in patients. Rousseau, R. and D. Marx (2000). "Exploring the electronic structure of elemental lithium: from small molecules to nanoclusters, bulk metal, and surfaces." Chemistry 6(16): 2982-93. Clusters of lithium atoms ranging in size from Li4 to Li40 and bulk metallic solids, including surfaces, are investigated through first principles electronic structure calculations, which are based upon density functional theory and the electron localization function (ELF). It is found that large lithium ppi-type contributions in the electronic wavefunction cause the electrons to localize in interstitial regions, which leads to multicenter bonding for both the clusters and the solids, including their surfaces. For the smaller clusters these stabilizing ppi interactions also lead to short Li-Li interatomic distances, which in conjunction with the longer bonds induces &quot;distance alternation&quot; in the range from 2.45 A to 3.15 A. This consequence of the additional ppi interactions is absent in simple solids due to symmetry. The electronic structure of the clusters is topologically insensitive to deformations that do not affect their general shape, but changes significantly upon isomerization. The ramifications upon dynamic properties is that the clusters are quasi-rigid at low temperatures and retain their shape though the distance alternation pattern is suppressed. The picture which emerges for bonding in the bulk solid is that the metallic state arises from the presence of a large number of partially occupied multicenter bonds. For nanoscale clusters only the surface of these clusters exhibits strong localization, whereas their interiors display localization properties similar to the bulk metallic solid. On the other hand, localized states similar to those of the clusters (&quot;dangling bonds&quot;) are found on the (001) surface of body-centered cubic (bcc) and face-centered cubic (fcc) lithium solids. Rouzes, C., R. Gref, et al. (2000). "Surface modification of poly(lactic acid) nanospheres using hydrophobically modified dextrans as stabilizers in an o/w emulsion/evaporation technique." Journal of Biomedical Materials Research 50(4): 55765. Sterically stabilized biocompatible poly(lactic acid) (PLA) nanospheres were prepared by an o/w emulsion/evaporation technique, using hydrophobically modified dextrans (DexP) as the emulsion stabilizer. Photon correlation spectroscopy, zetametry, and differential scanning calorimetry studies corroborated that interfacial adhesion between immiscible dextran and PLA chains was achieved by compatibilization of polymer segments via hydrophobic groups grafted onto dextran and thus leading to the formation of entanglements between the hydrophobic dextran parts and the PLA matrix. The presence of dextran exposed at the particle surface was confirmed by X-ray photoelectron spectroscopy and by the fact that the suspensions showed an increased stability in concentrated NaCl solutions and a reduction of bovine serum albumin adsorption compared to uncoated PLA nanoparticles. A comparison of the characteristics of PLA nanospheres DexP-coated via the emulsion procedure (NS(em)) with those of PLA particles coated by DexP adsorption (NS(ad)) suggests that the

conformation of the polymer in the superficial layers may be different. However, both DexP layers behave similarly in terms of stability and protein adsorption. Roy, K., H. Q. Mao, et al. (1999). "Oral gene delivery with chitosan--DNA nanoparticles generates immunologic protection in a murine model of peanut allergy." Nature Medicine 5(4): 387-91. Food allergy is a common and often fatal disease with no effective treatment. We describe here a new immunoprophylactic strategy using oral allergen-gene immunization to modulate peanut antigen-induced murine anaphylactic responses. Oral administration of DNA nanoparticles synthesized by complexing plasmid DNA with chitosan, a natural biocompatible polysaccharide, resulted in transduced gene expression in the intestinal epithelium. Mice receiving nanoparticles containing a dominant peanut allergen gene (pCMVArah2) produced secretory IgA and serum IgG2a. Compared with non-immunized mice or mice treated with 'naked' DNA, mice immunized with nanoparticles showed a substantial reduction in allergen-induced anaphylaxis associated with reduced levels of IgE, plasma histamine and vascular leakage. These results demonstrate that oral allergen-gene immunization with chitosan-DNA nanoparticles is effective in modulating murine anaphylactic responses, and indicate its prophylactic utility in treating food allergy. Rudin, M., N. Beckmann, et al. (1997). "Analysis of tracer transit in rat brain after carotid artery and femoral vein administrations using linear system theory." Magn Reson Imaging 15(5): 551-8. Determination of tissue perfusion rates by MRI bolus tracking methods relies on the central volume principle which states that tissue blood flow is given by the tissue blood volume divided by the mean tracer transit time (MTT). Accurate determination of the MTT requires knowledge of the arterial input function which in MRI experiments is usually not known, especially when using small animals. The problem of unknown arterial input can be circumvented in animal experiments by directly injecting the contrast agent into a feeding artery of the tissue of interest. In the present article the passage of magnetite nanoparticles through the rat cerebral cortex is analyzed after injection into the internal carotid artery. The results are discussed in the framework of linear system theory using a one-compartment model for brain tissue and by using the well characterized gamma-variate function to describe the tissue concentration profile of the contrast agent. The results obtained from the intraarterial tracer administration experiments are then compared with the commonly used intra-venous injection of the contrast agent in order to estimate the contribution of the peripheral circulation to the MTT values in the latter case. The experiments were analyzed using a two-compartment model and the gamma-variate function. As an application perfusion rates in normal and ischemic cerebral cortex of hypertensive rats were estimated in a model of focal cerebral ischemia. The results indicate that peripheral circulation has a significant influence on the MTT values and thus on the perfusion rates, which cannot be neglected. Russell-Jones, G. J. (1998). "Use of vitamin B12 conjugates to deliver protein drugs by the oral route." Critical Reviews in Therapeutic Drug Carrier Systems 15(6): 557-86. The treatment of patients with most peptide and protein pharmaceuticals must currently be performed by injection, with the accompanying disadvantages of patient discomfort, increased medical costs, and reduced patient compliance. It would be much easier and more acceptable if these drugs could be given by the oral route. Unfortunately, this route cannot be used with most proteins and with peptides due to both the degradation of these molecules within the intestine and their poor uptake across the intestinal wall. In this review, an uptake system is described that potentially overcomes both these problems. This system relies upon the natural uptake mechanism for vitamin B12 to cotransport peptides and proteins linked to the vitamin B12 from the intestine to the circulation. In an exciting extension to this technology, it has been found that it is also possible to transport nanoparticles, linked to the vitamin B12, into the circulation. Such nanoparticles can potentially be loaded with peptides or proteins of choice, and so protect these molecules from degradation in the intestine, while simultaneously transporting them into the circulation. These findings are an important step in realizing the possibility of delivering almost all peptides and proteins via the oral route. Russell-Jones, G. J. and D. H. Alpers (1999). "Vitamin B12 transporters." Pharmaceutical Biotechnology 12(1): 493-520. The uptake of vitamin B12 from the intestine into the circulation is perhaps the most complex uptake mechanism of all the vitamins, involving no less than five separate VB12-binding molecules, receptors and transporters. Each molecule involved in uptake has a separate affinity and specificity for VB12 as well as a separate cell receptor. Thus VB12 is initially bound by haptocorrin in the stomach, then by IF in the small intestine. An IF receptor is then involved in uptake of the IF-VB12 complex by the intestinal epithelial cell, with the subsequent proteolytic release of VB12 and subsequent binding to TcII. The TcII receptor then transports the TcII-VB12 complex across the cell, whence it is released into the circulation. It is surprising, then, that despite its complexity, it has been possible to harness the vitamin VB12 uptake mechanism to enhance the oral uptake of peptides, proteins, and nanoparticles. Russell-Jones, G. J., H. Veitch, et al. (1999). "Lectin-mediated transport of nanoparticles across Caco-2 and OK cells." International Journal of Pharmacy 190(2): 165-74. Recent experiments by a number of workers have suggested that it may be possible to use various targeting

molecules, which bind to the intestinal epithelium, to promote the uptake and transport of nanoparticles from the intestine to the circulation. We have used commercial nanoparticles to examine the effect of size, density and inhibitors on uptake of lectin-coated nanoparticles by epithelial cells. The degree of uptake was most influenced by the density of lectin on the particle, with size and type of lectin being less important. Uptake could be inhibited by the presence of specific sugars or free lectin. These studies should provide a good basis for the design of targetable biodegradable drug-loadable particles suitable for oral delivery. Russell-Jones, G. J., L. Arthur, et al. (1999). "Vitamin B12-mediated transport of nanoparticles across Caco-2 cells." International Journal of Pharmacy 179(2): 247-55. Several studies have shown that Caco-2 cells have the capability to transport peptides and proteins from their apical to basal surfaces when these molecules are linked to vitamin B12 (VB12). In this study we have extended these studies and have shown that Caco-2 cells are also able to internalize and transport VB12-modifed nanoparticles from their apical to basal surfaces. Uptake and transport of nanoparticles was found to occur in both a VB12-dependent intrinsic factor (IF)-independent manner as well as in a VB12-dependent IF-dependent manner. Both IF-independent and IF-dependent VB12-mediated uptake and transport were dependent upon the surface density of VB12 as a reduction in surface modification of the nanoparticles with VB12 resulted in a reduced level of both VB12-mediated and IF-mediated uptake. At lower levels of VB12 modification there was no apparent non-IF-mediated uptake; however, VB12-IF-mediated uptake was still measurable. These studies show that Caco-2 cell cultures are a suitable model for the study of VB12-mediated uptake and transport of nanoparticles, and suggest that for effective oral uptake of VB12-coated nanoparticles high surface densities of VB12 are required.Copyright Russell-Jones, G. J. (2000). "Oral vaccine delivery." Journal of Controlled Release 65(1-2): 49-54. Oral vaccination of animals and man, to provide effective mucosal and/or systemic immunity, is largely ineffective. This is due mainly to the very small quantity of antigen that survives degradation in the intestine and that crosses the intestinal wall. Over the past decade or so, a number of proteins have been identified that are effective at eliciting mucosal and systemic immune responses following oral administration. Uptake of these molecules by the gastro-intestinal tract (GIT) epithelium is dependent upon specific binding to the GIT epithelial cells. The identity of these molecules is discussed, as well as their possible application as 'carriers' for co-transporting haptens, proteins and nanoparticles across the GIT epithelium. Ryu, J., Y. I. Jeong, et al. (2000). "Clonazepam release from core-shell type nanoparticles of poly(varepsiloncaprolactone)/poly(ethylene glycol)/poly(varepsilon-caprolactone) triblock copolymers." International Journal of Pharmacy 200(2): 231-42. The triblock copolymer based on poly(varepsilon-caprolactone) (PCL) as hydrophobic part and poly(ethylene glycol) (PEG) as hydrophilic one was synthesized and characterized. Core-shell type nanoparticles of poly(varepsilon-caprolactone)/poly(ethylene glycol)/poly(varepsilon-caprolactone) (CEC) block copolymer were prepared by a dialysis technique. According to the amphiphilic characters, CEC block copolymer can selfassociate at certain concentration and their critical association concentration (CAC) was determined by fluorescence probe technique. CAC value of the CEC-2 block copolymer was evaluated as 0.0030 g/l. CAC values of CEC block copolymer decreased with the increase of PCL chain length, i.e. the shorter the PCL chain length, the higher the CAC values. From the observation of transmission electron microscopy (TEM), the morphologies of CEC-2 core-shell type nanoparticles were spherical shapes. Particle size of CEC-2 nanoparticles was 32.3+/-17.3 nm as a monomodal and narrow distribution. Particle size, drug loading, and drug release rate of CEC-2 nanoparticles were changed by the initial solvents and the molecular weight of CEC. The degradation behavior of CEC-2 nanoparticles was observed by 1H NMR spectroscopy. It was suggested that clonazepam (CNZ) release kinetics were dominantly governed by diffusion mechanism. Saenger, J. F., K. Skeff Neto, et al. (1998). "Investigation of the anisotropy in frozen nickel ferrite ionic magnetic fluid using magnetic resonance." Journal of Magnetic Resonance 134(1): 180-3. Magnetic resonance is used to obtain the temperature dependence of the magnetic anisotropy of noninteracting NiFe2O4 nanoparticles from 100 to 250 K. The 10.3 nm particles are dispersed as a stable ionic magnetic fluid which is frozen under the action of an external field to perform angular variation measurements. The thermal fluctuation of the easy axis and magnetic moment about the direction of the external field is included in order to obtain the anisotropy from the angular dependence of the resonance field. Copyright 1998 Academic Press. Saez, A., M. Guzman, et al. (2000). "Freeze-drying of polycaprolactone and poly(D,L-lactic-glycolic) nanoparticles induce minor particle size changes affecting the oral pharmacokinetics of loaded drugs." European Journal of Pharmaceutics and Biopharmaceutics 50(3): 379-387. The present study was geared at identifying the conditions to stabilize poly (D,L-lactic-glycolic) (PLGA) and polycaprolactone (PCL) nanoparticles (NP) by freeze-drying with several cryoprotective agents. Differential scanning calorimetry and freeze-thawing studies were used to optimize the lyophilization process. These studies

showed that all samples were totally frozen at -45degreeC and evidenced the necessity of adding sucrose, glucose, trehalose or gelatine to preserve the properties of NP regardless of the freezing procedure. However, only 20% sucrose and 20% glucose exerted an acceptable lyoprotective effect on PLGA and PCL NP, respectively. Nonetheless, the final to initial size ratios (apprx1.5) indicated that particle size was slightly affected in both cases. In vivo studies with CyA-loaded PCL NP whose sizes matched those obtained after NP preparation (100 nm) and after being lyophilized (160 nm) showed that the changes of particle size might have some relevance on drug pharmacokinetics. The MRT was significantly (P < 0.05) modified after an oral CyA dose of 5 mg/kg and the treatment with 160-nm sized CyA-loaded NP produced a higher drug partition into the liver of Wistar rats potentially affecting the toxic and immunosuppressive profile of the drug. Therefore, although the particle size changes induced by NP lyophilization were slight, they need to be carefully evaluated and cannot be neglected. Sahli, H., J. Tapon-Bretaudiere, et al. (1997). "Interactions of poly(lactic acid) and poly(lactic acid-co-ethylene oxide) nanoparticles with the plasma factors of the coagulation system." Biomaterials 18(4): 281-8. When surfactant-stabilized biodegradable poly(lactic acid) (PLA) particles are injected into rats, the rate of clearance from blood is fast. The rate can be strongly reduced by using particles made from diblock copolymers of PLA and poly(ethylene oxide) (PLA-PEO), resulting in an increased duration of contact with the components of the coagulation system. Thus, possible adverse effects such as activation of the coagulation cascade could occur. In this paper, the interactions of surfactant-stabilized PLA and PLA-PEO nanoparticle suspensions with the plasma factors of the coagulation system are presented. PLA suspensions stabilized by sodium cholate (PLA-Ch) interact with thrombin, factor V and calcium ions. Formation of complexes and aggregates is induced by addition of calcium ions to PLA-Ch suspensions in the presence or in the absence of plasma. On the contrary, PLA-PEO suspensions are remarkably inert towards the coagulation factors and calcium ions, even when cholate is present. Steric repulsion owing to the high surface density of PEO is sufficient to avoid strong interations with the proteins and formation of aggregates between particles. Sakuma, S., R. Sudo, et al. (1999). "Mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal tract." International Journal of Pharmacy 177(2): 161-72. The mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal (GI) tract was investigated in rats. Radiolabeled nanoparticles were synthesized by adding hydrophobic 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine in the final process of nanoparticle preparation. The radioiodonated diazirine seemed to be incorporated in the hydrophobic polystyrene core of nanoparticles. The incorporation rate was less than 10%, irrespective of nanoparticle type. The diazirine incorporated in nanoparticles exhibited little leakage from them even though they were mixed with a solution corresponding to GI juice. The change in blood ionized calcium concentration after oral administration of salmon calcitonin (sCT) with nanoparticles showed that the in vivo enhancement of sCT absorption by radiolabeled nanoparticles was the same as that by non-labeled nanoparticles. The GI transit rates of nanoparticles having surface poly(Nisopropylacrylamide), poly(vinylamine) and poly(methacrylic acid) chains, which can improve sCT absorption, were slower than that of nanoparticles covered by poly(N-vinylacetamide), which does not enhance sCT absorption at all. These slow transit rates were probably the result of mucoadhesion of nanoparticles. The strength of mucoadhesion depended on the structure of the hydrophilic polymeric chains on the nanoparticle surface. The mucoadhesion of poly(N-isopropylacrylamide) nanoparticles, which most strongly enhanced sCT absorption, was stronger than that of ionic nanoparticles, and poly(N-vinylacetamide) nanoparticles probably did not adhere to the GI mucosa. These findings demonstrated that there is a good correlation between mucoadhesion and enhancement of sCT absorption. Sakuma, S., M. Hayashi, et al. (2001). "Design of nanoparticles composed of graft copolymers for oral peptide delivery." Advances in Drug Delivery Review 47(1): 21-37. The development of a dosage form that improves the absorption of peptide and protein drugs via the gastrointestinal tract is one of the greatest challenges in the pharmaceutical field. Many researchers have taken up the challenge, using approaches including mucoadhesive drug delivery, colon delivery, particulate drug delivery such as nanoparticles, microcapsules, liposomes, emulsions, micelles, and so on. The objective of this article is to provide the reader with outlines of novel nanoparticle technologies for oral peptide delivery based on polymer chemistry. The physicochemical properties of nanoparticles and their behavior on exposure to physiological media are greatly dominated by their chemical structures and surface characteristics. We will especially focus on the design of nanoparticles composed of novel graft copolymers having a hydrophobic backbone and hydrophilic branches as drug carriers. Salgueiro, A., M. A. Egea, et al. (1999). "An inductively coupled plasma method for determination of cyclophosphamide loaded to polymeric systems." Journal of Pharmaceutical and Biomedical Analysis 21(3): 611-8. A new method for the determination of cyclophosphamide content of polyalkylcyanoacrylate nanoparticles was developed. The analyses were carried out by inductively coupled plasma atomic emission spectrometry (ICP-

AES) by measuring the phosphorus content in the drug. The results obtained by this non-selective technique were compared with those given by high performance liquid chromatography (HPLC) a selective procedure that permits the detection of the cyclophosphamide molecule, and its degradation products. Sensitivity and reproducibility of both procedures were also determined. The ICP-AES method was demonstrated to be valid for sensitivity, precision, accuracy and specificity. In spite of ICP method is not a suitable procedure to analyze the degradation products of cyclophosphamide, the sensitivity of ICP is higher than chromatographic technique. Nevertheless, both procedures are appropriate for the determination of cyclophosphamide-loaded nanoparticles. Saltiel, C. and H. Giesche (2000). "Needs and opportunities for nanoparticle characterization." Journal of Nanoparticle Research 2: 325-326. Sanchez-Lopez, J. C. and A. Fernandez (2000). "TEM study of fractal scaling in nanoparticle agglomerates obtained by gas-phase condensation." Acta Materialia 48(14): 3761-71. The morphology of the nanoparticle agglomerates obtained during the gas-phase condensation method has been catalogued as fractal but no attempt has been made to determine their fractal dimension (D'). In the present study, we used transmission electron microscopy (TEM) to investigate the fractal character of such samples by processing two-dimensional TEM images. The area-perimeter method gives a fractal dimension of around 1.3, and its suitability to distinguish between nanocrystalline samples prepared under different experimental conditions or synthesised by different methods has been also demonstrated. The fractal dimension has been related to band-gap and surface area measurements for some selected examples. The advantages and limitations of the fractal technique applied to these systems are examined and discussed. (23 References). Sankar, S., A. E. Berkowitz, et al. (2000). "Spin-dependent transport of Co-SiO2 granular films approaching percolation." Physical Review B Condensed Matter 62(21): 14273-8. Spin-dependent transport in Co/sub x/(SiO/sub 2/)/sub 1-x/ granular films was investigated just below percolation (volume fraction x=0.38, 0.41, 0.46, and 0.50). Co-SiO/sub 2/ is an ideal system for investigating magnetic nanoparticle properties since the Co-SiO/sub 2/ interfaces are of high quality with no evidence of intermixing, and the saturation magnetization is consistent with bulk values. Transport in these films involves tunneling or hopping. The magnetoresistance is consistent with a spin polarization of 0.26 for the electrons tunneling across the CoSiO/sub 2/ interface, independent of metallic volume fraction and temperature. Ferromagnetic correlations among the Co nanoparticles are evident in the zero-field-cooled (ZFC) state of Co-SiO/sub 2/ granular films. For x=0.41, the correlation is among isolated particles of 40 AA diameter. For x=0.46 and 0.50, at room temperature, there is some ferromagnetic correlation due to dipolar fields from short chains of connected particles. In the ZFC state at 77 K for x=0.46 and 0.50, there are ferromagnetic correlations involving particles that are superparamagnetic at room temperature, similar to the correlation observed for x=0.41 at 77 K. (15 References). Santos, B. S., G. A. L. Pereira, et al. (2000). "Effect of size and surface modification on first hyperpolarizability of CdS nanoparticles." Conference Digest(00TH8504). Summary form only given. We measured the values of the first hyperpolarizability beta for aqueous suspensions of CdS nanoparticles by a hyper-Rayleigh scattering (HRS) technique. The samples consisted of nanoparticles with three types of surface: as-prepared (Cd/sup +2/-rich surface stabilized by polyphosphate), modified by OH/sup -/, and Pt-loaded. The samples were characterized by UV-visible absorption spectroscopy and by transmission electron microscopy (Carl Zeiss, TEM 902, 80 keV). The nanoparticle sizes were estimated from UV-visible absorption spectra using the well-established relationship between absorption and size for panicles in the quantum confinement regime. The beta values were determined from HRS measurements using a Q-switched Nd-YAG laser. The orientation averaged hyperpolarizability < beta /sup 2/> was determined from the intensity of the doubled frequency light by external and internal reference methods. (2 References). Santra, S., K. Wang, et al. (2001). "Development of novel dye-doped silica nanoparticles for biomarker application." Journal of Biomedical Optics 6(2): 160-6. We report the development of novel luminescent nanoparticles composed of inorganic luminescent dye, Tris(2,2'bipyridyl) dichlororuthenium (II) hexahydrate, doped inside a silica network. These dye doped silica (DDS) nanoparticles have been synthesized using a water-in-oil microemulsion technique in which controlled hydrolysis of the tetraethyl orthosilicate leads to the formation of monodispersed nanoparticles. They are prepared with a variety of sizes: small (5+/-1 nm), medium (63+/-4 nm), and large (400+/-10 nm), which shows the efficiency of the microemulsion technique for the synthesis of uniform nanoparticles. All these nanoparticles are suitable for biomarker application since they are much smaller than cellular dimension. These nanoparticles are highly photostable in comparison to most commonly used organic dyes. These nanoparticles have been characterized by various microscopic and spectroscopic techniques. The amount of dye content in these nanoparticles has been optimized to eliminate self-quenching. It has been observed that maximum luminescence intensity is achieved when the dye content is around 20 wt%. Silica surface of DDS nanoparticles is available for surface modification and bioconjunction. For demonstration as a biomarker, the DDS nanoparticle's surface has been

biochemically modified to attach membrane-anchoring groups and applied successfully to stain human leukemia cells. Sanz, N., P. L. Baldeck, et al. (2000). "Ultrafast electron dynamics in germanium nanoparticles." Conference Digest(00TH8504). We report on a detailed analysis of the ultrafast electron relaxation in Ge nanoparticles. The experiments have been performed on Ge nanocrystals with radii in the range 4-16 nm embedded in a dielectric material. Transient measurements were performed by pump-probe technique. The differential transmission spectra of nanoparticles at three pump energies are shown. The experimental results are described using a model based on Ge bulk band structure. (2 References). Sasaki, T. and N. Koshizaki (2000). "Preparation of metal oxide nanoparticles by laser ablation." Review of Laser Engineering 28(6): 348-53. Nanoparticles of metal oxides such as iron and cobalt oxides were prepared by pulsed laser ablation in Ar ambient at room temperature. The off-axis configuration of target and substrate greatly improved size distribution of the deposited nanoparticles. The morphology, crystallinity and oxidation states of the deposited nanoparticles and the nanoparticle-aggregated films were strongly dependent on the ablation pressure. The continuous and amorphous films consisting of the lower oxides such as FeO and CoO were deposited at lower pressure than 10 Pa. The formations of oxide nanoparticles of highly oxidized and crystallized phase such as Fe/sub 2/O/sub 3/ and Co/sub 3/O/sub 4/ were observed under the medium pressure range at around 100 Pa. The aggregates of nanoparticles were observed under higher pressure than 267 Pa. The size of the iron and cobalt oxide nanoparticles ranged from 2-9 nm and 2-4 nm, respectively. The basic ideas of growth mechanism are discussed. (32 References). Sasaki, S., K. Nakamura, et al. (2001). "Production of iron nanoparticles by laser irradiation in a simulation of lunar-like space weathering." Nature 410(6828): 555-7. 'Space weathering' is the term applied to the darkening and reddening of planetary surface materials with time, along with the changes to the depths of absorption bands in their optical spectra. It has been invoked to explain the mismatched spectra of lunar rocks and regolith, and between those of asteroids and meteorites. The formation of nanophase iron particles on regolith grains as a result of micrometeorite impacts or irradiation by the solar wind has been proposed as the main cause of the change in the optical properties. But laboratory simulations have not revealed the presence of these particles, although nano-second-pulse laser irradiation did reproduce the optical changes. Here we report observations by transmission electron microscopy of olivine samples subjected to pulse laser irradiation. We find within the amorphous vapour-deposited rims of olivine grains nanophase iron particles similar to those observed in the rims of space-weathered lunar regolith grains. Reduction by hydrogen atoms implanted by the solar wind is therefore not necessary to form the particles. Moreover, the results support the idea that ordinary chondrites came from S-type asteroids, and thereby provides some constraints on the surface exposure ages of those asteroids. Sastry, M. and K. S. Mayya (2000). "Metal nanoparticles grown in the nanostructured matrix of poly(octadecylsiloxane)." Langmuir 16(22): 8221-5. Metal nanoparticles grown within the nanostructured matrix of the amphiphilic polymer poly(octadecylsiloxane) (PODS) are investigated here by transmission electron microscopy. Due to its silanol groups and alkyl chain, PODS forms a bilayered nanostructure containing an intercalated layer of water within an aqueous environment, replacement of water molecules with metal ions within the siloxy bilayers, followed by reduction, results in the formation of metal nanoparticles. The increase in electron density upon nanoparticle formation permits direct visualization of these bilayers, as well as the individual nanoparticles residing within them. These nanoparticles measure about 1-2 nm in diameter and possess a relatively narrow size distribution due presumably to volume availability within the ordered bilayers of PODS. (15 References). Sastry, M., A. Gole, et al. (2000). "Formation of patterned, heterocolloidal nanoparticle thin films." Langmuir 16(7): 3553-6. It is shown that spatially defined, patterned multicomponent colloidal particle films can be grown by a simple procedure based on blocking electrostatically driven diffusion pathways of charged colloidal particles into ionizable lipid films. The diffusion into the films appears to be normal to the film surface (i.e., little lateral diffusion within the plane of the film), and once complete cluster incorporation has been achieved, exchange of clusters with other clusters during immersion in different colloidal solutions does not occur. This result is important and indicates that seamless, multicolloidal particle films can be deposited in this fashion and can be used in the growth of multicomponent polyelectrolyte films as well. (13 References). Sastry, M. and K. S. Mayya (2000). "Hetero-colloidal metal particle multilayer films grown using electrostatic interactions at the airwater interface." Journal of Nanoparticle Research 2: 183-190.

Sbarbati, A., A. Reggiani, et al. (2000). "Regional cerebral blood volume mapping after ischemic lesions." Neuroimage 12(4): 418-24. The possible persistence of a microvascular deficit at long time intervals after cerebral ischemia induction is not well established. In rats, we have generated in vivo maps of the regional cerebral blood volume (rCBV) at different time intervals after middle cerebral artery occlusion (MCAo) with the aim to evaluate the persistence of a rCBV deficit in the damaged area or in the surrounding regions. The rats were examined by magnetic resonance imaging (MRI) at different time intervals, starting from the first day until three months after ischemia and postmortem histological and ultrastructural correlation was obtained. All MRI experiments were carried out using an imager-spectrometer equipped with a 4.7 Tesla magnet. To produce the susceptibility-weighted rCBV images, a suspension of superparamagnetic iron oxide nanoparticles (AMI-25) was injected to the rat. In a control group (nonoperated or sham-operated rats), a symmetrical distribution of rCBV values was found between the two hemispheres (differences between left and right cortex below 8%). In the rats with MCAo an evident vascular asymmetry was found 24 h after ischemia (differences between left and right ranging from 22 and 77%) and reduced rCBV values were evident in the ischemic areas. In a time range following the 15th day most of the rats showed a complete recovery of the lesion while only four animals still had a small residual lesion, as probed by T2-weighted (T2W) images. In three of these four cases, the reduction of rCBV in the ipsilateral cortex with respect to the contralateral was greater than 20%. Correlation was found (Y &gt; 0.8) between late rCBV measurement and the initial volume of the lesion (hyperintense region in T2W images). The postmortem measurements correlate much better with the rCBV data than with the T2W ones. In conclusion, the present work demonstrates that cortical lesions may result in a deficit of rCBV for long periods and that a mismatch between T2w and rCBV data can be present during the repair process. Scarlett, B. (2000). "Standardization of nanoparticle measurements." Journal of Nanoparticle Research 2: 1-2. Schaertl, S., F.-J. Meyer-Almes, et al. (2000). "A novel and robust homogeneous fluorescence-based assay using nanoparticles for pharmaceutical screening and diagnostics." Journal of Biomolecular Screening. [ print] 5(4): 227-237. We have established a new type of homogeneous immunoassay based on nanoparticles (nanoparticle immunoassay, or NPIA) being analyzed using fluorescence intensity distribution analysis (FIDA). This method allows the characterization of single fluorescently labeled molecules or particles with respect to their molecular brightness and concentration. Upon binding of conjugates to molecules coupled to the nanoparticle surface, the brightness of the complex scales with the number of bound conjugates. The complexes can then be distinguished accurately from free conjugate and concentrations of free and bound molecules can be determined reliably. In this study we present various examples of NPIAs where capture antibodies were linked to the nanoparticles, which were either artificial beads or bacteria. Two assay formats have been developed; first, direct labeling of the conjugate was used to quantitate free antigen through competition experiments, and second, an antigen-directed antibody was labeled to establish an assay similar to a sandwich ELISA setup. The major advantages of a NPIA are the robustness and high signal-to-noise ratio at short measurement times, as demonstrated with a miniaturized experiment in a NanocarrierTM holding a volume of 1 mul/well. In addition to the good data quality, NPIAs are straightforward to perform because they require no washing steps. NPIAs open new dimensions for high throughput pharmaceutical screening and diagnostics. Assay development times can be reduced significantly because of a simple toolbox principle that is applicable to most types of assays. Schaertl, S., F. J. Meyer-Almes, et al. (2000). "A novel and robust homogeneous fluorescence-based assay using nanoparticles for pharmaceutical screening and diagnostics." Journal of Biomolecular Screening 5(4): 227-38. We have established a new type of homogeneous immunoassay based on nanoparticles (nanoparticle immunoassay, or NPIA) being analyzed using fluorescence intensity distribution analysis (FIDA). This method allows the characterization of single fluorescently labeled molecules or particles with respect to their molecular brightness and concentration. Upon binding of conjugates to molecules coupled to the nanoparticle surface, the brightness of the complex scales with the number of bound conjugates. The complexes can then be distinguished accurately from free conjugate and concentrations of free and bound molecules can be determined reliably. In this study we present various examples of NPIAs where capture antibodies were linked to the nanoparticles, which were either artificial beads or bacteria. Two assay formats have been developed; first, direct labeling of the conjugate was used to quantitate free antigen through competition experiments, and second, an antigen-directed antibody was labeled to establish an assay similar to a sandwich ELISA setup. The major advantages of a NPIA are the robustness and high signal-to-noise ratio at short measurement times, as demonstrated with a miniaturized experiment in a Nanocarriertrade mark holding a volume of 1 microl/well. In addition to the good data quality, NPIAs are straightforward to perform because they require no washing steps. NPIAs open new dimensions for high throughput pharmaceutical screening and diagnostics. Assay development times can be reduced significantly because of a simple toolbox principle that is applicable to most types of assays. Schafer, V., H. von Briesen, et al. (1992). "Phagocytosis of nanoparticles by human immunodeficiency virus (HIV)-infected macrophages: a possibility for antiviral drug targeting." Pharmacetical Research 9(4): 541-6.

Human monocytes/macrophages (MO/MAC) were isolated from peripheral blood and cultivated on hydrophobic Teflon membranes. This culture system is suitable for HIV infection of MO/MAC in vitro. After transfer into 24-well plates the mature macrophages (infected or uninfected) were used for measurements of phagocytosis. The uptake of different, radioactively labeled nanoparticles (NP) made of polyalkylcyanoacrylate, polymethylmethacrylate (PMMA), and human serum albumin (HSA) by the macrophages was determined. In addition, the influence on phagocytosis of size and composition, concentration, and surface of the NP was studied. Further, macrophages of different state of activation were tested. NP made of polyhexylcyanoacrylate (PHCA) or human serum albumin with a diameter of about 200 nm were found most useful for targeting antiviral substances such as azidotymidine to macrophages. Cells infected in vitro with HIV-1D117/III, a monocytotropic HIV isolate from a perinatally infected child, possessed an even higher phagocytotic activity than noninfected cells. Macrophages isolated from HIV-infected patients also showed good incorporation of NP. Thus, the concept of a specific targeting of antiviral substances to macrophages in HIV-infected individuals appears quite promising. Schafer, V., H. von Briesen, et al. (1994). "Phagocytosis and degradation of human serum albumin microspheres and nanoparticles in human macrophages." Journal of Microencapsulation 11(3): 261-9. Nanoparticles and microspheres made from human serum albumin are biodegradable and, as a physiological material, less cytocidal than cyanoacrylates. Therefore, they should be a suitable carrier system for targeting drugs into cells of the mononuclear phagocyte system. Nevertheless, the process of phagocytic uptake and degradation of albumin particles by macrophages has so far not been documented in detail. For this reason the presented electron microscopical investigation was performed. To study both cellular particle uptake and intracellular degradation, human monocytes were isolated from the peripheral blood of healthy donors and cultivated in plastic plates. After maturation to macrophages, the cells were incubated with the particles for 2h, then washed with buffer and further cultivated for 1-7 days. After fixing with glutaraldehyde, the cells were prepared for electron microscopy. The process of incorporation was demonstrated to be phagocytosis, by scanning and transmission electron microscopy. The degradation of the microspheres was followed by transmission electron microscopy. The metabolism started some hours after particle uptake. After 3 days the process was almost terminated. After 7 days of cultivation only small numbers of intact microspheres were found in the cytoplasm. Scheffler, K., E. Seifritz, et al. (1999). "Titration of the BOLD effect: separation and quantitation of blood volume and oxygenation changes in the human cerebral cortex during neuronal activation and ferumoxide infusion." Magn Reson Med 42(5): 829-36. Most functional magnetic resonance imaging (fMRI) techniques are sensitive to susceptibility variations and rely on the change in blood oxygenation level in response to neuronal activation (BOLD). The BOLD effect is accompanied by a change in cerebral blood flow (rCBF) and cerebral blood volume (rCBV). Intravascular contrast agents, such as magnetite nanoparticles, can be used to measure changes in rCBV. A new measuring protocol has been developed that enables the separate quantification of changes in blood volume and oxygenation levels. A combination of alternating acoustic stimulation blocks and infusion of a superparamagnetic contrast agent offers the possibility to disentangle the competing influences of oxygenation and blood volume changes. Serial blood sampling during infusion was used to assess the actual contrast agent concentration during infusion in order to calculate absolute blood volume changes during neuronal resting and activation states. Magn Reson Med 42:829836, 1999. Scherer, D., F. C. Mooren, et al. (1993). "In vitro permeability of PBCA nanoparticles through porcine small intestine." Journal of Drug Targeting 1(1): 21-7. Peroral nanoparticle-mediated drug absorption was studied using a laser scanning confocal microscope. Additional diffusion studies in side-by-side diffusion cells with radiolabelled polybutylcyanoacrylate (PBCA) nanoparticles were carried out to confirm the results of this study. Fluorescence-labelled PBCA nanoparticles were incubated in vitro in the lumen of freshly excised intestine. Computer-aided optical sectioning of thick samples with dramatically improved resolution and the possibility of rejecting out-of-focus noise enabled tracking of the fluorescence-labelled PBCA nanoparticles in the intestinal tissue after incubation of the particles in freshly excised porcine small intestine. The results of this study suggest that the nanoparticles are absorbed by the surface of the gut wall, creating a high concentration gradient, thereby enhancing the absorption of drugs that may be loaded to the nanoparticles. A significant amount of particles was found in hot (very fluorescent) spots that were assumed to be Peyer's patches. No particles, however, traversed the entire gut wall over a period of 2 to 4 h. These results were confirmed by the diffusion study. No radioactivity permeated through Peyer's-patch-free intestine within 4 h, whereas the amount of radioactivity that was transported through intestine with Peyer's patches during this time was 1.1% of the total amount in the donor chamber. Schild, A., A. Gutsch, et al. (1999). "Simulation of nanoparticle production in premixed aerosol flow reactors by interfacing fluid mechanics and particle dynamics." Journal of Nanoparticle Research 1: 305-315.

Schmidt, C. and R. Bodmeier (1999). "Incorporation of polymeric nanoparticles into solid dosage forms." Journal of Controlled Release 57(2): 115-25. Besides parenteral delivery, polymeric nanoparticles have been used for oral drug delivery. In this study, model polymeric nanoparticles (aqueous colloidal polymer dispersions: Eudragit(R) RL 30D, L 30D, NE 30D, or Aquacoat(R)) with different physicochemical properties were incorporated into various solid dosage forms (granules, tablets, pellets or films). The compatibility of the nanoparticles with commonly used tabletting excipients and the redispersibility of the nanoparticles after contact of the solid dosage forms with aqueous media were investigated. Ideally, the nanoparticles should be released from the solid dosage forms with their original properties. The addition of polymeric binders (e.g. polyvinylpyrrolidone, Na carboxymethylcellulose or hydroxypropyl methylcellulose) to the aqueous nanoparticle dispersions prior to wet granulation resulted in phase separation (depletion or bridging flocculation) for many nanoparticle/binder systems. Two critical parameters for the complete redispersibility/release of the nanoparticles with the original particle size properties from the solid dosage forms were a (1) high minimum film formation temperature (MFT) of the polymer dispersion and (2) a good wettability of the dried polymeric nanoparticles. Nanoparticle dispersions with a low MFT were not redispersible, they coalesced into larger agglomerates/films during the drying step. Contact angle measurements correlated well with the redispersibility of the nanoparticles, with ethylcellulose particles having high contact angles and poor redispersibility and Eudragit(R) RL, a polymer stabilized with quaternary ammonium groups, having low contact angles and good redispersibility. Schmidt, J., C. Guesdon, et al. (1999). "Engineering aspects of preparation of nanocrystalline particles in microemulsions." Journal of Nanoparticle Research 1: 267-276. Schmidt, H. K. and M. Mennig (2000). "Electrochromism of highly doped nanocrystalline SnO2:Sb." Journal of Physical Chemistry B 104(40): 9388-95. The electrochromic effect of layers of nanocrystalline tin dioxide highly doped with antimony has been investigated in detail, using chronoamperometry, cyclic voltammetry, potential-dependent IR spectroscopy and UV-vis spectroscopy. It is shown that two different mechanisms are responsible for the color changes observed upon negative polarization of porous SnO/sub 2/:Sb nanocrystal layers. Injection of electrons via the back contact increases the plasma absorption of the material, which has its maximum intensity in the near-infrared region. This increase is accompanied by a strong increase of the electrical conductivity of the layer, indicating that the grain boundary potentials of the nanoparticle layer decrease at negative potentials applied. In the presence of small ions such as Li/sup +/ or in protic electrolytes such as water, insertion of Li/sup +/ and H/sup +/ takes place, resulting in an additional color change mainly in the visible. The rate of the color changes is mainly determined by the conductivity of the substrate. Very fast coloration and decoloration is observed (t/sub 1/2/<10 ms) if the particle layer is deposited onto highly conductive substrates such as platinum. (37 References). Schneider, B. H., E. L. Dickinson, et al. (2000). "Highly sensitive optical chip immunoassays in human serum." Biosensensors and Bioelectronics 15(1-2): 13-22. Over the past decade the ability of refractometric optical sensors to quantitatively measure a wide range of biomolecules has been demonstrated. These include proteins, nucleic acids, microorganisms, and in competitive formats small molecules such as drugs and pesticides. Furthermore, by using high refractive index nanoparticles to amplify the biomolecular binding signal, sensitivities approaching those of well established diagnostic assays have been achieved. However, to date it has not been possible to show rapid detection of analytes in complex bodily fluids such as serum, in a one-step procedure, due to the interference resulting from non-specific binding (NSB) to the sensor surface. We have carried out preliminary work on the control of interference due to NSB using an optical chip based on the Hartman interferometer. This interferometer configuration employs a reference sensing region that can be functionalized separately from the specific sensing region. Optical chips were stored dry after surface functionalization, and rehydrated in serum. The observed level of background drift in serum was reduced by an order of magnitude when an exposed reference was used, compared to a reference which was blind to the sample. An additional 70% reduction in signal drift in serum was achieved by controlling the surface chemistry of the optical chip using a biotin-poly(ethylene glycol) (PEG) blocking agent. This functionalization procedure was combined with a sandwich assay using gold nanoparticles to develop a one-step assay for human chorionic gonadotropin (hCG) in human serum with a detection limit of 0.1 ng/ml for a 35 min assay. Schneider, B. H., E. L. Dickinson, et al. (2000). "Optical chip immunoassay for hCG in human whole blood." Biosensensors and Bioelectronics 15(11-12): 597-604. We report on the development of an integrated optic chip sensor for performing rapid and sensitive immunoassays with human whole blood using human chorionic gonadotropin (hCG) as the model system. The optical chip is based on the Hartman interferometer, which uses a single planar lightbeam to address multiple interferometers, each comprising a signal/reference pair of sensing regions. The binding of antigen to specific capture antibodies on the signal sensing region causes a change in the refractive index of the surface layer, which is detectable by its effect on the evanescent field of the guided lightbeam. The reference-sensing region is

coated with an irrelevant antibody, which optically cancels a large fraction of the non-specific adsorption that occurs on the specific-sensing region when the sensor is tested with clinical specimens. This work extends previous experiments with buffer and human serum to measurements in undiluted whole human blood. Optical chips were stored dry after surface functionalization, and rehydrated with blood. Colloidal gold nanoparticles conjugated to a second anti-hCG monoclonal antibody were used to provide signal amplification, thereby enhancing assay sensitivity, in a one-step procedure with the gold conjugate added to the test sample immediately prior to measurement. Background signals due to non-specific binding (NSB) in blood were found to be higher than those previously reported with human serum. In addition, a high level of background signal was found with the gold conjugate, which had not been observed in experiments with either buffer or serum. Nevertheless, hCG could be detected at 0.5 ng/ml within 10 min of sample application. The sensor response was linear over the concentration range 0.5-5 ng/ml hCG, as compared with the clinically-relevant range 0.3-1.5 ng/ml. Detection at higher concentrations was affected by scattering from large amounts of bound gold nanoparticles. However, initial binding rate measurements could be used to maintain assay quantitation. Schneider, J. J., N. Czap, et al. (2000). "Metallorganic routes to nanoscale iron and titanium oxide particles encapsulated in mesoporous alumina: formation, physical properties, and chemical reactivity." Chemistry 6(23): 4305-21. Iron and titanium oxide nanoparticles have been synthesized in parallel mesopores of alumina by a novel organometallic &quot;chimie douce&quot; approach that uses bis(toluene)iron(0) (1) and bis(toluene)titanium(0) (2) as precursors. These complexes are molecular sources of iron and titanium in a zerovalent atomic state. In the case of 1, core shell iron/iron oxide particles with a strong magnetic coupling between both components, as revealed by magnetic measurements, are formed. Mossbauer data reveal superparamagnetic particle behavior with a distinct particle size distribution that confirms the magnetic measurements. The dependence of the Mossbauer spectra on temperature and particle size is explained by the influence of superparamagnetic relaxation effects. The coexistence of a paramagnetic doublet and a magnetically split component in the spectra is further explained by a distribution in particle size. From Mossbauer parameters the oxide phase can be identified as low-crystallinity ferrihydrite oxide. In agreement with quantum size effects observed in UV-visible studies, TEM measurements determine the size of the particles in the range 5-8 nm. The particles are mainly arranged alongside the pore walls of the alumina template. TiO2 nanoparticles are formed by depositing 2 in mesoporous alumina template. This produces metallic Ti, which is subsequently oxidized to TiO2 (anatase) within the alumina pores. UV-visible studies show a strong quantum confinement effect for these particles. From UVvisible investigations the particle size is determined to be around 2 nm. XPS analysis of the iron- and titaniaembedded nanoparticles reveal the presence of Fe2O3 and TiO2 according to experimental binding energies and the experimental line shapes. Ti4+ and Fe3+ are the only oxidation states of the particles which can be determined by this technique. Hydrogen reduction of the iron/iron-oxide nanoparticles at 500 degrees C under flowing H2/N2 produces a catalyst, which is active towards formation of carbon nanotubes by a CVD process. Depending on the reaction conditions, the formation of smaller carbon nanotubes inside the interior of larger carbon nanotubes within the alumina pores can be achieved. This behavior can be understood by means of selectively turning on and off the iron catalyst by adjusting the flow rate of the gaseous carbon precursor in the CVD process. Schoeler, N., E. Zimmermann, et al. (2000). "Preserved solid lipid nanoparticles (SLN) at low concentrations do cause neither direct nor indirect cytotoxic effects in peritoneal macrophages." International Journal of Pharmaceutics 196(2): 235-239. In order to investigate the interaction of preserved solid lipid nanoparticles (SLN) with murine peritoneal macrophages (Mvariant phi), cytotoxicity and proinflammatory effects of two different solid lipid nanoparticles (SLN) preparations consisting of either compritol (CO) or cetyl palmitate (CP) preserved with thiomersal were analyzed. Concentration-dependent cytotoxic effects were observed using the 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyl-tetra-zolium bromide (MTT) assay. Secretion of interleukin-6 by Mvariant phi following incubation with CO and CP SLN did not differ from secretion by untreated cells; proinflammatory cytokines interleukin-12 and tumor-necrosis-factor-alpha as further indicators of immunomodulatory effects were not detectable. These findings paralleled our previous findings that unpreserved CO and CP SLN did not induce immunomodulatory effects but cytotoxicity at higher concentrations. There were no synergistic cytotoxic effects of preservative and SLN. Thus, preservation of SLN using thiomersal does not appear to cause increased cytotoxicity and immunomodulatory effects following incubation with Mvariant phi. Scholer, N., E. Zimmermann, et al. (2000). "Effect of solid lipid nanoparticles (SLN) on cytokine production and the viability of murine peritoneal macrophages." Journal of Microencapsulation 17(5): 639-50. The purpose of this study was to investigate possible immunomodulatory and cytotoxic effects of solid lipid nanoparticles (SLN) on murine peritoneal macrophages. Immunomodulatory effects of SLN composed of either a lipid- (glycerol-behenate) or a wax (cetylpalmitate) matrix stabilized by the surfactant Poloxamer 188 were analysed by detection of proinflammatory and down-regulatory cytokines in supernatants of thioglycollate-elicited peritoneal macrophages using enzyme-linked immunosorbent assay (ELISA). Cytotoxicity of SLN was assessed

using the ITT test. Incubation of macrophages with either SLN at low concentrations did not increase production of interleukin (IL)-6, IL-12, and tumour necrosis factor (TNF)-alpha. At higher SLN concentrations, a concentration-dependent decrease in IL-6 secretion was observed compared to background production of IL-6 by untreated macrophages. IL-12 and TNF-alpha production was neither detected in supernatants of macrophages treated with SLN at any concentration nor in those of untreated cells. The decrease in IL-6 secretion was paralleled by concentration-dependent cytotoxicity of SLN on these cells. In contrast, incubation with polystyrene reference particles neither resulted in decreased IL-6 production nor in a loss of viability. SLN-treated macrophages were found to up-regulate their cytokine production following stimulation with Pansorbin, despite the concentration-dependent cytotoxicity induced by SLN. Down-regulatory effects on SLN-treated macrophages by IL-10 were not observed. In conclusion, incubation of SLN with murine peritoneal macrophages did not induce the production of proinflammatory and down-regulatory cytokines. At high concentrations of SLN, cytotoxic effects on these cells were observed. Cytotoxicity appears to be the main cause of decreased cytokine production by these cells. Scholer, N., E. Zimmermann, et al. (2000). "Preserved solid lipid nanoparticles (SLN) at low concentrations do cause neither direct nor indirect cytotoxic effects in peritoneal macrophages." International Journal of Pharmacy 196(2): 235-9. In order to investigate the interaction of preserved solid lipid nanoparticles (SLN) with murine peritoneal macrophages (Mpsi), cytotoxicity and proinflammatory effects of two different solid lipid nanoparticles (SLN) preparations consisting of either compritol (CO) or cetyl palmitate (CP) preserved with thiomersal were analyzed. Concentration-dependent cytotoxic effects were observed using the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Secretion of interleukin-6 by Mpsi following incubation with CO and CP SLN did not differ from secretion by untreated cells; proinflammatory cytokines interleukin-12 and tumor-necrosis-factoralpha as further indicators of immunomodulatory effects were not detectable. These findings paralleled our previous findings that unpreserved CO and CP SLN did not induce immunomodulatory effects but cytotoxicity at higher concentrations. There were no synergistic cytotoxic effects of preservative and SLN. Thus, preservation of SLN using thiomersal does not appear to cause increased cytotoxicity and immunomodulatory effects following incubation with Mpsi. Scholer, N., C. Olbrich, et al. (2001). "Surfactant, but not the size of solid lipid nanoparticles (SLN) influences viability and cytokine production of macrophages." International Journal of Pharmacology 221(1-2): 57-67. After intravenous (i.v.) injection, solid lipid nanoparticles (SLN) interact with mononuclear cells. Murine peritoneal macrophages were incubated with SLN formulations consisting of Dynasan 114 coated with different surfactants. The present study was performed to examine the impact of surfactants, which are important surface defining components of SLN, on viability and cytokine production by macrophages. Cytotoxicity, as assessed by the 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) test, was strongly influenced by the surfactant used being marked with cetylpyridinium chloride- (CPC-) coated SLN at a concentration of 0.001% and further increased at SLN concentrations of 0.01 and 0.1%. All other SLN formulations -- containing Poloxamine 908 (P908), Poloxamer 407 (P407), Poloxamer 188 (P188), Solutol HS15 (HS15), Tween 80 (T80), Lipoid S75 (S75), sodium cholate (SC), or sodium dodecylsulfate (SDS) -- when used at the same concentrations reduced cell viability only slightly. None of the SLN formulations tested induced cytokine production but a concentrationdependent decrease of IL-6 production was observed, which appeared to be associated with cytotoxic effects. IL12 and TNF-alpha were detected neither in supernatants of macrophages treated with SLN at any concentration nor in those of untreated cells. In contrast to the type of surfactant, the size of SLN was found neither to affect cytotoxicity of SLN nor to result in induction or digression of cytokine production by macrophages. In conclusion, testing the effects of surfactants on SLN on activity of macrophages is a prerequisite prior to in vivo use of SLN. Schoonman, J. (1999). "Vapour-phase synthesis and processing of nanoparticle materials (esf/nano): four years of european collaboration." Journal of Nanoparticle Research 1: 325-328. Schroder, U., S. Segren, et al. (1986). "Magnetic carbohydrate nanoparticles for affinity cell separation." Journal of Immunological Methods 93(1): 45-53. Magnetically responsive nanoparticles were prepared from enzymatically hydrolysed starch and magnetite. Two different monoclonal antibodies were covalently coupled to the particles. The antibody-coupled particles were in the size range of 100-300 nm and had an iron content of about 60%. Using 100 micrograms of magnetic particles (coupled with monoclonal mouse anti-rat Ig kappa light chain antibody) a very high depletion of surface Ig positive cells (mostly B-cells) from one million rat peripheral blood mononuclear cells could be achieved. The separation efficiency was evaluated by flow cytofluorometric analysis. This technique permits the detection of a small number of surface Ig positive cells among 10,000 negative cells. Schroder, U. and B. A. Sabel (1996). "Nanoparticles, a drug carrier system to pass the blood-brain barrier, permit central analgesic effects of i.v. dalargin injections." Brain Research 710(1-2): 121-4. The Leu-enkephalin dalargin does not normally penetrate the blood brain barrier when given intravenously. Drug

targeting to the brain was investigated by using poly(butylcyanoacrylate) nanoparticles which were coated with polysorbate 80. When injected intravenously in mice, dalargin-loaded nanoparticles coated with the polysorbate 80 induced an analgesic effect at doses of 5.0 mg/kg and 7.5 mg/kg dalargin as shown by hindlimb licking on the hot plate. Neither the intravenous injection of dalargin alone at various doses nor the mixture of dalargin-loaded nanoparticles without the polysorbate 80 were able to induce an analgesic activity. This confirms previous observations that nanoparticles provide a convenient method to deliver drugs across the blood-brain barrier. Schroeder, U., P. Sommerfeld, et al. (1998). "Nanoparticle technology for delivery of drugs across the blood-brain barrier." Journal of Pharmaceutical Sciences 87(11): 1305-7. The Leu-enkephalin dalargin and the Met-enkephalin kyotorphin normally do not cross the blood-brain barrier (BBB) when given systemically. To transport these neuropeptides across the BBB they were adsorbed onto the surface of poly(butylcyanoacrylate) nanoparticles (NPs) and the NPs were coated with polysorbate 80. Central analgesia was measured by the hot plate test in mice. The antidepressant amitriptyline, which normally penetrates the BBB, was used to examine the versatility of the NP method. The concentration of amitriptyline in serum and brain of mice was determined by a gas chromatographic method. Furthermore, NPs were fabricated with different stabilizers. After the adsorption of the peptides on polysorbate 85-stabilized NPs, analgesia was noted after intravenous application when NPs were not coated. The amitriptyline level was significantly enhanced in brain when the substance was adsorbed onto the NP and coated or when the particles were stabilized with polysorbate 85. Schroeder, U., P. Sommerfeld, et al. (1998). "Efficacy of oral dalargin-loaded nanoparticle delivery across the blood-brain barrier." Peptides 19(4): 777-80. The Leu-enkephalin dalargin normally does not penetrate the blood-brain barrier (BBB) when given intravenously. To transport dalargin across the blood-brain barrier, the peptide was adsorbed onto the surface of poly(butyl)cyanoacrylate nanoparticles and coated with polysorbate 80. After systemic administration the central analgesia was measured by hot plate test. Furthermore, nanoparticles were fabricated with different stabilizers. After the adsorption of the peptide on polysorbate 85 stabilized nanoparticles analgesia was observable after intravenously and oral application even when nanoparticles were not coated. Thus, our data support the usefulness of nanoparticles as a method to deliver drugs to the brain. Schroeder, U., B. A. Sabel, et al. (1999). "Diffusion enhancement of drugs by loaded nanoparticles in vitro." Progress in Neuropsychopharmacoly and Biological Psychiatry 23(5): 941-9. 1. Dalargin, a Leu-enkephaline analogue, does normally not pass the blood-brain barrier (BBB). When it was adsorbed onto the surface of polybutylcyanoacrylate, nanoparticles dalargin can cross the BBB and induce central analgesic effects after intravenously as well as after oral application. 2. The mechanisms of this effect are unknown. Therefore, the authors evaluated whether neuronal transport was involved in this effect. In hippocampal synaptosomes and in tissue slices in vitro the active neuronal uptake and diffusion processes were determined by use of labelled D-aspartate as a marker of the aspartate/glutamate transporter and orotic acid as marker of diffusion. 3. Transporter-mediated uptake into hippocampal tissue preparations was not altered in comparison to control whereas diffusion processes were enhanced. These data indicate that the nanoparticles can modify neuronal uptake mechanisms. Schroeder, U., H. Schroeder, et al. (2000). "Body distribution of 3H-labelled dalargin bound to poly(butyl cyanoacrylate) nanoparticles after i.v. injections to mice." Life Sciences 66(6): 495-502. The blood-brain barrier (BBB) limits the penetration of substances into the brain. Because many drugs, particularly peptides, therefore can not be delivered to the brain, carrier systems were developed to overcome this problem. In earlier studies we demonstrated central analgesic effects of a peptide, dalargin (dal), after systemic administration when this substance was bound onto the surface of polybutylcyanoacrylate nanoparticles and coated with polysorbate 80 but not when it was given alone. The aim of the present study was to investigate the body distribution of 3H-labelled dal bound to nanoparticles compared to unbound dal after i.v. injection in mice. The radioactivity in several tissues, including the brain, was separated in subcellular preparations and was measured after a single i.v. injection over time. Dal radioactivity level in brain preparations was 3 times higher when the drug was bound to nanoparticles whereas the first pass pathway in liver was reduced. The results support previous data that nanoparticles can be used to transport peptides across the BBB. Schryvers, D., C. Goessens, et al. (1993). "Internal calibration technique for HREM studies of nanoscale particles." Microscopy Research and Technique 25(2): 185-6. Schulz, J., A. Roucoux, et al. (2000). "Stabilized rhodium(0) nanoparticles: a reusable hydrogenation catalyst for arene derivatives in a biphasic water-liquid system." Chemistry 6(4): 618-24. A colloidal system based on an aqueous suspension of rhodium(o) nanoparticles proved to be an efficient catalyst for the hydrogenation of arene derivatives under biphasic conditions. The rhodium nanoparticles (2-2.5 nm) were

synthesized by the reduction of RhCl3 x 3H2O with sodium borohydride and were stabilized by highly watersoluble N-alkyl-N-(2-hydroxyethyl)ammonium salts (HEA-Cn). These surfactant molecules were characterized by measurements of the surface tension and the aqueous dispersions with rhodium were observed by transmission electron cryomicroscopy. The catalytic system is efficient under ultramild conditions, namely room temperature and 1 atm H2 pressure. The aqueous phase which contains the protected rhodium(0) colloids can be reused without significant loss of activity. The microheterogeneous behavior of this catalytic system was confirmed on a mercury poisoning experiment. Schwab, G., C. Chavany, et al. (1994). "Antisense oligonucleotides adsorbed to polyalkylcyanoacrylate nanoparticles specifically inhibit mutated Ha-ras-mediated cell proliferation and tumorigenicity in nude mice." Proceedings of the National Academy of Sciences U S A 91(22): 10460-4. Ras oncogenes owe their transforming properties to single point mutations in the sequence coding for the active site of the p21 protein. These mutations lead to changes in cellular proliferation and induce tumorigenic properties. Point mutations represent a well-defined target for antisense oligonucleotides that can specifically suppress the translation of the targeted mutant mRNA. We show that the stability and cellular disponibility of antisense oligonucleotides can be markedly improved by adsorption to polyalkylcyanoacrylate nanoparticles. Nanoparticle-adsorbed antisense oligonucleotides directed to a point mutation (G--&gt;U) in codon 12 of the Haras mRNA selectively inhibited the proliferation of cells expressing the point-mutated Ha-ras gene at a concentration 100 times lower than free oligonucleotides. In addition they markedly inhibited Ha-ras-dependent tumor growth in nude mice after subcutaneous injection. These experiments show that inhibition of ras oncogenes by antisense oligonucleotides can block tumor development even though ras oncogenic activation might be an early event in tumor progression. Schwab, G., I. Duroux, et al. (1994). "An approach for new anticancer drugs: oncogene-targeted antisense DNA." Annals of Oncology 5(Suppl 4(1)): 55-8. BACKGROUND: Ras oncogenes owe their transforming properties to single point mutations in the sequence coding for the catalytic part of the p21 protein. These mutations lead to changes in cellular proliferation and tumorigenic properties. Point mutations represent a defined target for antisense oligonucleotides which specifically suppress translation of the targeted mRNA. However, the use of oligonucleotides in vivo has, until now, been limited by their instability in serum. NEW TECHNIQUES: Different strategies have been developed to protect the oligonucleotides and increase their transport into the target cell. Linking intercalating agents, hydrophobic groups or polycations to oligonucleotides or encapsulating them in liposomes resulted in a higher resistance to exonucleases and increased oligonucleotide penetration into cells. The stability and cellular uptake of antisense oligonucleotides can also be improved by associating them with polyalkylcyanoacrylate nanoparticles. The polymeric nature renders these small particles more stable than liposomes in biological fluids and during storage. METHOD: Antisense oligonucleotides directed to the point mutation (G to T) in codon 12 of the Ha-ras mRNA were adsorbed to nanoparticles in the presence of hydrophobic cations. RESULTS: These stabilized oligonucleotides selectively inhibited the proliferation of cells expressing this point mutation and partially reversed their tumorigenicity in nude mice. Schwarz, C. and W. Mehnert (1997). "Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN)." International Journal of Pharmacy 157(2): 171-179. Solid lipid nanoparticles (SLN) of a quality acceptable for i.v. administration were freeze-dried. Dynasan 112 and Compritol ATO 888 were used as lipid matrices for the SLN, stabilisers were Lipoid S 75 and poloxamer 188, respectively. To study the protective effect of various types and concentrations of cryoprotectants (e.g. carbohydrates), freeze-thaw cycles were carried out as a pre-test. The sugar trehalose proved to be most effective in preventing particle growth during freezing and thawing and also in the freeze-drying process. Changes in particle size distribution during lyophilisation could be minimised by optimising the parameters of the lyophilisation process, i.e. freezing velocity and redispersion method. Lyophilised drug-free SLN could be reconstituted in a quality considered suitable for i.v. injection with regard to the size distribution. Loading with model drugs (tetracaine, etomidate) impairs the quality of reconstituted SLN. However, the lyophilisate quality is sufficient for formulations less critical to limited particle growth, e.g. freeze-dried SLN for oral administration. Schwarz, C. and W. Mehnert (1999). "Solid lipid nanoparticles (SLN) for controlled drug delivery. II. Drug incorporation and physicochemical characterization." Journal of Microencapsulation 16(2): 205-13. Solid lipid nanoparticles (SLN) are a colloidal carrier system for controlled drug delivery. The lipophilic model drugs tetracaine and etomidate were incorporated to study the maximum drug loading, entrapment efficacy, effect of drug incorporation on SLN size, zeta potential (charge) and long-term physical stability. Drug loads of up to 10% could be achieved whilst simultaneously maintaining a physically stable nanoparticle dispersion. Incorporation of drugs showed no or little effect on particle size and zeta potential compared to drug-free SLN. The optimized production parameters previously established for drug-free SLN dispersions can therefore be transferred to drug-loaded systems to facilitate product development.

Schwarz, U. S. and S. A. Safran (2000). "Phase behavior and material properties of hollow nanoparticles." Physical Review E. Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics 62(5 Pt B): 6957-67. Effective pair potentials for hollow nanoparticles such as those made from carbon (fullerenes) or metal dichalcogenides (inorganic fullerenes) consist of a hard core repulsion and a deep, but short-ranged, van der Waals attraction. We investigate them for single-walled and multiwalled nanoparticles and show that in both cases, in the limit of large radii the interaction range scales inversely with the radius R, while the well depth scales linearly with R. We predict the values of the radius R and the wall thickness h at which the gas-liquid coexistence disappears from the phase diagram. We also discuss unusual material properties of the solid, which include a large heat of sublimation and a small surface energy. Schwarze, C. R., D. A. Pommet, et al. (2000). "Enhancement of chi in nanoparticle composite media exhibiting electrostriction and quantum confinement." Waves in Random Media 10(1): 43-52. A new model is described that combines the interaction between two physical mechanisms responsible for bulk third-order optical nonlinearity. They are: (1) saturable absorption, due to quantum confinement in nanoparticles, and (2) electrostriction, causing particles to migrate in the fluid host. We show that enhanced nonlinearities are predicted resulting from local field coupling and that oscillations can occur under certain conditions. (12 References). Schweitzer, B. and S. Kingsmore (2001). "Combining nucleic acid amplification and detection." Current Opinions in Biotechnology 12(1): 21-7. Major recent advances in molecular amplification in the past year were initial validation of two new amplification technologies (rolling circle amplification and Invader), a significant increase in the number of molecular diagnostic assays, achievement of amplification directly on microarrays (by strand displacement amplification and rolling circle amplification), and description of two new read-out probes (Scorpions and nanoparticles). Seehof, K., M. Kresse, et al. (2000). "Interactions of nanoparticles with body proteins: Improvement of 2D-PAGE-analysis by internal standard." International Journal of Pharmaceutics 196(2): 231-234. Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) is the method of choice to investigate protein adsorption of blood proteins (opsonization) onto nanoparticular drug carriers. In general the reproducability of the obtained adsorption patterns is satisfying. However, direct comparison between the amounts of single protein spots from gels obtained in different runs is difficult, because 2D-PAGE is a multistep procedure. A possible solution of the problem is to establish a protein as internal standard. Therefore, selected proteins (Bio-rad) were under investigation. Due to its molecular weight and isoelectric point, soybean trypsin inhibitor (TI) does not interfere with plasma components. Therefore, a method was established to use TI as an internal standard protein to improve comparability between the 2D-PAGE gels obtained in different analytical runs. Sen, N., A. Samanta, et al. (1998). "Development of amphotericin B loaded nanoparticles." Bolletino Chimico Farmaceutico 137(8): 295-7. Amphotericin B loaded nanoparticles were successfully prepared by in-situ emulsion polymerization technique using Ethylcyanoacrylate monomer. Scanning Electron Micrographs (SEM) of the nanoparticles showed that the particles were spherical and discrete. Average particle size analysis of two samples were found to be within the range of 475.3 +/- 91.68 to 479.75 +/- 105.49 nm. Thus the particles formed were within the colloidal range. With increase in monomer concentration, the percentages of drug adsorbed on the surface of nanoparticles were also increased. At the optimum concentration of Ethylcyanoacrylate (21.6 microliters/ml), 72.1% of Amphotericin B was adsorbed. Sennerfors, T. and F. Tiberg (2001). "Adsorption of polyelectrolyte and nanoparticles at the silica-aqueous solution interface: Influence of the history of additions of the two components." Journal of Colloid and Interface Science 238(1): 129-135. The interfacial properties of a mixed system of low-charged cationic polyelectrolyte and silica nanoparticles has been studied by means of ellipsometry. Special attention was devoted to the effect that the order of addition of the two components has on the adsorption behavior of the mixed system. Adsorption on silica was in one case studied after simultaneous addition of the components to the aqueous solution. The measured adsorption rates were then much slower than expected for a mass-transfer limited process. This behavior signifies the presence of an electrosteric barrier arising due to preadsorbed polymer-particle complexes. Interfacial layers containing particles were at plateau conditions shown to be highly swollen, whereas the cationic polymer in the particle-free systems adopted a more flat surface conformation. The layer thickness was observed to monotonously increase with an increasing presence of nanoparticles in solution, while the surface excess showed a maximum at intermediate values. The finding was rationalized by the competition between particles and the surface for polymer charges leading to swelling and a decreased effective interaction between polymer and surface. In the other case studied, when polyelectrolyte and nanoparticles were added sequentially, a much more rapid
3

concentration-dependent adsorption was observed. The kinetic adsorption barrier for nonassociated particles was clearly negligible compared with that for the polymer-particle complex. The surface excess did not exhibit an adsorption maximum as a function of added nanoparticles in this situation, indicating that the polymer layer to some degree is irreversibly anchored at the silica surface. Some implications of the above findings for practical papermaking using multicomponent retention systems are put forward. Copyright 2001 Academic Press. Sergeev, G. B., T. I. Shabatina, et al. (2000). "Spectroscopic study of low temperature interactions in metal-organic cocondensates." Spectrochimica Acta A Molecular and Biomolecular Spectroscopy 56(13): 2527-37. The results on spectroscopic study of low temperature interactions of metal atoms, small clusters and nanoparticles with different organic and inorganic substances in the temperature range 12-300 K are presented. Complexation and reactions of atoms and clusters of magnesium, samarium and silver with carbon dioxide, ethylene and some mesogenic cyanophenyls were studied by the technique of matrix isolation and low temperature co-condensation of metal and ligand vapors, low temperature UV-Vis, IR- and ESR-spectroscopy in combination with quantum chemistry calculations. It was shown that cryochemical reactions of metal particles of different sizes reflected the system's redundant energy. Sershen, S. R., S. L. Westcott, et al. (2000). "Temperature-sensitive polymer-nanoshell composites for photothermally modulated drug delivery." Journal of Biomedical Materials Research 51(3): 293-8. Composites of thermally sensitive hydrogels and optically active nanoparticles have been developed for the purpose of photothermally modulated drug delivery. Copolymers of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) exhibit a lower critical solution temperature (LCST) that is slightly above body temperature. When the temperature of the copolymer exceeds the LCST, the hydrogel collapses, causing a burst release of any soluble material held within the hydrogel matrix. Gold-gold sulfide nanoshells, a new class of nanoparticles designed to strongly absorb near-infrared light, have been incorporated into poly(NIPAAm-co-AAm) hydrogels for the purpose of initiating a temperature change with light; light at wavelengths between 800 and 1200 nm is transmitted through tissue with relatively little attenuation, absorbed by the nanoparticles, and converted to heat. Significantly enhanced drug release from composite hydrogels has been achieved in response to irradiation by light at 1064 nm. We have investigated the release of methylene blue and proteins of varying molecular weight. Additionally, the nanoshell-composite hydrogels can release multiple bursts of protein in response to repeated near-IR irradiation. Serwer, P., S. A. Khan, et al. (1995). "Non-denaturing gel electrophoresis of biological nanoparticles: viruses." Journal of Chromatography A 698(1-2): 251-61. Although gel electrophoresis is usually used for the fractionation of monomolecular particles, it is also applicable to the fractionation of the multimolecular complexes produced during both cellular metabolism and assembly of viruses in virus-infected cells. Gel electrophoretic procedures have been developed for determining both the size of a spherical particle and some aspects of the shape of a non-spherical particle. Capsids bound to DNA outside of the capsid can also be both fractionated and characterized. The procedures developed will be used for screening viral mutants; they also can potentially be used for diagnostic virology. Sensitivity of detection, the major current limitation, is being improved by use of both improved stains and scanning fluorimetry. The gels used for fractionation sometimes approximate random straight fiber gels, but become increasingly biphasic as the gel concentration is decreased. Sestier, C., D. Sabolovic, et al. (1995). "Use of annexin V-ferrofluid to enumerate erythrocytes damaged in various pathologies or during storage in vitro." Comptes Rendus de L'Acadamie Sciences Serie III. Sciences de la Vie 318(11): 1141-6. Recombinant human annexin V was bound covalently to 9 nm maghemite (gamma Fe2O3) nanoparticles, yielding annexin-ferrofluid (AnxFF), and used to separate annexin-bound red blood cells (RBC) in a magnetic field and estimate their percentage in various bloods. Annexin binding in normal human RBC increased proportionately with storage from 8% on day 2 to 42% on day 100. Enhanced AnxFF binding was associated with various pathologies. Thus, normal blood contained 10.7 +/- 5.9% AnxFF binding RBC; bloods with normal sedimentation rates (albeit with some disease necessitating analysis) contained 23.5 +/- 6.2%; those with high sedimentation rates contained 51.5 +/- 12.3%; sickle cell anaemia patients' blood contained 50.0 +/- 9.3%, and bloods from patients with other pathologies (deforming rheumatic disease, cancer necessitating chemotherapy, etc.) contained 58.6 +/- 7.6% AnxFF binding RBC. Enhanced Ca+2-dependent annexin binding reflects a loss of the asymmetric distribution of anionic phospholipids in plasma membranes which may constitute a signal for the destruction of the modified cells by the reticuloendothelial system. Once these preliminary results are confirmed, the determination of the fraction of AnxFF bound erythrocytes, following their magnetic separation, could prove a simple and rapid quality test for example in the context of blood transfusion. Sestier, C., M. F. Da-Silva, et al. (1998). "Surface modification of superparamagnetic nanoparticles (Ferrofluid) studied with particle electrophoresis: application to the specific targeting of cells." Electrophoresis 19(7): 1220-6.

Colloidal aqueous suspension of superparamagnetic nanoparticles (9 nm in diameter) composed of maghemite (gamma Fe2O3) and forming an ionic ferrofluid in aqueous solution are covalently coupled with lectins, enzymes or antibodies, using specific thiol chemistry. The surface charge modifications of nanoparticles, caused by ligand coupling, were monitored by measuring their electrophoretic mobilities using laser-Doppler velocimetry. Particle electrophoretic mobility (PEM) changes are shown to correlate well with the amount of ligand fixed on the particles, as probed by its biological activity. The PEM method provides a useful tool to optimize ligand immobilization at the surface of nanoparticles, and may be advantageous when biological activity measurements are not convenient. Shahbazyan, T. V. and I. E. Perakis (2000). "Surface collective excitations in ultrafast pump-probe spectroscopy of metal nanoparticles." Chemical Physics 251: 1-3. The role of surface collective excitations in the electron relaxation in small metal particles is studied. It is shown that the dynamically screened electron-electron interaction in a nanoparticle contains a size-dependent correction induced by the surface. This leads to new channels of quasiparticle scattering accompanied by the emission of surface collective excitations. In noble-metal particles, the dipole collective excitations (surface plasmons) mediate a resonant scattering of d-holes to the conduction band. The role of this effect in the ultrafast optical dynamics of small nanoparticles is studied. With decreasing nanoparticle size, it leads to a drastic change in the differential absorption lineshape and a strong frequency dependence of the relaxation near the surface plasmon resonance. The experimental implications of these results in ultrafast pump-probe spectroscopy are addressed. We also discuss the size-dependence of conduction electron scattering rates. (42 References). Shaik, M. S., O. Ikediobi, et al. (2001). "Long-circulating monensin nanoparticles for the potentiation of immunotoxin and anticancer drugs." Journal of Pharmacy and Pharmacology 53(5): 617-27. The carboxylic ionophore monensin was formulated into long-circulating nanoparticles with the help of polyethylene glycol/poly (DL-lactide-co-glycolide) diblock copolymers, in an attempt to enhance the cytotoxicity of a ricin-based immunotoxin, anti-My9, and anticancer drugs like adriamycin and tamoxifen. This study looked into various aspects involving the preparation (using a homogenizer and an EmulsiFlex homogenizer-extrusion device) and lyophilization of long-circulating monensin nanoparticles (LMNP) of particle size < 200 nm in diameter. The particle size of LMNP was reduced from 194 nm to 160 nm by passing the nanoparticles through an EmulsiFlex, before freeze-drying. There was a 4.8-83.7% increase in the particle size of LMNP after freezedrying, which was dependent upon the manufacturing conditions such as use of the EmulsiFlex for size reduction before freeze-drying, the freezing method (rapid/slow) and the concentration of lyoprotectant (mannitol or trehalose) employed for freeze-drying. LMNP freeze-dried with 2.4% of trehalose showed minimal size change (< 9%) after freeze-drying. Further, the freezing method was found to have negligible effect on the particle size of LMNP freeze-dried with trehalose in comparison with mannitol. The entrapment efficiency of monensin in LMNP was found to be 14.2 +/- 0.3%. The LMNP were found to be spherical in shape and smooth in surface texture as observed by atomic force microscopy. In-vitro release of monensin from LMNP in phosphate buffered saline (PBS) pH 7.4 or PBS supplemented with 10% human serum indicated that there was an initial rapid release of about 40% in the first 8 h followed by a fairly slow release (about 20%) in the next 88 h. In-vivo studies conducted with Sprague-Dawley rats showed that 20% of monensin remained in circulation 4-8 h after the intravenous administration of LMNP. An in-vitro dye-based cytotoxicity assay (MTS/PMS method) showed that there was 500 times and 5 times potentiation of the cytotoxicity of anti-My9 immunotoxin by LMNP (5 x 10(-8) M of monensin) in HL-60 sensitive and resistant human tumour cell lines, respectively. Further, LMNP (5 x 10(-8) M of monensin) potentiated the cytotoxicity of adriamycin in MCF 7 and SW 620 cell lines by 100 fold and 10 fold, respectively, and that of tamoxifen by 44 fold in MCF 7 cell line as assessed by crystal violet dye uptake assay. Our results suggest that it is possible to prepare LMNP possessing appropriate particle size (< 200 nm), monensin content and in-vitro and in-vivo release characteristics with the help of a homogenizer and an EmulsiFlex homogenizerextrusion device. LMNP can be freeze-dried with minimal increase in particle size by using a suitable concentration of a lyoprotectant like trehalose. Furthermore, LMNP could potentiate the cytotoxicity of immunotoxin, adriamycin and tamoxifen by 5-500 fold in-vitro, which will be further investigated in-vivo in a suitable animal model. Shaoqin, L., T. Zhiyong, et al. (2000). "Gas and pressure dependence for the mean size of nanoparticles produced by laser ablation of flowing aerosols." Journal of Nanoparticle Research 2(2): 141-5. Silver nanoparticles were produced by laser ablation of a continuously flowing aerosol of microparticles entrained in argon, nitrogen and helium at a variety of gas pressures. Nanoparticles produced in this new, high-volume nanoparticle production technique are compared with our earlier experiments using laser ablation of static microparticles. Transmission electron micrographs of the samples show the nanoparticles to be spherical and highly non-agglomerated under all conditions tested. These micrographs were analyzed to determine the effect of carrier gas type and pressure on size distributions. We conclude that mean diameters can be controlled from 4 to 20 nm by the choice of gas type and pressure. The smallest nanoparticles were produced in helium, with mean sizes increasing with increasing molecular weight of the carrier gas. These results are discussed in terms of a

model based on cooling via collisional interaction of the nanoparticles, produced in the laser exploded microparticle, with the ambient gas. (11 References). Sharma, D., T. P. Chelvi, et al. (1996). "Novel Taxol formulation: polyvinylpyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy." Oncol Res 8(7-8): 281-6. Taxol is a novel antitumor alkaloid that has shown clinical activity against several tumors. However, due to its low aqueous solubility, Cremophor EL (polyoxyethylated castor oil) and ethanol are used as excipients in the pharmaceutical drug formulations. These agents are implicated in hypersensitivity reactions. Hence the goal of this work was to design a novel Taxol formulation using polymeric nanoparticles to eliminate the Cremophor EL vehicle for drug delivery. Polyvinylpyrrolidone nanoparticles containing Taxol were prepared by a reverse microemulsion method. The size of the nanoparticles as determined by quasielastic light scattering was found to be between 50 and 60 nm. The antitumor effect of Taxol encapsulated nanoparticles was evaluated in B16F10 murine melanoma transplanted in C57B1/6 mice. The in vivo efficacy of Taxol-containing nanoparticles as measured by reduction in tumor volume and increased survival time was significantly greater than that of an equivalent concentration of free Taxol. These results suggest that encapsulation of Taxol in polymeric nanoparticles could be useful in improving its therapeutic efficacy in treatment of solid tumors. Sheng, J., B. K. Samten, et al. (1995). "[Study on the specific killing activity of albumin nanoparticles containing adriamycin targeted by monoclonal antibody BDI-1 to human bladder cancer cells]." Yao Xue Xue Bao 30(9): 706-10. A highly specific immuno-nanoparticle (ADR-NP-Ab) has been constituted by chemically coupling a monoclonal antibody BDI-1 to albumin nanoparticle containing adriamycin (ADR-NP). Different molecular ratios of antibody to ADR-NP were tried to determine the optimal condition for preparing the immuno-nanoparticle. The results of immunoflurecence and microphotographic analysis showed that the activity of ADR-NP-Ab was well preserved. The result of the cytotoxicity of ADR-NP-Ab in vitro assay showed strong killing activity of ADR-NP-Ab to bladder cancer cells (EJ), while no apparent cytotoxic activity to non-targeted human colon carcinoma cells (Lovo) was observed. Shi, K., C. Li, et al. (2000). "[Magnetic drug delivery system--adriamycin-carboxymethyl dextran magnetic nanoparticles]." Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 17(1): 21-4. A novel magnetic drug carrier-carboxymethyl dextran magnetic nanoparticles(CMD MNPs) was prepared. Adriamycin (ADR) was coupled with two types of carrier-neutral dextran MNPs and anionic CMD MNPs, by periodate oxidation. The physico-chemical characteristics and the magnetic guidance effects in vitro and in vivo of ADR-CMD MNPs were studied. The distribution profiles of liver and spleen in mice were studied for both ADRdextran conjugate MNPs and ADR-CMD conjugate MNPs. The results showed ADR-CMD conjugate MNPs possessed superparamagnetism, the mean diameter was 56 nm, the mass magnetic susceptibility was 1.06 x 10(-4) emu.g-1, and the drug loading was 12.4%. The distribution profiles in liver and spleen revealed that conjugation with neutral dextran MNPs, excessive accumulation of loaded ADR was found in liver and spleen after intravenous administration, while conjugation with CMD MNPs gave a markedly lower concentration in these organs, which indicated less uptake of ADR-CMD conjugate MNPs by reticuloendothelial system(RES) and the advantage of delivering loaded drug to sites other than the RES; thus it opens a new perspective for the active delivery of drug. Shiku, H., L. Wang, et al. (2000). "Development of a cancer vaccine: peptides, proteins, and DNA." Cancer Chemotherapy and Pharmacology 46(Suppl(6)): S77-82. Genetic changes leading to protooncogene activation qualitatively and/or quantitatively alter their gene products and are exclusively or largely restricted to transforming cells and their precursors. The overexpression of HER2 is among those changes and is often detected in adenocarcinomas such as breast, ovarian, lung, and gastric cancer. This provides a rationale for exploring the possibility that HER2 is a target of host immune responses against cancer cells. We have recently demonstrated that HER2 can be a target for tumor-rejecting immune responses against syngeneic murine HER2+ tumor cells. We defined two different peptides, HER2p63-71 and HER2p780-788, with a Kd anchor motif that can induce CD8+ cytotoxic T lymphocytes (CTLs). The growth of HER2+ syngeneic tumors was suppressed in mice immunized with HER2p63-71 or p780-788. Since murine Kd and human HLA-A24 share a similar anchor motif for peptides, HER2p63 71 and HER2p780-788 were examined for induction of CTLs in HLA-A24+ individuals. CD8+ CTL clones specific for these peptides were established and they lysed HER2+ tumor cells in a human leukocyte antigen (HLA)-A24-restricted manner. To elicit specific CD8+ T cell immune responses against cancer, the development of efficient devices to deliver tumor antigen peptides to the major histocompatibility complex (MHC) class I pathway constitutes a central issue. We have developed a novel formula of hydrophobized polysaccharide nanoparticles which can deliver a HER2 oncoprotein containing an epitope peptide to the MHC class I pathway. We designed a simple protein delivery system: cholesteryl groupbearing polysaccharides, mannan or pullulan (CHM or CHP, respectively), complexed with the truncated HER2 protein containing the 147 N-terminal amino acids. These complexes were able to induce CD8+ CTLs against HER2+ tumors. CTLs were MHC class I restricted and specifically recognized HER2p63-71, a part of a truncated

HER2 protein used as an immunogen. The complete rejection of tumors also occurred when CHM-HER2 was applied early after tumor implantation. In the effector phase of in vivo tumor rejection, CD8+ T cells played a major role. The results suggest that this unique hydrophobized polysaccharide may help soluble proteins to induce cellular immunity. Such a novel vaccine may be of potential benefit in cancer prevention and cancer therapy. Shinde, S. R., S. D. Kulkarni, et al. (2000). "Magnetic properties of nanosized powders of magnetic oxides synthesized by pulsed laser ablation." Journal of Applied Physics 88(3): 1566-75. We present a detailed study of synthesis by pulsed laser ablation and the magnetic characterization of nanosized powders of iron oxides and strontium ferrite. In the case of iron oxide, it is found that the particle formation and their growth take place in the gas phase before reaching the cold finger (used as substrate for condensation). However, in the case of strontium ferrite, the as-condensed material is amorphous, and requires annealing at high temperature to induce nanoparticle growth. Very high values of intrinsic coercive field (~6665+or-10 Oe) are realized for the strontium ferrite powder having an average particle size of about 35 nm. The temperature variation of coercive field and remanence of the nanosized powders is found to be substantially different from those of the corresponding bulk materials. (40 References). Shvartsburg, A. A. and M. F. Jarrold (2000). "Solid clusters above the bulk melting point." Physical Review Letters 85(12): 2530-2. The fact that the melting points of nanoparticles are always lower than those of the corresponding bulk material is a paradigm supported by extensive experimental data for a large number of systems and by numerous calculations. Here we demonstrate that tin cluster ions with 10-30 atoms remain solid at approximately 50 K above the melting point of bulk tin. This behavior is possibly related to the fact that the structure of the clusters is completely different from that of the bulk element. Siekmann, B. and K. Westesen (1995). "Preparation and physicochemical characterization of aqueous dispersions of coenzyme Q10 nanoparticles." Pharmacetical Research 12(2): 201-8. The present study describes a novel pharmaceutical formulation of coenzyme Q10, viz. submicron-sized dispersions of the substance prepared by emulsification of molten coenzyme Q10 in an aqueous phase. Photon correlation spectroscopy reveals mean diameters of 60 to 300 nm depending on process parameters. Coenzyme Q10 nanoparticles remain stable on storage for more than 30 months. Lipophilic drugs can be incorporated into the nanoparticles demonstrating their potential use as a drug carrier system. Transmission electron micrographs of freeze-fractured replica show spherical particles with an amorphous core. Cryo-electron microscopy reveals the coexistence of small unilamellar vesicles in phospholipid stabilized dispersions. Thermoanalysis and X-ray studies indicate that the dispersed and emulsified coenzyme Q10 does not recrystallize even at 4 degrees C over 30 months. These agree with 1H NMR data which demonstrate that coenzyme Q10 molecules have a high mobility when formulated as nanoparticles and that colloidally dispersed coenzyme Q10 remains in the state of a supercooled melt. Despite the high melting point of the bulk material, coenzyme Q10 dispersions represent no suspensions but O/W emulsions according to the IUPAC definition (1). Siiman, O., K. Gordon, et al. (2000). "Immunophenotyping using gold or silver nanoparticle-polystyrene bead conjugates with multiple light scatter." Cytometry. [ print] 41(4): 298-307. Background: The type of antibody-conjugated polystyrene (PS) latex beads for use as light scatter shift agents for targeted lymphocyte populations in whole blood has been expanded to include gold and silver nanoparticleaminodextran-PS latex bead conjugates with antibodies. The linkers between antibody and colloidal metal were an aminotrithiol ligand or aminodextran polymer molecules. Methods: A modified flow instrument, including forward light scatter (FS), side light scatter (SS), light scatter at other intermediate angle ranges, LMALS (1020degree) and UMALS (20-65degree) was used for simultaneous bead probe measurements. A conventional flow cytometer was used in simultaneous bead-fluorescent marker experiments. Results: Two mutually exclusive cell populations, CD4+ and CD8+ lymphocytes, have been simultaneously enumerated in blood by using a mixture of CD4-PS, CD8-Au-PS or CD4-Au-PS, CD8-PS beads, and one laser line, 633 nm, excitation. Similar measurements were made with mixtures of CD4-PS, CD8-Ag-PS or CD4-Ag-PS, CD8-PS beads. Also, simultaneous use of bead and fluorescent markers mixed with whole blood was demonstrated with CD4-PS beads and with the CD4-RD1/CD8-FITC dual marker. Conclusions: Enumeration of CD4 and CD8 lymphocytes in whole blood by light scatter parameters only compared well with standard analyses with fluorescent markers. In simultaneous bead-fluorescent marker labeling of lymphocytes, the labeled bead had to be mixed first with cells in whole blood. Silly, F., A. O. Gusev, et al. (2000). "Coupled plasmon modes in an ordered hexagonal monolayer of metal nanoparticles: A direct observation." Physical Review Letters 84(25): 5840-3. We report on the experimental observation of STM-induced photon emission in ultrahigh vacuum on a network of 4-nm silver spheres. The spheres are covered by a dielectric, electrically insulating, organic layer and deposited on Au(111). The bias-dependent spatial distribution of the photon emission rates reveals the electric-field

distribution of the different coupled plasmon modes in this model. Simeonova, M., M. Ilarionova, et al. (1991). "Nanoparticles as drug carriers for vinblastine. Acute toxicity of vinblastine in a free form and associated to polybutylcyanoacrylate nanoparticles." Acta Physiologica et Pharmacologica Bulgarica 17(4): 43-9. The possibility of reducing toxicity of Vinblastine by fixing it in polybutyl-2-cyanoacrylate nanoparticles was studied. A significant reduction of mortality of mice was recorded after a single intraperitoneal (i. p.) injection of nanoparticle-associated Vinblastine. A wide range of doses of Vinblastine (1.04-6.25 mg/kg) were used. There was a considerable decrease of leucopenia caused by Vinblastine-loaded polybutyl-2-cyanoacrylate nanoparticles as compared to that induced by free Vinblastine. Simeonova, M. and M. Antcheva (1994). "In vitro study of cytotoxic activity of vinblastine in a free form and associated with nanoparticles." Acta Physiologica et Pharmacologica Bulgarica 20(2): 31-5. The cytotoxic activities of unloaded polybutylcyanoacrylate nanoparticles (PBCN), free vinblastine, vinblastineloaded nanoparticles (by incorporation and adsorption processes) and a mixture of vinblastine-free and unloaded PBCN were compared in vitro on human erythroleukemic K-562 cells. Enhanced cytotoxicity was observed when vinblastine was either adsorbed on PBCN or mixed with them rather than free. When vinblastine was incorporated into polymer matrix of nanoparticles, a lag period and postponed cytotoxic effect on K-562 cells were observed. Simeonova, M., T. Ivanova, et al. (1994). "Tissue distribution of polybutylcyanoacrylate nanoparticles loaded with spinlabelled nitrosourea in Lewis lung carcinoma-bearing mice." Acta Physiologica et Pharmacologica Bulgarica 20(3-4): 7782. The tissue distribution of polybutylcyanoacrylate nanoparticles (PBCN) with a diameter of 127 nm, loaded with 1(2-chloroethyl)-3-(1-oxyl-2,2,6,6-tetramethylpiperidinyl)-1- nitrosourea (spin-labelled nitrosourea, SLCNU) is described. PBCN-suspensions were intraperitoneally (i.p.) injected into Lewis lung carcinoma bearing mice. The biodistribution of PBCN in the visceral organs, blood and tumor was studied by electron spin resonance (ESR) spectroscopy. A relatively low accumulation of nanoparticles in the liver and spleen was found. The accumulation was negligible in the i.m. implanted primary tumor. SLCNU-loaded nanoparticles were mainly found in the lungs, kidneys, and heart. The highest content of the particles studied was observed in the lungs of tumor bearing experimental animals damaged by metastases. These findings suggest that PBCN offer some opportunities in the targeting of SLCNU to lung metastases. Simeonova, M., K. Chorbadjiev, et al. (1998). "Study of the effect of polybutylcyanoacrylate nanoparticles and their metabolites on the primary immune response in mice to sheep red blood cells." Biomaterials 19(23): 2187-93. Polybutylcyanoacrylate nanoparticles (PBCN) and their metabolites (polycyanoacrylic acid--PCAA, and n-butanol) were compared with respect to their effects on the primary immune response of mice to sheep red blood cells (SRBC). PCAA was synthetized via a Knoevenagel reaction. Antibody production (hemagglutinins) and E-rosetteforming cells (E-RFC) were used to document the induction of antigen-specific immune response to SRBC in all immunized mice. PBCN showed a time- and dose-dependent effect on the immune response, both humoral and cellular. The inductive phase of immune response was affected preferably. The high dose of PBCN (200 mg kg(1)) tended to suppress the immune response. This was expressed more in mice treated before antigenic stimulation. Lower dose (10 mgkg(-1)) stimulated the immune response. A significant difference was found in the effects of PBCN and their metabolites on the immune response. PCAA and n-butanol administered at doses equivalent (after lysosomal hydrolysis) to the doses applied of intact PBCN did not impair significantly the immune response. A clear time dependence and dose dependence were not observed. The study led to the hypothesis that the greater suppressive effect of PBCN, relative to either PCAA or n-butanol, or a mixture of them, is probably due to the blocking of the immunopresenting function of macrophages instead of some toxicity towards the immunocompetent cells. Simon, B. H., H. Y. Ando, et al. (1995). "Circulation time and body distribution of 14C-labeled amino-modified polystyrene nanoparticles in mice." Journal of Pharmaceutical Sciences 84(10): 1249-53. Commercially available amino-modified polystyrene particles of size range 100-1,000 nm were radioactively labeled with [14C]-formaldehyde. A study of the circulation time and body distribution of these particles was carried out in mice. The animals were sacrificed at 1-30 min after intravenous administration of the particles. The blood and organ (liver, spleen, lung) profiles of particles were determined by measuring their radioactivity by means of liquid scintillation counting. In general, larger particles were eliminated from blood faster than smaller particles. The blood elimination half-life ranged from 1.36 to 4.92 min. The particles were mainly taken up by the liver with larger particles being taken up faster than the smaller particles. At 30 min after injection, 60% of the administered 100 nm particles were present in the liver, whereas 85% of the 100 nm particles were found in the liver. Accumulation in the spleen was 1-3% of the total number administered in the entire size range. At 1 min after injection, less than 3% of the total dose administered was present in the lungs and this value decreased rapidly to less than 1% at 2 min. The only exception occurred for 100 nm, where 2.35% was present in the lungs

at 2 min after injection. Simon, U. (2000). "Can we determine the barrier resistance for electron transport in ligand stabilized nanoparticles from integral conductance measurements?" Nanophase and Nanocomposite Materials III. Symposium 581: 77-82. By means of integral temperature dependent conductance measurements, the effective capacitance of ligand stabilized nanoparticles, arranged in dense packings or networks, can be deduced from the activation energy of the charge transport, for which the use of the Landauer formula is proposed. According to this, the barrier resistance in ligand stabilized nanoparticle arrangements depends predominantly on the inter particle spacing rather than on the chemical composition of the molecules. Comparison with data of the single molecule resistance determined by local probe techniques or by theoretical methods shows remarkable agreement. (14 References). Sirbat, D., L. Marchal-Heussler, et al. (2000). "[Ways to improve ocular bioavailability for topical applications]." Journal de Francais de Ophtalmologie 23(5): 505-9; quiz 523. The anatomical, physiological and pharmacological properties of the eye explain the short pre-corneal residence time and the poor bioavailability of most eye-drop solutions. Many approaches have been proposed to increase ocular bioavailability of drugs. Most eye-drops include a viscosity agent in their formulation to significantly prolong residence time although the increased viscosity is limited due to patient discomfort. More recent developments include biodegradable inserts, eye-drop based on cyclodextrins, liposomes or nanoparticles. Sjostrom, B., A. Kaplun, et al. (1995). "Structures of nanoparticles prepared from oil-in-water emulsions." Pharm Res 12(1): 39-48. Hydrophobic substances were dissolved in an organic solvent and emulsified with an aqueous solution at very high shear. Droplets of very small sizes (50-100 nm) were obtained by using surfactants which were combinations of lecithins and bile salts. After emulsification, the organic solvent was removed by evaporation, yielding stable dispersions of solid particles. The sizes, shapes, and structures of the particles were examined through quasielastic light scattering, small-angle neutron scattering and cryotransmission electron microscopy. Cholesterol acetate particles stabilized by lecithin and bile salts were found to be platelets of 10-20 nm thickness and 80 nm diameter. Cholesteryl acetate particles stabilized with POE-(20)-sorbitan monolaurate were dense spherical globules of diameter 100 nm. Particles with a composition similar to the endogenously occurring, lipoprotein, LDL, were large spherical globules studded with small vesicles. The subsequent evolution of the cholesteryl acetate dispersion upon aging was examined. There was no transfer of cholesteryl acetate between particles nor to large crystals. However, some aggregation of the particles was observed when the volume fraction of the particles in the aqueous dispersion exceeded 0.05. Thus, the structure of the nanoparticles obtained through deswelling of emulsion droplets changes according to the nature of the emulsifiers and to the composition of the hydrophobic substances which they contain. Sloan, J., M. C. Novotny, et al. (2000). "Effect of ultrafine gold particles and cationic surfactant on burning as-grown single-wall carbon nanotubes." Chemical Physics Letters 328: 4-6. Mizoguti et al. (see ibid., vol.321, p.297 (2000)) reported that amorphous carbon (a-C) contained in as-grown single-wall carbon nanotubes could be burned preferentially by using ultrafine gold particles and cationic surfactant, benzalkonium chloride (BKC). We confirmed this result and found additionally that the optimum concentration of the ultrafine gold particles and BKC were, respectively, 0.6 atom% and 7 g/I. We studied the roles of ultrafine gold particles and BKC in this phenomenon; the ultrafine gold particles catalyzed the oxidation of carbonaceous materials leading to the decrease of the burning temperatures. BKC had the function of homogenizing the a-C aggregation states, which resulted in the burning of a-C in a narrow temperature range. (14 References). Soma, C. E., C. Dubernet, et al. (1999). "Ability of doxorubicin-loaded nanoparticles to overcome multidrug resistance of tumor cells after their capture by macrophages." Pharm Res 16(11): 1710-6. PURPOSE: Investigation of the ability of doxorubicin-loaded nanoparticles (NP/Dox) to overcome multidrug resistance (MDR) when they have first been taken up by macrophages. METHODS: The growth inhibition of P388 sensitive (P388) and resistant (P388/ADR) tumor cells was evaluated in a coculture system consisting of wells with two compartments. The tumor cells were seeded into the lower compartment, the macrophages were introduced into the upper part in which the drug preparations were also added. RESULTS: Doxorubicin exerted lower cytotoxicity on tumor cells in coculture compared with direct contact. In P388/ADR, NP/Dox cytotoxicity was far higher than that of free doxorubicin (Dox). Three different formulations of cyclosporin A (either free (CyA), loaded to nanoparticles (NP/CyA) or in a combined formulation with doxorubicin (NP/Dox-CyA)), were added to modulate doxorubicin efficacy. The addition of cyclosporin A to Dox increased drug cytotoxicity. Both CyA added to NP/Dox and NP/Dox-CyA were able to bypass drug resistance. CONCLUSIONS: Despite the barrier role of macrophages, NP/Dox remained far more cytotoxic than Dox against P388/ADR. Both NP/Dox + CyA and NP/Dox-CyA allowed to overcome MDR, but the last one should present greater advantage in vivo by confining both drugs in the same compartment, hence reducing the adverse effects.

Soma, C. E., C. Dubernet, et al. (2000). "Investigation of the role of macrophages on the cytotoxicity of doxorubicin and doxorubicin-loaded nanoparticles on M5076 cells in vitro." Journal of Controlled Release 68(2): 283-9. Doxorubicin-loaded PACA nanoparticles have been shown to be more efficient than free drug in mice bearing hepatic metastasis of the M5076 tumour. Due to the high phagocytic activity of Kupffer cells in the liver, it may be that these cells played a role of drug reservoir after nanoparticle phagocytosis. Therefore, the objective of this study was to assess the role of macrophages in mediating the cytotoxicity of doxorubicin-loaded nanoparticles on M5076 cells. The growth inhibition of tumour cells was evaluated in two ways: firstly, the cells were incubated in a coculture system consisting of special wells with two compartments separated by a porous membrane. M5076 cells were seeded into the lower compartment and the macrophages J774.A1 were introduced into the upper part. The macrophages were activated or not by IFN-gamma. The drug preparations were added only in the macrophage insert. Secondly, growth inhibition was also assessed in the conventional way, i.e. in direct contact with the tumour cells to serve as a reference. After direct contact, free doxorubicin (Dox) and doxorubicin-loaded nanoparticles (NP-Dox) had the same efficacy against M5076 cell growth. The coculture experiments led to a 5fold increase in the IC(50) for both Dox and NP-Dox. The activation of macrophages by IFN-gamma in coculture significantly decreased the IC(50) values. In conclusion, after phagocytosis of doxorubicin-loaded nanoparticles, J774.A1 cells were able to release active drug, allowing it to exert its cytotoxicity against M5076 cells. Drug efficacy was potentiated by the activation of macrophages releasing cytotoxic factors such as NO, which resulted in increased tumour cell death. Thereby, the coculture system permitted us to investigate the macrophagemediated cytotoxicity of colloidal carriers loaded with an anticancer drug, which is of great interest when further i.v. administration is envi saged. Soma, C. E., C. Dubernet, et al. (2000). "Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles." Biomaterials 21(1): 1-7. Individual and combined polyalkylcyanoacrylate nanoparticle formulation of cyclosporin A and doxorubicin were prepared and evaluated in an attempt to show improved growth inhibition efficacy in a resistant cell culture line. The drug loaded nanoparticles were prepared using the well established emulsion polymerization process without using any modification for the hydrophilic doxorubicin drug whereas the incorporation of cyclosporin A needed to wait a moment after the polymerization reaction started. This was necessary to avoid cyclosporin A precipitation and polymer aggregation. Cyclosporin A release from the nanoparticles was rapid probably because the drug was adsorbed onto the nanoparticles surface rather than embedded into the polymeric core. Doxorubicin displayed also a burst effect but with a slower second phase probably related with the nanoparticles bioerosion rate owing to its entrapment in the polymeric network. Finally, it was shown in resistant cell culture experiments that the association of both cyclosporin A and doxorubicin within a single nanoparticle formulation elicited the most effective growth rate inhibition as compared to other combinations of both drugs while using a lower amount of polymer compared to separated nanoparticle formulations. This result was probably due to the synergistic effect achieved by combining the chemo-sensitizing compound cyclosporin A, with an effective cytotoxic drug like doxorubicin. Sommer, A. P., W. Rohlke, et al. (1999). "Free energy reduction by molecular interface crossing: novel mechanism for the transport of material across the interface of nanoscale droplets induced by competing intermolecular forces for application in perfluorocarbon blood substitutes." Naturwissenschaften 86(7): 335-9. Perfluorocarbons (PFCs) are inert liquids which can dissolve--and release--approximately 50 times more oxygen than blood plasma. Oxygen carriers based on PFCs are easy to produce, free of biological components, and more rigorously sterilizable than blood. PFCs injected into the body are eliminated by expiration through the lungs. Before reaching the lungs, PFCs accumulate in storage organs such as liver and spleen. In these organs nanoscale PFC droplets reduce their free energy by unifying to microscopic drops, thus indirectly lowering the rate of their expiration. The model of free energy reduction by molecular interface crossing (FERMIC), a novel emulsion breaking mechanism derived from first principles as presented here, leads to a better understanding of the structure formation processes relevant in perfluorocarbons (PFCs) in vivo. Sommerfeld, P., B. A. Sabel, et al. (2000). "Long-term stability of PBCA nanoparticle suspensions." Journal of Microencapsulation 17(1): 69-79. In this study, the stability of poly(butyl cyanoacrylate) (PBCA) nanoparticle suspensions was examined for up to 1 year by measuring the nanoparticle sizes. The nanoparticles were prepared with different stabilizers (dextran 70.000, poloxamer 188, or polysorbate 85), and the particle size was determined before and after purification by centrifugation and after dilution with different solutions (0.1 N HCl, 0.01 N HCl, H2O, and PBS). The most constant sizes were with the untreated acidic nanoparticle suspensions. In all other cases, agglomeration of the particles occurred: the extent of this agglomeration and the time at which the agglomeration occurred depended on the experimental conditions. Nanoparticle polymer degradation, as indicated by size decrease, was not observed. Thus, PBCA nanoparticles can be stored as suspensions, making the lyophilization and the sometimes problematic resuspension by ultrasonication, unnecessary, which is advantageous for clinical applications.

Sondi, I., O. Siiman, et al. (2000). "Preparation of aminodextran-CdS nanoparticle complexes and biologically active antibody-aminodextran-CdS nanoparticle conjugates." Langmuir 16(7): 3107-18. Stable aqueous dispersions consisting of CdS nanoparticles having modal diameters, ranging between 2 and 8 nm, were prepared with amino-derivatized polysaccharides (aminodextrans, hence abbreviated as Amdex) as the stabilizing agents. The size, stability, and luminescence intensity of such dispersions were shown to be dependent on the types of the cadmium salts and aminodextrans used, as well as on the reactant concentrations. Specifically, it was demonstrated that the degree of substitution of amino groups in the aminodextran molecules greatly affected the properties of the dispersions; i.e., with higher degree of substitution, smaller CdS particles and higher luminescence intensity were achieved. It was also shown that the Amdex-CdS nanoparticle complexes could be activated and conjugated with antibody by conventional means. Molecular weight ranges of the Amdex and their complexes with CdS nanoparticles and the purity of antibody-Amdex-CdS nanoparticle conjugates were determined by polyacrylamide gel electrophoresis combined with Coomassie blue staining of resultant gel bands. The purified conjugate of the aminodextran-CdS nanoparticle complex with anti-CD4 monoclonal antibody was mixed with a whole blood control, followed by indirect sheep antimouse antibody-phycoerythrin (SAM-PE) labeling of washed cells incubated with T4-5X-Amdex-CdS. Red blood cells were then lysed and quenched, and the resulting mixture, which was run on a flow cytometer with 488.0 nm argon ion laser excitation, suggested that the T4 antibody from the conjugate was present specifically on lymphocytes. (74 References). Song, C., V. Labhasetwar, et al. (1998). "Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model." Journal of Controlled Release 54(2): 201-11. Biodegradable nanoparticles (NP) with a spherical diameter ranging from 70 to 160 nm were investigated for potential usefulness for the local intraluminal therapy of restenosis, the disease process responsible for arterial reobstruction following angioplasty. NPs containing a water-insoluble anti-proliferative agent U-86983 (U-86, Pharmacia and Upjohn, Kalamazoo, MI) were formulated from oil-water emulsions using biodegradable polymers such as poly(lactic acid-co-glycolic acid) (PLGA), and specific additives after particle formation, to enhance arterial retention using either heparin, didodecylmethylammonium bromide (DMAB), or fibrinogen, or combinations. Femoral and carotid arteries of male mongrel dogs were isolated in situ, and were then subjected to a balloon angioplasty. A NP suspension of a predetermined concentration was then infused into the artery for various durations. This was followed by a 30 min restoration of blood flow through the vessel. The arterial segments were excised and analyzed for drug levels. From the drug loading the NP and the drug levels in the artery, the quantity of nanoparticles retained was calculated and expressed as microgram per 10 mg dry arteries. In general, repeated short infusions of nanoparticle suspension (15 s x 4) were two-fold more effective in terms of higher arterial U-86 levels than a single prolonged infusion (60 s). A single 15 s infusion was not significantly different than a 60 s compared to non-modified NPs (39.2 +/- 2.5 and 49.1 +/- 2.4 vs. 21.5 +/- 0.6 micrograms/10 mg mean +/- s.e., respectively). A comparably enhanced NP uptake was noted with a combined heparin/DMAB modification. Increasing the concentration of NP in infusate from 5 to 30 mg ml-1 significantly increased arterial NP uptake level (from 22.5 +/- 3.5 to 83.7 +/- 1.4 micrograms/10 mg). Thus, the results support the view that modified nanoparticles along with optimized infusion conditions could enhance arterial wall drug concentrations of agents to treat restenosis. Soppimath, K. S., T. M. Aminabhavi, et al. (2001). "Biodegradable polymeric nanoparticles as drug delivery devices." Journal of Control Release 70(1-2): 1-20. This review presents the most outstanding contributions in the field of biodegradable polymeric nanoparticles used as drug delivery systems. Methods of preparation, drug loading and drug release are covered. The most important findings on surface modification methods as well as surface characterization are covered from 1990 through mid-2000. Sordet, F., Y. Aumjaud, et al. (1998). "Assessment of the activity of atovaquone-loaded nanocapsules in the treatment of acute and chronic murine toxoplasmosis." Parasite 5(3): 223-9. The aim of this work was to develop a new pharmaceutical form of atovaquone and to study its activity against Toxoplasma gondii in vitro and in vivo. Nanocapsules were chosen as the oral dosage form of administration. An analytical method was developed to determine the drug content in nanocapsules. The stability of these nanocapsules were assessed by following drug content, size, pH and osmolarity for a period of six months. The in vitro activity of atovaquone-loaded nanocapsules against tachyzoites of T. gondii (RH stain) was comparable to its suspension form. In vivo studies were carried out in murine models of acute and chronic toxoplasmosis. Mice acutely infected with the virulent RH strain were orally treated with a dose regimen of 15 mg/kg/day for 10 days, starting from day 1 post-infection. 75% of the mice receiving atovaquone-loaded nanocapsules survived 30 days post-infection, compared to none of untreated controls and none of mice treated with the suspension with the same dose regimen. In mice chronically infected by the COUL or the ME49 strain (Type II strains), then treated for six weeks, treatment with atovaquone (15 mg/kg/d, nanoparticles or suspension) resulted in a decrease of brain parasitic burden, which was significantly more pronounced in ME49-infected mice and in those treated with

drug-loaded nanocapsules. These results show that the sensibility of T. gondii to atovaquone is different according to the strains and that the activity of atovaquone in the treatment of toxoplasmosis is enhanced when administered in nanoparticular form. Sorescu, M. (2000). "Mechanochemical activation of magnetite nanoparticles." Journal of Nanoparticle Research 2: 305308. Soukka, T., J. Paukkunen, et al. (2001). "Supersensitive time-resolved immunofluorometric assay of free prostate-specific antigen with nanoparticle label technology." Clinical Chemistry 47(7): 1269-78. BACKGROUND: The extreme specific activity of the long-lifetime fluorescent europium(III) chelate nanoparticles and the enhanced monovalent binding affinity of multivalent nanoparticle-antibody bioconjugates are attractive for noncompetitive immunoassay. METHODS: We used a noncompetitive, two-step immunoassay design to measure free prostate-specific antigen (PSA). Europium(III) chelate nanoparticles (107 nm in diameter) were coated with a monoclonal anti-PSA antibody (intrinsic affinity, 6 x 10(9) L/mol). The nanoparticle-antibody bioconjugates had an average of 214 active binding sites per particle and a monovalent binding affinity of 7 x 10(10) L/mol. The assay was performed in a low-fluorescence microtitration well passively coated with an another monoclonal anti-PSA antibody (affinity, 2 x 10(10) L/mol), and the europium(III) fluorescence was measured directly from the bottom of the well by a standard time-resolved microtitration plate fluorometer. RESULTS: The detection limit (mean + 2 SD) was 0.040 ng/L (7.3 x 10(5) molecules/mL), and the dynamic detection range covered four orders of magnitude in a 3-h total assay time. The imprecision (CV) over the whole assay range was 2-10%. The detection limit of the assay was limited by the fractional nonspecific binding of the bioconjugate to the solid phase (0.05%), which was higher than the nonspecific binding of the original antibody (<0.01%). CONCLUSIONS: The sensitivity of the new assay is equal to that of the ambient-analyte, microspot immunoassay and will be improved by use of optimized, high binding-site density nanoparticle-antibody bioconjugates with reduced nonspecific binding and improved monovalent binding affinity. Soukka, T., H. Harma, et al. (2001). "Utilization of kinetically enhanced monovalent binding affinity by immunoassays based on multivalent nanoparticle-antibody bioconjugates." Analytical Chemistry 73(10): 2254-60. The monovalent binding affinity of high binding site density nanoparticle-antibody bioconjugates is shown to exceed the intrinsic affinity of the original, monoclonal antibody. The nanoparticle-antibody bioconjugates were prepared by covalent coupling of antibodies to long-lifetime fluorescent, europium(III) chelate nanoparticles, 107 nm in diameter. Experiments were carried out in standard microtitration wells to determine solid-phase association and dissociation rate constants, nonspecific binding, and affinity constants of the various binding site density nanoparticle-antibody bioconjugates and the conventionally labeled monoclonal antibody. The affinity constant for monovalent binding of a high binding site density bioconjugate (5.4 x 10(10) M(-1)) was 8-fold higher than the intrinsic affinity of the antibody (6.6 x 10(9) M(-1)). The separately measured association (2.5 x 10(6) M(1) s(-1)) and dissociation (3.7 x 10(-5) s(-1)) rate constants of the bioconjugate were 2-fold higher and 4-fold lower, respectively, compared to the antibody. The dependence of the association rate constant of the density of the binding sites enhanced the kinetics and the affinity of the high binding site density bioconjugates. The nanoparticle labels with high specific activity, low nonspecific binding, and enhanced binding affinity of the nanoparticle-antibody bioconjugates contribute to the design of the next generation immunoassays with extreme sensitivity. Soulantica, K., A. Maisonnat, et al. (2001). "Synthesis and self-assembly of monodisperse indium nanoparticles prepared from the organometallic precursor." Angewandte Chemistry International Edition English 40(2): 448-451. Speiser, P. (1984). "Drug targeting by drug entrapment into ultrafine compartments as carriers." Applied Biochemistry and Biotechnology 10(3): 221-35. The incorporation of drugs into vesicles is one of several technological methods for the optimization of targeted drug delivery and controlled drug targeting. The main problems will always remain: To design inert auxiliary accompanying materials in order to overcome side reactions; To use body-friendly and biodegradable macromolecular carrier materials for the therapeutic system; To miniaturize the dosage form dramatically in the submicroscopic size range in order to eliminate foreign body irritations; To develop ultrafine solid and amorphous vesicular compartments (nanocapsules, nanopellets, nanoparticles) to get stable systems with good tissue transfer and organ targeting properties The actual stand of the incorporation of drugs and biologic active material into ultrafine colloidal solid capsules is reviewed here as for instance: Immunoactive material; Fluorescent indicators in body fluids; Controlled and sustained release systems Nonspecific drug targeting of the first-order (passage through endothelial tissues); Second-order targeting (a specific transparenchymal migration), and a highly specific targeting of the third-order (transcellular passage, especially lysosomal transports). Examples for some of these applications are given. It can be shown that such ultrafine vesiculated capsules offer some advantages when applied parenterally, but also partly for oral application. In the future, still more studies are necessary finally to clarify the importance and practical use of such ultrafine targeting carriers.

Speiser, P. P. (1991). "Nanoparticles and liposomes: a state of the art." Methods and Findings in Experimental and Clinical Pharmacology 13(5): 337-42. The loading of drugs into ultrafine host vesicles or colloidal capsules in the nanometer size range is an acknowledged technique for the optimization of controlled drug delivery. The main purpose will always be to design inert auxiliary accompanying materials; to use body-friendly and biodegradable excipients; and to miniaturize the drug carrier system dramatically in order to get good stability, excellent absorption, quantitative tissular transfer and, therefore, the expected pharmacodynamic activity. Furthermore, side effects and foreign body irritation should be avoided and a good local and systemic tolerance during and after medication should be a condition sine qua non. The actual state of the art is shown with 4 practical application examples, namely: a cellular uptake by endocytosis and a specific lysosomotropic cell transfer with cell tracer-loaded nanoparticles; the strong immunosuppressive stimulation of nanocapsules--as new adjuvants--when loaded with viral or other antigens; the better blood-brain barrier transfer of an antiparkinson drug when covalently bound to special liposomes; and the use of minivesicles for controlled site-specific anticancer drug release (tumor targeting). In the future, we must find a possibility to deliver the correct dose of the drug precisely to the diseased target organs, tissues or cells of destination, without flooding the organism with massive drug doses. One technologic answer could be the minicarrier concept with specific pathfinders and aspecific pretargeters that serve as switchmen to guide the drug-loaded carrier to the organs, with precise spot landing. Spinu, L., H. Srikanth, et al. (2000). "Dynamic radio-frequency transverse susceptibility in magnetic nanoparticle systems." Journal of Applied Physics 87(9): 1-3. A novel resonant method based on a tunnel-diode oscillator is used to study the dynamic transverse susceptibility in a Fe nanoparticle system. The magnetic system consists of an aggregate of nanometer-size core (Au)-shell (Fe) structure, synthesized by reverse micelle methods. Static and dynamic magnetization measurements carried out in order to characterize the system reveal a superparamagnetic behavior at high temperature. The fielddependent transverse susceptibility at radio-frequencies for different temperatures reveals distinct peak structure at characteristics fields (+or-H/sub K/,H/sub C/) which changes with temperature. It is proposed that relaxation processes could explain the influence of the temperature on the field dependence of the transverse susceptibility. (12 References). Sqalli, O., M. P. Bernal, et al. (2000). "Improved tip performance for scanning near-field optical microscopy by the attachment of a single gold nanoparticle." Applied Physics Letters 76(15): 2134-6. Nanometer-size optical probes are gaining increasing interest in near-field optical microscopy. Optimization of the probe shape is still a challenging research and development issue. Here, we propose to improve the optical properties of a fiber-based probe by attachment at the tip apex of one single gold particle of 60 nm diameter. This probe produces an enhancement of the light throughput, both in the near and the far fields, a homogenization of the diffracted light polarization, and a higher accuracy of the topographic sensitivity. In this letter, the chemical procedure for the fixation of one single gold particle on the apex of a standard tip for scanning near-field microscopy is described. Far-field as well as near-field measurements with this probe are performed, showing improvement of the light distribution in excellent agreement with the theory. (14 References). Steinfort, A. J., P. M. Scholte, et al. (1996). "Strain in Nanoscale Germanium Hut Clusters on Si(001) Studied by X-Ray Diffraction." Physical Review Letters 77(10): 2009-2012. Stella, B., S. Arpicco, et al. (2000). "Design of folic acid-conjugated nanoparticles for drug targeting." Journal of Pharmaceutical Sciences 89(11): 1452-64. The new concept developed in this study is the design of poly(ethylene glycol) (PEG)-coated biodegradable nanoparticles coupled to folic acid to target the folate-binding protein; this molecule is the soluble form of the folate receptor that is overexpressed on the surface of many tumoral cells. For this purpose, a novel copolymer, the poly[aminopoly(ethylene glycol)cyanoacrylate-co-hexadecyl cyanoacrylate] [poly(H(2)NPEGCA-co-HDCA)] was synthesized and characterized. Then nanoparticles were prepared by nanoprecipitation of the obtained copolymer, and their size, zeta potential, and surface hydrophobicity were investigated. Nanoparticles were then conjugated to the activated folic acid via PEG terminal amino groups and purified from unreacted products. Finally, the specific interaction between the conjugate folate-nanoparticles and the folate-binding protein was evaluated by surface plasmon resonance. This analysis confirmed a specific binding of the folate-nanoparticles to the folate-binding protein. This interaction did not occur with nonconjugated nanoparticles used as control. Thus, folate-linked nanoparticles represent a potential new drug carrier for tumor cell-selective targeting. Stepanov, A. L., D. E. Hole, et al. (2000). "Excimer laser annealing of glasses containing implanted metal nanoparticles." Nuclear Instruments and Methods in Physics Research Section B Beam Interactions with Materials and Atoms 166(167): 882-6. Silver and copper nanoparticles have been synthesized by ion implantation in silica and soda-lime silicate glass at

60 keV to a dose of 4*10/sup 16/ ion/cm/sup 2/ and at 50 keV to a dose of 8*10/sup 16/ ion/cm/sup 2/, respectively. The glasses were annealed using pulses of a high-power KrF excimer laser (248 nm) in ambient atmosphere. This employed a single (25 ns) pulse fluence of 0.25 J/cm/sup 2/ for Ag-implanted samples or of 0.21 J/cm/sup 2/ for Cu-implanted ones. Several pulses from 1 to 250 of the same energy density at a frequency of 1 Hz were accumulated in the same area on the surface. The formation and modification of metal nanoparticle was assessed via optical reflectance, combined with Rutherford backscattering analysis. Generally, changes induced by laser pulses suggest there are both reductions of the nanoparticles and some longer-range diffusion of metal atoms into the glass. However, before the total dissolution of metal nanoparticles is accrued, the substrate temperature, increasing during many-pulse treatments, initiates the regrowth of new metal nanoparticles that leads to a rise of the reflectance. These results are discussed on the basis of a surface substrate melting. This work is part of an attempt to gain control over the size and depth distribution of such metal nanoparticles. (10 References). Stieneker, F., J. Kreuter, et al. (1991). "High antibody titres in mice with polymethylmethacrylate nanoparticles as adjuvant for HIV vaccines." AIDS 5(4): 431-5. The aim of the present study was to determine the effect of polymethylmethacrylate (PMMA) nanoparticles as adjuvants for an HIV-2 whole-virus vaccine in mice. The data clearly revealed that PMMA nanoparticles induced 10-100-fold higher antibody titres than aluminium hydroxide or an aqueous vaccine control preparation as measured by enzyme-linked immunosorbent assay. Moreover, the high antibody titres obtained with PMMA as adjuvant appeared to be stable for between 10 and 20 weeks after immunization. In contrast, the titres of the control preparations, fluid or aluminium hydroxide formulations, decreased after 10 weeks. Stietz, F., J. Bosbach, et al. (2000). "Decay times of surface plasmon excitation in metal nanoparticles by persistent spectral hole burning." Physical Review Letters 84(24): 5644-7. We describe a new technique to determine the homogeneous linewidths of surface plasmon resonances of metal nanoparticles and thus measure the decay time of this collective electron excitation. The method is based on spectral hole burning and has been applied to supported oblate Ag particles with radii of 7.5 nm. From the experimental results and a theoretical model of hole burning the linewidth of 260 meV corresponding to a decay time of 4.8 fs was extracted. This value is shorter than expected for damping by bulk electron scattering. We conclude that additional damping mechanisms have been observed and reflect confinement of the electrons in nanoparticles with sizes below 10 nm. Stiskal, M., H. C. Schwickert, et al. (1996). "Contrast enhancement in experimental radiation-induced liver injury: comparison of hepatocellular and reticuloendothelial particulate contrast agents." Journal of Magnetic Resonance Imaging 6(2): 286-90. We compared the liver enhancement of two superparamagnetic agents, polycrystalline iron oxide nanoparticles (PION) and PION coated with asialofetuin (ASF), in an experimental model of focal radiation-induced hepatitis. PION, a reticuloendothelial system-directed agent, and PION-ASF, a hepatocellular-directed agent, were compared for time-dependent liver enhancement in an experimental model of radiation-induced liver injury. Using the reticuloendothelial system (RES)-directed PION, the normal, nonirradiated portion of the liver decreased in signal intensity (SI) with a mean negative enhancement of -66% +/- 4, whereas the irradiated portion (60 Gy, 3 days before imaging) of the liver decreased in SI by -24% +/- 2, significantly less (P &lt;.05). SI changes in irradiated liver tissue using PION were dose-dependent, being more pronounced with lower radiation exposure. The difference in SI changes induced by PION-ASF between irradiated and nonirradiated liver was not statistically different, but SI decreased with a mean negative enhancement of -80% +/- 2. The RES-directed PION is more sensitive for the detection of radiation-induced hepatitis than is the hepatocyte-directed PION-ASF. The insensitivity of PION-ASF enhancement for diffuse liver injury may be clinically advantageous for detecting focal lesions in the presence of diffuse hepatic injury. Suh, H., B. Jeong, et al. (1998). "Cellular uptake study of biodegradable nanoparticles in vascular smooth muscle cells." Pharm Res 15(9): 1495-8. Sukhorukov, G. B., E. Donath, et al. (2000). "Microencapsulation by means of step-wise adsorption of polyelectrolytes." Journal of Microencapsulation 17(2): 177-85. Step-wise adsorption of polyelectrolytes is used for the fabrication of micro- and nanocapsules with determined size, capsule wall composition and thickness. The capsule walls made of polyelectrolyte multilayers exclude high molecular weight compounds. Assembling of lipid layers onto these polyelectrolyte capsules prevents the permeation of small dyes. Encapsulation of magnetite nanoparticles is demonstrated and the features of these novel capsules are discussed. Sun, X., A. Gutierrez, et al. (2000). "Investigations on magnetic properties and structure for carbon encapsulated nanoparticles of Fe, Co, Ni." Materials Science and Engineering A Structural Materials Properties Microstructure and

Processing(1): 157-60. In the present work, experiments aim at the encapsulation of foreign materials within hollow graphitic cage have been carried out for iron group metals (Fe, Co, Ni) using a modified arc-discharge (carbon arc) reactor. HRTEM (high resolution transmission electron microscope), and XRD (X-ray diffractometer) studies, for three carbon encapsulated materials, showing nanoparticles of both a metallic phase ( alpha -Fe, gamma -Fe; hcp-Co, fcc-Co; fcc-Ni) and also a carbide phase (M/sub 3/C, M=Fe, Co, Ni) are encapsulated in graphitic carbon. The magnetic measurement for the three as-made nanoparticles, indicating that the values of saturation magnetic moment of three nanoparticle are 37.6, 55.5 and 15.7% of the bulk ferromagnetic elements counterparts, respectively. The different comparison values (M/sub r//M/sub s/) of remanent magnetization (M/sub r/) and saturation magnetization (M/sub s/) suggest, the encapsulated Fe and Co nanoparticles are shown to be ferromagnetic with a ratio of remnant to saturation magnetization M/sub r//M/sub s/~0.3; whereas, the encapsulated Ni nanoparticles exhibits superparamagnetic behavior at room temperature. (7 References). Sun, S., C. B. Murray, et al. (2000). "Monodisperse FePt nanoparticles and ferromagnetic FePt nanocrystal superlattices." Science 287(5460): 1989-92. Synthesis of monodisperse iron-platinum (FePt) nanoparticles by reduction of platinum acetylacetonate and decomposition of iron pentacarbonyl in the presence of oleic acid and oleyl amine stabilizers is reported. The FePt particle composition is readily controlled, and the size is tunable from 3- to 10-nanometer diameter with a standard deviation of less than 5%. These nanoparticles self-assemble into three-dimensional superlattices. Thermal annealing converts the internal particle structure from a chemically disordered face-centered cubic phase to the chemically ordered face-centered tetragonal phase and transforms the nanoparticle superlattices into ferromagnetic nanocrystal assemblies. These assemblies are chemically and mechanically robust and can support high-density magnetization reversal transitions. Suvorova, E. I. and P. A. Buffat (1999). "Electron diffraction from micro- and nanoparticles of hydroxyapatite." Journal of Microscopy 196(1): 46-58. Hydroxyapatite (HAP) obtained from aqueous solutions under different conditions has been examined by highresolution transmission electron microscopy (HRTEM) and electron diffraction, including selected-area electron diffraction (SAED) and microdiffraction. A Philips CM300 field-emission gun electron microscope with a Schottky W/ZrO field-emission tip and a spherical aberration constant of 0.65 mm was used at 300 kV. The HAP crystals had different sizes, ranging from a few nanometres to a few micrometres. Single-crystal diffraction patterns have been obtained from the largest microcrystals using the conventional SAED technique. Assemblies of nanoparticles gave only broad diffuse rings. Nevertheless, microdiffraction with electron microprobes 3.5-10 nm in diameter clearly indicated the crystalline character of the nanoparticles in these assemblies. Experimental HRTEM images, Fourier transforms and calculated images exhibited the fine structure of the HAP crystals. Suzuki, K., T. Uruno, et al. (2000). "Preparation technique of single-phase silicon borides films for nanoparticle deposition by laser ablation." Review of Laser Engineering 28(6): 359-64. We report a successful selective technique for preparing single-phase boron-rich silicon borides (SiB/sub x/) films employing a pulsed Nd:YAG laser ablation method for multilayer deposition, the results of which are designed for use in thermoelectric energy conversion devices. In this process, SiB/sub x/ films on silicon substrates were produced by the pulsed laser ablation method using a multi-target (single bulk material target: Si and B) in 0.1 Torr argon gas. Nanometer order silicon particles and boron particles were ablated by different shot numbers of Nd:YAG laser pulses, which deposited several hundred alternating layers of the particles. After the films were heated to about 1670 K for 10 hours under argon gas, X-ray diffraction patterns and electron probe microanalyzer (EPMA) analysis of these films showed a single-phase composition. As a result of the laser ablation process under several processing conditions, thin films of SiB/sub 4/ or SiB/sub 6/ are selectively presented about three microns thick and about six centimeters square. The influence of process parameters on morphology, phase diagram, electrical conductivity, thermal conductivity and Seebeck coefficient of the films were also discussed. (12 References). Swati, D., A. Pal, et al. (2000). "Molecular photonic switches employing ions and nanoparticles of coinage and platinum metals." Langmuir 16(17): 6855-61. Organic molecules containing a fluorophore-spacer-receptor (F-S-R) combination are a hot topic of contemporary research due to their wide applicability in information processing devices. This work is the first report of the use of metal ions and nanoparticles of coinage metals (Cu, Ag, Au) and platinum metals (Ni, Pt, Pd) in developing molecular photonic switches. In the presence of these metals, the photoinduced electron transfer (PET) normally responsible for fluorescence quenching of F-S-R molecules is hindered. These metal ions and their corresponding nanoparticles interact with the receptor (R) site, preventing its participation in PET, thus increasing the fluorescence of the F-S-R molecule. This is comparable to the "switching-on" operation of a light switch. However, beyond a certain critical concentration that varies from metal to metal, the quenching effect of the ions overrules their fluorescence enhancement (FE) effect and thus the fluorescence of the probe decreases. This is equivalent

to the "switching-off" operation of a switch. Thus, digital instruments operating with the 1 (on) or 0 (off) principle can employ such metal ion/nanoparticle-probe combinations as efficient molecular photonic switches. Maintaining the critical concentration as a borderline, such systems can efficiently function as OR logic gates. (23 References). Syler, I., M. Appel, et al. (1999). "Macrophage activation by a lipophilic derivative of muramyldipeptide within nanocapsules: investigation of the mechanism of drug delivery." Journal of Nanoparticle Research 1: 91-97. Takatori, K., T. Tani, et al. (1999). "Preparation and characterization of nano-structured ceramic powders synthesized by emulsion combustion method." Journal of Nanoparticle Research 1: 197-204. Takeuchi, H., H. Yamamoto, et al. (2001). "Mucoadhesive nanoparticulate systems for peptide drug delivery." Advances in Drug Delivery Review 47(1): 39-54. This chapter describes the preparation of and methods for evaluating mucoadhesive nanoparticulate systems, including liposomes and polymeric nanoparticles. Mucoadhesive ability is conferred on the particulate systems by coating their surface with mucoadhesive polymers such as chitosan and Carbopol. The feasibility of this surface modification was confirmed by measuring the zeta potential. Several methods of evaluating the mucoadhesive properties of particulate systems have been reported in the literature. We have also developed some novel evaluation procedures including a particle counting method using a Coulter counter for polymer-coated liposomes. The mucoadhesive properties of the polymer-coated liposomes and polymeric nanoparticles were confirmed by means of these mucoadhesion tests. In applying these mucoadhesive nanoparticles to the oral and pulmonary administration of peptide drugs, more effective and prolonged action was observed in comparison with noncoated systems, thereby confirming the usefulness of mucoadhesive nanoparticulate systems for the delivery of peptide drugs. Tam, W. Y., W. Wen, et al. (2000). "Electrorheological fluids using bi-dispersed particles." Physica B 279: 1-3. We report a large enhancement of static yield stress for electrorheological fluids by adding ferroelectric nanoparticles of lead zirconate titanate (PZT) or lead titanate (PbTiO/sub 3/) to ER fluids consisting of 50 mu m glass spheres. It is found that the enhancement peaks at certain nanoparticle/microparticle ratios for fixed solid/liquid volume fractions. The results are explained by calculations using an effective medium approach, based on the physical picture that the nanoparticles modify the properties of the liquid and solid components. (6 References). Tamaki, Y., T. Asahi, et al. (2000). "Tailoring nanoparticles of aromatic and dye molecules by excimer laser irradiation." Applied Surface Science 168(15): 85-8. Nanosecond 351 nm excimer laser irradiation of microcrystalline powders of aromatic hydrocarbons and phthalocyanine (Pc) dyes in water results in conversion from opaque suspensions to transparent colloidal solutions. Formation of ~100 nm sized particles are successfully confirmed for oxo(phthalocyaninato)vanadium(IV) (VOPc) by AFM observation. The particles in solution are stable, while some Pc colloid solutions show interesting slow UV absorption spectral changes, which is interpreted in terms of phase transition. The present laser ablation of solution is regarded not only as a new nanoparticle formation method but also as a way of controlling the molecular aggregation in nanoparticles. (12 References). Tan, J. S., D. E. Butterfield, et al. (1993). "Surface modification of nanoparticles by PEO/PPO block copolymers to minimize interactions with blood components and prolong blood circulation in rats." Biomaterials 14(11): 823-33. The biological fate of injected foreign particles is believed to be closely related to their interactions with blood plasma proteins and cells. In order to verify this correlation, we have quantitatively measured protein adsorption and blood retention profiles in rats by using model polystyrene latex nanoparticles. The in vitro interactions of these non-biodegradable particles with plasma proteins and whole blood can be altered by modifying their surfaces with a family of amphiphilic polymeric surfactants, PEO/PPO Pluronic or Tetronic block copolymers. Protein adsorption was measured by several techniques, including photon correlation spectroscopy, centrifugation, high performance liquid chromatography and field-flow fractionation. Pluronic F108 and Tetronic 908 and 1508 copolymers (with PEO terminal block MWPEO &gt; 5000, PPO middle block MWPPO &gt; 3000, and HLB values &gt; 24) were shown to be the most effective surface modifiers in reducing adsorption of plasma proteins on the particles. Minimum interaction of coated particles with whole blood was also observed by optical microscopy. The blood circulation half-life of the particles injected in rats was increased from 20 min to 13 h when the latex particles (75 nm) were precoated with these block copolymers. These results suggest that nanoparticles designed for use as injectable drugs or drug carriers should display similar surface characteristics provided by such amphiphilic surface modifiers. Tang, Z. X., C. M. Sorensen, et al. (1991). "Size-dependent Curie temperature in nanoscale MnFe2O4 particles." Physical Review Letters 67(25): 3602-3605.

Taton, T. A., C. A. Mirkin, et al. (2000). "Scanometric DNA array detection with nanoparticle probes." Science 289(5485): 1757-60. A method for analyzing combinatorial DNA arrays using oligonucleotide-modified gold nanoparticle probes and a conventional flatbed scanner is described here. Labeling oligonucleotide targets with nanoparticle rather than fluorophore probes substantially alters the melting profiles of the targets from an array substrate. This difference permits the discrimination of an oligonucleotide sequence from targets with single nucleotide mismatches with a selectivity that is over three times that observed for fluorophore-labeled targets. In addition, when coupled with a signal amplification method based on nanoparticle-promoted reduction of silver(I), the sensitivity of this scanometric array detection system exceeds that of the analogous fluorophore system by two orders of magnitude. Taton, T. A., A. Mirkin Chad, et al. (2000). "Scanometric DNA array detection with nanoparticle probes." Science 289(5485): 1757-1760. A method for analyzing combinatorial DNA arrays using oligonucleotide-modified gold nanoparticle probes and a conventional flatbed scanner is described here. Labeling oligonucleotide targets with nanoparticle rather than fluorophore probes substantially alters the melting profiles of the targets from an array substrate. This difference permits the discrimination of an oligonucleotide sequence from targets with single nucleotide mismatches with a selectivity that is over three times that observed for fluorophore-labeled targets. In addition, when coupled with a signal amplification method based on nanoparticle-promoted reduction of silver(I), the sensitivity of this scanometric array detection system exceeds that of the analogous fluorophore system by two orders of magnitude. Taylor, J. R., M. M. Fang, et al. (2000). "Probing specific sequences on single DNA molecules with bioconjugated fluorescent nanoparticles." Analytical Chemistry 72(9): 1979-86. Nanometer-sized fluorescent particles (latex nanobeads) have been covalently linked to DNA binding proteins to probe specific sequences on stretched single DNA molecules. In comparison with single organic fluorophores, these nanoparticle probes are brighter, are more stable against photobleaching, and do not suffer from intermittent on/off light emission (blinking). Specifically, we demonstrate that the site-specific restriction enzyme EcoRI can be conjugated to 20-nm fluorescent nanoparticles and that the resulting nanoconjugates display DNA binding and cleavage activities of the native enzyme. In the absence of cofactor magnesium ions, the EcoRI conjugates bind to specific sequences on double-stranded DNA but do not initiate enzymatic cutting. For single DNA molecules that are stretched and immobilized on a solid surface, nanoparticles bound at specific sites can be directly visualized by multicolor fluorescence microscopy. Direct observation of site-specific probes on single DNA molecules opens new possibilities in optical gene mapping and in the fundamental study of DNA-protein interactions. Teo, K. L., S. H. Kowk, et al. (2000). "Sandwich-structured thin film of silicon nanoparticles embedded in Al2O3 matrices." Journal of Physics D Applied Physics 33(21): 2687-90. Silicon nanoparticles embedded in the host matrix of an Al/sub 2/O/sub 3/ thin film, with a thickness of about 260 nm, were prepared by using the pulsed laser deposition method. The laser target consisted of a small silicon wafer glued onto the surface of a circular Al/sub 2/O/sub 3/ plate, which was set to rotate uniformly when laserablating. TEM and EDS results showed that the films consisted of silicon nanoparticles in the form of nanocrystals with diameters of less than 6 nm dispersed in the amorphous Al/sub 2/O/sub 3/ matrices. A secondary ion mass spectroscopy depth profile of the silicon content of the film indicated that the silicon nanoparticles in the Al/sub 2/O/sub 3/ matrices were arranged in fairly well demarcated thin layers sandwiched between layers of the host material, FTIR results evidently suggested that the encapsulating amorphous Al/sub 2/O/sub 3/ material forms a good host for the prevention of atmospheric oxidation of the silicon nanoparticles. However, prolonged annealing can cause the silicon nanoparticle surface interfacing the host material to be oxidized by the oxygen mostly from the Al/sub 2/O/sub 3/ molecules and to be bonded to the Al or O-Al bonds. (18 References). Theil Kuhn, L., A. K. Geim, et al. (2000). "Magnetisation of isolated single crystalline Fe-nanoparticles measured by a ballistic Hall micro-magnetometer." European Physical Journal D 10(2): 259-63. We present here the first magnetisation measurements on isolated single crystalline Fe-nanoparticles performed with a ballistic Hall micro-magnetometer. The measurements have a sensitivity of 10/sup 4/ mu /sub B/ and thus provide us the possibility to study the mechanisms of magnetisation reversal in a single nanoparticle. The magnetic properties of the nanoparticles are influenced by their crystal structure and shape, and the presence of an oxide surface layer. They exhibit curling of the magnetic moments, but also a novel hysteresis behaviour. The spin configurations found for the system agree well with numerical calculations based on a Heisenberg Hamiltonian including the exchange and dipole interaction and surface anisotropy. (19 References). Thioune, O., C. Chaumat, et al. (1999). "[Evaluation of film forming properties of a hydroxypropylmethylcellulose phthalate

(HP 55) pseudolatex]." Journal de Pharmacie de Belgique 54(5): 147-51. An hydroxypropylmethyl cellulose phthalate (HP55) pseudolatex was prepared by a nanoprecipitation method. This allows nanoparticles formation when a solution of the polymer in an organic solvent (phase S1 or organic phase) is introduced in a precipitant medium (phase S2 or aqueous phase) which consists of water containing surfactant. A modification of the solvent nature of phase S1 resulted in an improvement of the yield of the preparation. Then, the obtained pseudolatex was used to prepare films which were evaluated by mechanical tests and coating of tablets containing theophylline. Thomas, M. D. R., H. Ahmed, et al. (2000). "Electron-beam-induced conduction in a ruthenium carbonyl nanoparticle polymer." Applied Physics Letters 76(13): 1773-5. A polymer composed of ruthenium carbonyl and of the formula Ru/sub 6/C(CO)/sub 15/Ph/sub 2/PCCPPh/sub 2//sub n/ has been synthesized. It is found to behave as a negative electron-beam resist with a sensitivity of 400 C/m/sup 2/. Upon exposure to the electron beam, the electrical conductivity of the patterned films is found to vary over seven orders of magnitude according to a power-law dependence on dose. Temperature dependence of the conductivity is studied, and the conduction is attributed to variable-range hopping between ruthenium superclusters in two dimensions. (9 References). Thompson, R. B., V. V. Ginzburg, et al. (2001). "Predicting the mesophases of copolymer-nanoparticle composites." Science 292(5526): 2469-72. The interactions between mesophase-forming copolymers and nanoscopic particles can lead to highly organized hybrid materials. The morphology of such composites depends not only on the characteristics of the copolymers, but also on the features of the nanoparticles. To explore this vast parameter space and predict the mesophases of the hybrids, we have developed a mean field theory for mixtures of soft, flexible chains and hard spheres. Applied to diblock-nanoparticle mixtures, the theory predicts ordered phases where particles and diblocks selfassemble into spatially periodic structures. The method can be applied to other copolymer-particle mixtures and can be used to design novel composite architectures. Thurmond, K. B., E. E. Remsen, et al. (1999). "Packaging of DNA by shell crosslinked nanoparticles." Nucleic Acids Research 27(14): 2966-71. We demonstrate compaction of DNA with nanoscale biomimetic constructs which are robust synthetic analogs of globular proteins. These constructs are approximately 15 nm in diameter, shell crosslinked knedel-like (SCKs) nanoparticles, which are prepared by covalent stabilization of amphiphilic di-block co-polymer micelles, selfassembled in an aqueous solution. This synthetic approach yields size-controlled nanoparticles of persistent shape and containing positively charged functional groups at and near the particle surface. Such properties allow SCKs to bind with DNA through electrostatic interactions and facilitate reduction of the DNA hydrodynamic diameter through reversible compaction. Compaction of DNA by SCKs was evident in dynamic light scattering experiments and was directly observed by in situ atomic force microscopy. Moreover, enzymatic digestion of the DNA plasmid (pBR322, 4361 bp) by Eco RI was inhibited at low SCK:DNA ratios and prevented when [le]60 DNA bp were bound per SCK. Digestion by Msp I in the presence of SCKs resulted in longer DNA fragments, indicating that not all enzyme cleavage sites were accessible within the DNA/SCK aggregates. These results have implications for the development of vehicles for successful gene therapy applications. Tian, X. X. and M. J. Groves (1999). "Formulation and biological activity of antineoplastic proteoglycans derived from Mycobacterium vaccae in chitosan nanoparticles." Journal of Pharmacy and Pharmacology 51(2): 151-7. Although heat-killed suspensions of Mycobacterium vaccae have been tested clinically against tuberculosis and cancer, from a pharmaceutical perspective it would be advantageous to utilize isolated active components rather than the heat-degraded bacterial materials. In our laboratory we have isolated from M. vaccae a number of highmolecular-weight proteoglycans with considerable immunological and antineoplastic activity. The structure of one of these, PS4A, obtained by extraction with boiling water, seems to consist of a basic unit with a 20-kDa protein core to which are attached glucans and O-methylated 4-kDa polysaccharides. The molecular weight is (approx.) 50 kDa, but because of self-association, that of the recovered high-molecular-weight fraction is greater than 150 kDa. A similar, but even larger, molecule (PS4alpha, MW approximately 20 MDa) is obtained by cold extraction with 8 M urea. Both are active in-vivo against an S-180 murine sarcoma model but have no activity in-vitro, suggesting an antitumour effect involving activated macrophages. For this reason gelatin nanoparticles are unsuitable as a vehicle but chitosan seemed to be a promising alternative. In this report we describe the production of stable 600-700-nm diameter nanoparticles of chitosan without organic solvents. Adsorption and release of bovine serum albumin seemed to be affected by the charge of the two reactants and at high doses not all adsorbate was released. PS4A, because of structural and compositional differences, had to be loaded on to the chitosan by freeze drying a suspension of the nanoparticles in a solution of the drug. After a rapid (burst) release phase, the rate of release into water was steady for the next 4 h, but not all the drug was released. In-vivo it was evident that PS4A and PS4alpha were equally active in solution or when formulated in the chitosan nanoparticles. These results show that chitosan nanoparticles, readily prepared without the use of organic

solvents, are a suitable vehicle for the delivery of these immunostimulants from M. vaccae; the formulations might find application as antitumour agents. Tibbe, A. G., B. G. de Grooth, et al. (1999). "Optical tracking and detection of immunomagnetically selected and aligned cells." Nature Biotechnology 17(12): 1210-3. We have developed a platform for cell analysis based on immunomagnetic selection and magnetic alignment of cells in combination with an epi-illumination tracking and detection system. Whole blood was labeled with ferromagnetic nanoparticles and fluorescent probes, and placed in a magnetic field in a chamber. Cells labeled with ferromagnetic nanoparticles moved upward and aligned along ferromagnetic lines deposited by lithographic techniques on an optically transparent surface of the chamber. An epi-illumination system using a 635 nm laser diode as a light source scanned the lines and measured signals obtained from the aligned cells. The cell counts per unit of blood volume obtained with the system correlated well with those obtained from the counts from a standard hematology analyzer and flow cytometer. The cell analysis platform is significantly less complex and more sensitive than current cell analysis equipment and provides additional functionality through its ability to subject the cells to repeated and varied analyses while they remain in a natural environment (i.e., whole blood). Tiefenauer, L. X., G. Kuhne, et al. (1993). "Antibody-magnetite nanoparticles: in vitro characterization of a potential tumorspecific contrast agent for magnetic resonance imaging." Bioconjugate Chemistry 4(5): 347-52. Target-specific superparamagnetic contrast agents may allow the localization of specific tissues such as tumors by magnetic resonance imaging (MRI). In this report the preparation and in vitro characterization of tumor-specific superparamagnetic particles (SMP) are described. Particles of uniform size (9.6 +/- 0.8 nm) were prepared from an alkaline solution of ferric and ferrous ions and isolated by differential centrifugation. The resulting nanoparticle suspension is stabilized in buffer using a polypeptide coat to which a monoclonal antibody, specific to carcinoembryonic antigen (CEA), was covalently attached at the hinge region. The resulting anti-CEA SMP have a hydrodynamic radius of less than 50 nm, and specifically bind to CEA in vitro. The visualization of epitopes, present on a cell surface in very low density as expected for tumor antigens or receptors, may be achieved due to the high R2 relaxivity of 300 L mmol-1s-1 of the contrast agent described here. Furthermore, the polypeptide coat chosen provides an ideal platform for the attachment of biological modifiers needed for the reduction of the antigenicity and blood clearance rate of anti-CEA SMP. Tiefenauer, L. X., A. Tschirky, et al. (1996). "In vivo evaluation of magnetite nanoparticles for use as a tumor contrast agent in MRI." Magn Reson Imaging 14(4): 391-402. Magnetite nanoparticles, coated by three different artificial polypeptides, were conjugated to an antibody specific to the carcinoembryonic antigen (CEA). To protect the particles from fast blood elimination, the coats were modified by various sugars, polyethyleneglycol, albumin, and sialoproteins, respectively. The protective effect was determined by using a specific in vitro test and by analyzing the biodistribution of the nanoparticles in nude mice grafted with CEA-tumors. In particular, a prolongation of the blood circulation time has been expected, if a natural modifier is attached to the coated nanoparticles. Although the elimination rate could hardly be decreased by any modifiers, the tumor accumulation is slightly improved by using the specific sialoprotein glycophorin B. The usefulness of nanoparticles as image contrast agents is probably limited by their microdistribution within the tumor tissue. The requirements for a contrast agent to be highly tissue specific are discussed. Tobias, H. J., D. E. Beving, et al. (2001). "Chemical analysis of diesel engine nanoparticles using a nano-DMA/thermal desorption particle beam mass spectrometer." Environment and Science Technology 35(11): 2233-43. Diesel engines are known to emit high number concentrations of nanoparticles (diameter < 50 nm), but the physical and chemical mechanisms by which they form are not understood. Information on chemical composition is lacking because the small size, low mass concentration, and potential for contamination of samples obtained by standard techniques make nanoparticles difficult to analyze. A nano-differential mobility analyzer was used to size-select nanoparticles (mass median diameter approximately 25-60 nm) from diesel engine exhaust for subsequent chemical analysis by thermal desorption particle beam mass spectrometry. Mass spectra were used to identify and quantify nanoparticle components, and compound molecular weights and vapor pressures were estimated from calibrated desorption temperatures. Branched alkanes and alkyl-substituted cycloalkanes from unburned fuel and/or lubricating oil appear to contribute most of the diesel nanoparticle mass. The volatility of the organic fraction of the aerosol increases as the engine load decreases and as particle size increases. Sulfuric acid was also detected at estimated concentrations of a few percent of the total nanoparticle mass. The results are consistent with a mechanism of nanoparticle formation involving nucleation of sulfuric acid and water, followed by particle growth by condensation of organic species. Tobio, M., R. Gref, et al. (1998). "Stealth PLA-PEG nanoparticles as protein carriers for nasal administration." Pharm Res 15(2): 270-5. PURPOSE: The aim of the study was to encapsulate a model protein antigen, tetanus toxoid (TT), within hydrophobic (PLA) and surface hydrophilic (PLA-PEG) nanoparticles and to evaluate the potential of these

colloidal carriers for the transport of proteins through the nasal mucosa. METHODS: TT-loaded nanoparticles, prepared by a modified water-in-oil-in-water solvent evaporation technique, were characterized in their size, zeta potential and hydrophobicity. Nanoparticles were also assayed in vitro for their ability to deliver active antigen for extended periods of time. Finally, 125I-TT-loaded nanoparticles were administered intranasally to rats and the amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 48 h. RESULTS: PLA and PLA-PEG nanoparticles had a similar particle size (137-156 nm) and negative surface charge, but differed in their surface hydrophobicity: PLA were more hydrophobic than PLAPEG nanoparticles. PLA-PEG nanoparticles, especially those containing gelatine as an stabilizer, provided extended delivery of the active protein. The transport of the radiolabeled protein through the rat nasal mucosa was highly affected by the surface properties of the nanoparticles: PLA-PEG nanoparticles led to a much greater penetration of TT into the blood circulation and the lymph nodes than PLA nanoparticles. Furthermore, after administration of 125I-TT-loaded PLA-PEG nanoparticles, it was found that a high amount of radioactivity persisted in the blood compartment for at least 48 h. CONCLUSIONS: A novel nanoparticulate system has been developed with excellent characteristics for the transport of proteins through the nasal mucosa. Tobio, M., A. Sanchez, et al. (2000). "The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration." Colloids Surf B Biointerfaces 18(3-4): 315-323. The aim of the present work was to evaluate if the presence of a polyethylenglycol (PEG) coating around PLA nanoparticles would affect their interaction with biological surfaces, following oral administration to rats. For this purpose, a model antigen, 125I-radiolabeled tetanus toxoid, was encapsulated in PLA and PLA-PEG nanoparticles by a modified water-in-oil-in-water solvent evaporation technique. Firstly, the stability of the nanoparticles in simulated gastrointestinal fluids was evaluated. Results showed an interaction between the nanoparticles and the enzymes of the digestive fluids, this interaction being considerably reduced by the PEG coating around the particles. On the other hand, the PLA forming the nanoparticles was found to be only slightly degraded (9% converted to lactate for PLA nanoparticles and 3% for PLA-PEG nanoparticles) and that the encapsulated tetanus toxoid remained mostly associated to the nanoparticles upon incubation in the digestive fluids for up to 4 h. Finally, the in vivo experiments showed that, after oral administration to rats, the levels of encapsulated radioactive antigen in the blood stream and lymphatics were higher for PLA-PEG nanoparticles than for PLA nanoparticles. In conclusion, the PLA-PEG nanoparticles have a promising future as protein delivery systems for oral administration. Tohver, V., J. E. Smay, et al. (2001). "Nanoparticle halos: A new colloid stabilization mechanism." Proceedings of the National Academy of Sciences USA 10: 10. A new mechanism for regulating the stability of colloidal particles has been discovered. Negligibly charged colloidal microspheres, which flocculate when suspended alone in aqueous solution, undergo a remarkable stabilizing transition upon the addition of a critical volume fraction of highly charged nanoparticle species. Zeta potential analysis revealed that these microspheres exhibited an effective charge buildup in the presence of such species. Scanning angle reflectometry measurements indicated, however, that these nanoparticle species did not adsorb on the microspheres under the experimental conditions of interest. It is therefore proposed that highly charged nanoparticles segregate to regions near negligibly charged microspheres because of their repulsive Coulombic interactions in solution. This type of nanoparticle haloing provides a previously unreported method for tailoring the behavior of complex fluids. Tokumitsu, H., H. Ichikawa, et al. (1999). "Chitosan-gadopentetic acid complex nanoparticles for gadolinium neutroncapture therapy of cancer: preparation by novel emulsion-droplet coalescence technique and characterization." Pharm Res 16(12): 1830-5. PURPOSE: The gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles (Gd-nanoCPs) were prepared for gadolinium neutron-capture therapy (Gd-NCT) and characterized and evaluated as a device for intratumoral (i.t.) injection. METHODS: Gd-nanoCPs were prepared by a novel emulsion-droplet coalescence technique. The effects of the deacetylation degree of chitosan and Gd-DTPA concentration in chitosan medium on the particle size and the gadolinium content in Gd-nanoCPs were examined. In vitro Gd-DTPA release from Gd-nanoCPs was evaluated using an isotonic phosphate-buffered saline solution (PBS, pH 7.4) and human plasma. In vivo GdDTPA retention in the tumor after i.t. injection of Gd-nanoCPs was estimated on mice bearing s.c. B16F10 melanoma. RESULTS: Gd-nanoCPs with the highest Gd content, which were obtained using 100% deacetylated chitosan in 15% Gd-DTPA aqueous solution, were 452 nm in diameter and 45% in Gd-DTPA content. A lower deacetylation degree of chitosan led to an increase in particle size and a decrease in Gd-DTPA content in GdnanoCPs. As Gd-DTPA concentration in the chitosan solution increased, Gd-DTPA content in Gd-nanoCPs increased but the particle size did not vary. Gd-DTPA loaded to Gd-nanoCPs was hardly released over 7 days in PBS (1.8%) despite the high water solubility of Gd-DTPA. In contrast, 91% of Gd-DTPA was released in plasma over 24 hours. When Gd-nanoCPs were i.t. injected, 92% of Gd-DTPA injected effectually without outflow was held in the tumor tissue for 24 hours, which was different from the case of gadopentetate solution injection (only 1.2%). CONCLUSIONS: Gd-nanoCPs highly incorporating Gd-DTPA were successfully prepared by the

emulsion-droplet coalescence technique. Their releasing properties and their ability for long-term retention of GdDTPA in the tumor indicated that Gd-nanoCPs might be useful as an i.t. injectable device for Gd-NCT. Tokumitsu, H., J. Hiratsuka, et al. (2000). "Gadolinium neutron-capture therapy using novel gadopentetic acid-chitosan complex nanoparticles: in vivo growth suppression of experimental melanoma solid tumor." Cancer Letters 150(2): 17782. The potential of gadolinium neutron-capture therapy (Gd-NCT) for cancer was evaluated using chitosan nanoparticles as a novel gadolinium device. The nanoparticles, incorporating 1200 microg of natural gadolinium, were administered intratumorally twice in mice bearing subcutaneous B16F10 melanoma. The thermal neutron irradiation was performed for the tumor site, with the fluence of 6. 32x10(12) neutrons/cm(2), 8 h after the second gadolinium administration. After the irradiation, the tumor growth in the nanoparticle-administered group was significantly suppressed compared to that in the gadopentetate solution-administered group, despite radioresistance of melanoma and the smaller Gd dose than that administered in past Gd-NCT trials. This study demonstrated the potential usefulness of Gd-NCT using gadolinium-loaded nanoparticles. Tondelli, L., M. Laus, et al. (1999). "Specifically designed polymeric nanospheres increase cellular uptake of unmodified antisense ODNs." Nucleosides Nucleotides 18(6-7): 1677-9. The cellular uptake and the inhibitory effect of c-myb unmodified antisense oligonucleotides reversibly bound to new polymeric nanoparticles in HL-60 cellular system have been found to increase by 50 folds if compared with the free ODN. An initial single dose (320 nM) of the nanoparticle bound unmodified antimyb ODN has been able to specifically inhibit HL-60 leukemia cell proliferation for at least 8 days. Torchilin, V. P. (1998). "Polymer-coated long-circulating microparticulate pharmaceuticals." Journal of Microencapsulation 15(1): 1-19. The field of long-circulating microparticulate drug carriers is reviewed. The protective effect of certain polymers including poly(ethylene glycol) on nanoparticulate carriers (liposomes, nanoparticles, micelles) is considered in terms of statistical behaviour of macromolecules in solution. Using liposomes as an example, the mechanism is discussed assuming that surface-grafted chains of flexible and hydrophilic polymers form dense 'conformational clouds' preventing other macromolecules from interaction with the surface even at low concentrations of the protecting polymer. The scale of the protective effect is interpreted as the balance between the energy of the hydrophobic anchor interaction with the liposome membrane core or with the particle surface and the energy of the polymer chain free motion in solution. The possibility of using protecting polymers other than poly(ethylene glycol) is analysed, and examples of such polymers are given, based on polymer-coated liposome biodistribution data. General requirements for protecting polymers are formulated. Sterically protected nanoparticles and micelles are considered, and differences in steric protection of liposomes and particles are discussed. The problem of the preparation of drug carriers combining longevity and targetability is analysed. The biological consequences of steric protection of drug carriers with surface-grafted polymers are discussed, and possible clinical applications for long-circulating pharmaceutical carriers are considered. Torres-Santos, E. C., J. M. Rodrigues, et al. (1999). "Improvement of in vitro and in vivo antileishmanial activities of 2', 6'dihydroxy-4'-methoxychalcone by entrapment in poly(D,L-lactide) nanoparticles." Antimicrobial Agents and Chemotherapy 43(7): 1776-8. The inhibition of intracellular Leishmania amazonensis growth by 2', 6'-dihydroxy-4'-methoxychalcone (DMC) isolated from Piper aduncum was further enhanced after encapsulation of DMC in polymeric nanoparticles. Encapsulated DMC also showed increased antileishmanial activity in infected BALB/c mice, as evidenced by significantly smaller lesions and fewer parasites in the lesions. Tribet, C. (1998). "Hydrophobically driven attachments of synthetic polymers onto surfaces of biological interest: lipid bilayers and globular proteins." Biochimie 80(5-6): 461-73. This paper gives a brief overview of the consequences of associations between amphiphilic water-soluble polymers and small colloidal particles of biological interest: proteins and vesicles. Typical structures of watersoluble synthetic polymers containing hydrophobic groups are presented. The segregation between polar and apolar units in these polymers induces self-organisation in micro-domains despite the lack of specific primary structure. In the presence of other amphiphilic particles like proteins and vesicles, mixed assemblies are formed. Examples of polymer associations with vesicles or globular proteins, mainly focused on the acrylic derivatives, bring out common features in these mixtures. When the size of the polymer is of the same order of magnitude as that of the particle, adsorption of polymer chains creates a protective layer around each individual particle. Depending on the hydrophobicity of the partners, the association can stabilise the dispersion of unmodified particles or induce structural changes (membrane disruption, leakage). When small particles are added to solutions of long polymers, multimolecular complexation occurs. In this case, the size of the resulting aggregates depends on the concentrations. It goes from the size of one polymer molecule up to formally infinity as revealed by gelation. The identification of non-specific association modes between biological nanoparticles and

macromolecules might be revealed by the general behaviour of these synthetic mixed systems. Troster, S. D. and J. Kreuter (1992). "Influence of the surface properties of low contact angle surfactants on the body distribution of 14C-poly(methyl methacrylate) nanoparticles." Journal of Microencapsulation 9(1): 19-28. The body distribution of surfactant-coated and non-coated poly(methyl methacrylate) nanoparticles with a size of 131 +/- 30 nm after intravenous injection into rats was investigated. The coating materials were poloxamine 904, poloxamine 908, poloxamine 1508, poloxamer 338, and Brij 35. These materials were preselected by the method of contact angle measurement. No overall valid relation between contact angles and the modification of body distribution could be found. However, the classification of surfactants by determination of the contact angles of the surfactant solution on the polymer material seems to be a very helpful method for preselection of poloxamers and poloxamines. Another parameter for preselection could be molecular weights of the poloxamines. Poloxamine 1508 was the most efficient coating material in reducing the liver uptake and increasing the blood levels of poly(methyl methacrylate) nanoparticles. Truong-Le, V. L., J. T. August, et al. (1998). "Controlled gene delivery by DNA-gelatin nanospheres." Human Gene Therapy 9(12): 1709-17. A novel system for gene delivery, based on the use of DNA-gelatin nanoparticles (nanospheres) formed by saltinduced complex coacervation of gelatin and plasmid DNA, has been developed. These particles were spherical, with a size range of 200-700 nm, contained 25-30% (w/w) DNA, and were stabilized by cross-linking of gelatin. As a consequence of being controlled by the cross-linking density of the gelatin matrix, the average release rate of DNA from nanospheres synthesized under standard conditions was 2.2%/day in serum. Nanosphere DNA incubated in bovine serum was more resistant to nuclease digestion than was naked DNA. Various bioactive agents could be encapsulated in the nanospheres by ionic interaction with the matrix components, physical entrapment, or covalent conjugation. Transfection of cultured cells with a luciferase plasmid was enhanced by conjugating human transferrin onto the nanosphere and coencapsulating the endolysolytic agent chloroquine. Under our experimental conditions, gene expression in mice subsequent to intramuscular injection of nanospheres containing 1 microg of a beta-galactosidase plasmid was greater and more prolonged than was observed after injection of an equal amount of naked DNA or DNA complexed with Lipofectamine. Truong-Le, V. L., S. M. Walsh, et al. (1999). "Gene transfer by DNA-gelatin nanospheres." Archives of Biochemistry and Biophysics 361(1): 47-56. A DNA and gelatin nanoparticle coacervate containing chloroquine and calcium, and with the cell ligand transferrin covalently bound to the gelatin, has been developed as a gene delivery vehicle. In this study, the coacervation conditions which resulted in the formation of distinct nanoparticles are defined. Nanospheres formed within a narrow range of DNA concentrations and achieved incorporation of more than 98% of the DNA in the reaction. Crosslinking of gelatin to stabilize the particles does not effect the electrophoretic mobility of the DNA. DNA in the nanosphere is partially resistant to digestion with concentrations of DNase I that result in extensive degradation of free DNA but is completely degraded by high concentrations of DNase. Optimum cell transfection by nanosphere DNA required the presence of calcium and nanospheres containing transferrin. The biological integrity of the nanosphere DNA was demonstrated with a model system utilizing DNA encoding the cystic fibrosis transport regulator (CFTR). Transfection of cultured human tracheal epithelial cells (9HTEo) with nanospheres containing this plasmid resulted in CFTR expression in over 50% of the cells. Moreover, human bronchial epithelial cells (IB-3-1) defective in CFTR-mediated chloride transport were complemented with effective transport activity when transfected with nanospheres containing the CFTR transgene. Tsai, T. R., W. H. Chuo, et al. (1998). "Preparation and pharmacological evaluation of physostigmine-loaded polyisobutylcyanoacrylate nanoparticles in rats." Kaohsiung Journal of Medical Science 14(1): 13-8. The nanoparticles of physostigmine were prepared by an emulsion polymerization of polyisobutylcyanoacrylate. The drug content, release and particle size distribution of the nanoparticles were characterized. In vitro drug release profiles displayed a retardation by the nanoparticles in comparison to the aqueous solution. Pharmacological evaluation of physostigmine nanoparticles in vivo were carried out with Sprague-Dawley rats. The endogenous acetylcholine was sampled by on-line microdialysis and determined by a sensitive microbore HPLC/ED system in the striatum of rats. The choline oxidase and catalase immobilized enzyme reactors were used as the pre-column to erase choline. Accordingly, this chromatographic flow sequence could be utilized for the quantitative assay of acetylcholine without interference. The results indicate that the increase of acetylcholine (%) in the rats striatum by the nanoparticle was 2.3 times (AUC) higher than that of aqueous solution. Tsunekawa, S., K. Ishikawa, et al. (2000). "Origin of anomalous lattice expansion in oxide nanoparticles." Physcial Review Letters 85(16): 3440-3. Anomalous lattice expansions have been measured for the first time in monodisperse CeO2-x nanoparticles and in BaTiO3 single nanoparticles by electron diffraction. X-ray photoelectron spectroscopy studies on CeO2-x nanoparticles and ab initio computer simulation on BaTiO3 clusters show that the origin of expansion is the

decrease of electrostatic force caused by valence reduction of Ce ions and the increase in ionicity of Ti ions, respectively. The lattice constant change of oxide (ionic) nanoparticles with the increase in ionicity would depend on the structure of the particles. Hence, first-principles calculations of large ionic clusters are indispensable. Tsutsumi, T., K. Ishii, et al. (2000). "Optical near-field properties of lithographically designed metallic nanoparticles." Semiconductor Quantum Dots. Symposium. 571: 95-100. We report on the experimental observation of localized surface plasmons sustained by small metallic particles using a photon scanning tunneling microscope (PSTM). The surface plasmons are excited in gold nanostructures tailored by electron beam lithography. The constant height operation of the PSTM allowed a direct comparison with theoretical computations of the distribution of the optical near-field intensity. Plasmon coupling above a chain of Au particles and electromagnetic energy transfer from a resonantly excited nanoparticle to a nanowire are demonstrated. Our experimental results appear to be in good agreement with theoretical computations based on Green's dyadic technique. (10 References). Ueda, M. and J. Kreuter (1997). "Optimization of the preparation of loperamide-loaded poly (L-lactide) nanoparticles by high pressure emulsification-solvent evaporation." Journal of Microencapsulation 14(5): 593-605. The entrapment of loperamide hydrochloride (LPM) in biodegradable polymeric drug carriers such as nanoparticles might enable its passage across the blood-brain barrier. The optimization of the preparation of the LPM-loaded PLA nanoparticles was performed employing high pressure emulsification-solvent evaporation. The resulting nanoparticles were characterized by particle size, distribution, thermal analysis, and drug release profiles. The partition of LPM into the organic phase increased with an increase in pH of the aqueous phase and with addition of lipophilic surfactants such as sorbitan fatty acid esters, resulting in an increase in the drug entrapment in the nanoparticles. Evaporation of the organic phase under reduced pressure and the addition of ethanol in the organic phase yielded a high drug entrapment due to the rapid polymer precipitation. The addition of the sorbitan fatty acid esters further increased the drug entrapment even at higher LPM concentrations. The results of thermal analysis suggest that LPM was homogeneously dispersed in the amorphous polymer matrix. The in vitro release of the drug from nanoparticles was biphasic, with a fast initial phase, followed by a second slower phase. Different drug release profiles from nanoparticles can be achieved by addition of sorbitan fatty acid esters, or the employment of different solvents as the organic phase. Ueda, M., A. Iwara, et al. (1998). "Influence of the preparation methods on the drug release behaviour of loperamideloaded nanoparticles." Journal of Microencapsulation 15(3): 361-72. Polylactide (PLA) or poly(lactide-coglycolide) (PLGA) nanoparticles containing loperamide (LPM) were prepared by an incorporation or adsorption method with the objective of developing nanoparticles with a rapid drug release. The use of polymers such as PLA with lower molecular weights and the addition of sorbitan fatty acid esters (SFAE) for the incorporation led to an almost complete entrapment of LPM in nanoparticles. Preparation of PLA nanoparticles by adsorption was performed by addition of LPM methanol solution before, during and after evaporation of dichloromethane from the system. The adsorption of LPM onto the nanoparticles with low molecular weight PLA (m.w. 2000) showed an isotherm with a good correlation to the Langmuir equation. A high amount of LPM can be entrapped or adsorbed in nanoparticles only with low molecular weights of PLA or PLGA. In the incorporation method, the addition of SFAEs increased drug entrapment. However, in the adsorption method they had no effect on nanoparticle drug adsorption. The drug-release profiles from both nanoparticles, prepared by the adsorption and incorporation methods, were biphasic with an initial rapid release and a second slower release phase, although their initial extents of release were different. The release rates were almost the same for both the adsorption and incorporation method without SFAEs. The addition of SFAEs to the adsorption system increased the extent of drug release from nanoparticles. In conclusion, a rapid loperamide release from nanoparticles can be achieved by use of PLA or PLGA with low molecular weights and in the adsorption method by the addition of SFAEs. Umeda, N., N. Kishimoto, et al. (2000). "Thermal stability of nanoparticles in silica glass implanted with high-flux Cu ions." Nuclear Instruments and Methods in Physics Research Section B Beam Interactions with Materials and Atoms 166(167): 864-70. Thermal stability of nanoparticles, fabricated by high-current negative ions, has been studied focusing on optical applications. Negative Cu ions of 60 keV were irradiated to silica glasses at high dose rates up to 50 mu A/cm/sup 2/, to a total dose of 3*10/sup 16/ ions/cm/sup 2/. The high-current implantation caused a bimodal distribution of Cu nanoparticles. Thermal annealing at 773-1273 K for 1 h was applied to the specimens. For each step, optical absorption was measured in an energy range from 0.5 to 6.5 eV and nanoparticle morphology was evaluated by cross-sectional TEM. Depth profiles of Cu atoms were compared to those by RBS. Thermal annealing below 873 K gave no discernible changes in either nanoparticle morphology or absorption spectra. Above 1073 K, pronounced coarsening of Cu particles occurred, with enhancing the bimodal distribution. Around 1273 K, all the Cu particles disappeared, suggesting evaporation of Cu implants from the surface. The result indicates that the nanoparticle structure is thermally stable below about 873 K, and becomes unstable at higher temperatures. (13
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References). Unal, B., S. C. Bayliss, et al. (2000). "Size effects on ferroelectricity of ultrafine particles of PbTiO3." Journal of Applied Physics 87(7): 3462-7. High resolution transmission electron microscopy is used to image the nanostructure of ultrafine ferroelectric lead titanate particles ranging from 20 to 2000 nm in diameter. The crystal structure, surface morphology, domain-wall structure, as well as surface reconstruction under a 400 KeV electron beam are studied. High resolution images and selected area diffraction patterns showed that all the particles had tetragonal structure; the c/a ratio and domain size both decreased with decreasing particle size and the particles became monodomain when their diameter was less than 20 nm. A domain wall width of 14 AA was deduced from strain contrast shown by 90 degrees domain walls. There is no evidence of amorphous surface layers; however surface reconstruction of lead titanate particles under the electron beam irradiation may produce small particles identified as face-centred PbO. The relationship between the physical properties and the observed nanostructures is discussed. (38 References). Unger, E. C., D. K. Shen, et al. (1993). "Status of liposomes as MR contrast agents." Journal of Magnetic Resonance Imaging 3(1): 195-8. Recent work on the development of liposomal magnetic resonance (MR) contrast agents has yielded structures with higher overall relaxivity than that of other nanoparticles of similar diameter. Liposomes incorporating membrane-bound complexes of manganase (&quot;memsomes&quot;) produce greater hepatic enhancement per micromole of metal ion than either ferrite particles or paramagnetic chelates. Memsomes also hold promise for targeting of sites outside the liver. Work is in progress to take these agents into clinical trials. Utreja, S., A. J. Khopade, et al. (1999). "Lipoprotein-mimicking biovectorized systems for methotrexate delivery." Pharmaceutica Acta Helvetiae 73(6): 275-9. The present investigation reports a new family of lipid nanoparticles biomimetic of lipoproteins, lipoproteinmimicking biovectorized systems (LMBVs), for the delivery of methotrexate. LMBVs were prepared by microemulsion congealing technique, and the composition and process were optimized. The palmitoylpolyethylene glycol 4000 (p-PEG 4000) was anchored on LMBVs as apoprotein analogue. Various formulations were prepared and characterized for size and polydispersity, zeta potential, drug entrapment efficiency, anchoring efficiency, release kinetics, pharmacokinetics and tissue distribution. The size was 70-76 nm and the polydispersity was 0.09-0.18. The zeta potential was -63.2 which was reduced to -19.3 after p-PEG 4000 coating. Entrapment efficiency varied from 22.6% to 30.2%. Anchoring efficiency was 74.0 +/- 3.9%. The drug release showed zero-order profile. Their circulation half-life was enhanced and exhibited capability to accumulate in tissues for longer periods. The composition of lipidic part of LMBVs and p-PEG 4000 anchoring impart similarity with natural lipoproteins in terms of in vivo behaviour. This new drug carrier named LMBVs, holds promise for targeting and systemic controlled release, which may prove effective in the treatment of various types of cancer. Vaisanen, V., H. Harma, et al. (2000). "Time-resolved fluorescence imaging for quantitative histochemistry using lanthanide chelates in nanoparticles and conjugated to monoclonal antibodies." Luminescence 15(6): 389-97. Tissue and cell examinations have a potential to produce extremely valuable information about antigen quantities in samples. Using currently available methods, a truly quantitative analysis is nearly impossible. We have previously shown that immunohistochemical (IHC) detection of prostate-specific antigen and human glandular kallikrein from prostatic tissue, together with time-resolved fluorescence imaging (TRFI), is a suitable method for obtaining quantitative data from biological samples and that the signal response is linear. In this paper we show that Eu-chelate containing particles in the nanometer range are suitable labels for quantitative IHC. Even single nanoparticle molecules can be detected by TRFI and the signals measured can be readily quantitated. The signal intensity correlates very well with the amount of bound label, and the use of nanoparticles could markedly improve the sensitivity of quantitative IHC methods. TRFI provides a powerful tool for providing quantitative data about antigens or transcripts in tissue sections or cultured cells. It is also of major importance in standardization and optimization of protocols for fixation and tissue preparation, including antigen retrieval methods. van der Zaag, P. J., A. Noordermeer, et al. (1992). "Comment on "Size-dependent Curie temperature in nanoscale MnFe2O4 particles"." Physical Review Letters 68(20): 3112. Vandelli, M. A., M. Fresta, et al. (1994). "An interpretative analysis of the effect of the surfactants used for the preparation of polyalkylcyanoacrylate nanoparticles on the release process." Journal of Microencapsulation 11(5): 531-8. The release of fluorescein from polyethylcyanoacrylate (PECA) or polyisobutylcyanoacrylate (PICA) nanoparticles was affected by the surfactants used for the preparation. The different surfactants also modified the molecular weight, size and loading of the nanoparticles. However, these factors were not be responsible for the different release. According to the release profiles and the Baker-Lonsdale model, a portion of fluorescein was concentrated near the nanoparticle surface. Thus, a non-homogeneous distribution of the fluorescent probe inside the nanoparticles was hypothesized. This distribution could reflect the fluorescein position inside the micella

during the polymerization stage, or could be reached during the washing stage as the consequence of a different effect of the surfactants on the porosity of the nanoparticle structure. Vandervoort, J. and A. Ludwig (2001). "Preparation factors affecting the properties of polylactide nanoparticles: a factorial design study." Pharmazie 56(6): 484-8. PLGA nanoparticles were produced using a w/o/w emulsification solvent evaporation method incorporating pilocarpine HCl as a model drug. The influence of four preparation parameters on the particle properties was studied. The factors studied were the concentration of the stabilizer in the outer water phase, the presence of buffer in the outer water phase, the amount of drug relative to the amount of polymer and the type of PLGA used. Particle size was influenced by the concentration of PVA in and the addition of buffer to the outer water phase. The ratio drug/polymer had an effect on the drug entrapment. Vandorpe, J., E. Schacht, et al. (1997). "Long circulating biodegradable poly(phosphazene) nanoparticles surface modified with poly(phosphazene)-poly(ethylene oxide) copolymer." Biomaterials 18(17): 1147-52. The biodistribution of biodegradable poly(organo phosphazene) nanoparticles surface modified by adsorption of a novel poly(organo phosphazene)-poly(ethylene oxide) copolymer with a 5000 M(W) PEO chain (PF-PEO[5000]), following intravenous administration in rats and rabbits, is described. The data are compared to the biodistribution of poly(organo phosphazene) and poly(lactide-co-glycolide) nanoparticles coated with a tetrafunctional copolymer of poly(ethylene oxide)-poly(propylene oxide) ethylenediamine, commercially available as Poloxamine 908. This copolymer has a PEO chain of the same size as the poly(organo phosphazene)-PEO derivative used. The results in the rat model reveal that poly(organo phosphazene) nanoparticles with a Poloxamine 908 coating were mainly captured by the liver, although a retardation in clearance from the systemic circulation was seen. In contrast, the poly(organo phosphazene) nanoparticles coated with PF-PEO(5000) showed a prolonged blood circulating profile, with only a small amount of the nanoparticles sequestered by the liver. This indicates the importance of the nature of both the anchoring group and the particle surface on the biological performances of the system. Study of the biodistribution of the PF-PEO(5000)-coated poly(organo phosphazene) nanoparticles in the rabbit model also indicated a prolonged systemic circulation lifetime and reduced liver uptake, whereby a significant amount of the administered nanoparticles was targeted to the bone marrow. Varela, M. C., M. Guzman, et al. (2001). "Cyclosporine-loaded polycaprolactone nanoparticles: immunosuppression and nephrotoxicity in rats." European Journal of Pharmacological Science 12(4): 471-8. AIM: The nephrotoxicity and immunosuppressive ability of cyclosporine (CyA) incorporated into polycaprolactone nanoparticles (CyA-NP) was assessed in vitro and in vivo and compared to the effects caused by free drug (Sandimmun. METHODS: The in vivo study included four groups (12 Wistar rats each) receiving oral CyA (10 mg/kg/day for 3 days) as an emulsion of Sandimmun in whole milk or CyA-NP and equivalent doses of empty NP or cremophor in milk as controls. CyA concentrations in blood, urine, liver, spleen and kidney at 24 h post-dosing were measured by fluorescence polarization immunoassay (FPIA). The nephrotoxicity induced by each drug treatment was determined by measuring creatinine plasma levels, malonyl dialdehyde production, and H(2)O(2) and reduced glutathione contents in glomeruli. On the other hand, the immunosuppressive effect was estimated in vivo by incubating lymphocyte suspensions obtained from CyA-, CyA-NP- and control-treated rats, as well as in vitro on lymphocyte suspensions from non-treated healthy animals. RESULTS: Significantly higher blood, urine and tissue levels were achieved with CyA-NP compared to free CyA. However, no changes in creatinine plasma levels were detected due to either CyA or CyA-NP treatment. Only the production of H(2)O(2) in the glomeruli exhibited a significant increase as compared to control groups, but no differences could be ascribed to the different drug treatments. In vivo, the immunosuppressive activity was also comparable for both drug treatments. In contrast, CyA-NP showed a better drug uptake in vitro at concentrations above 25 microM. No immunosuppression was detected in control groups. CONCLUSION: NP improve the oral bioavailability of CyA and its uptake by lymphocytes in vitro above 25 microM. On the contrary, specific immunosuppression and adverse effects were not simultaneously increased. Further studies are needed to clarify the results. Vauthier, C., C. Schmidt, et al. (1999). " Measurement of the density of polymeric nanoparticulate drug carriers by isopycnic centrifugation." Journal of Nanoparticle Research 1: 411-418. Velge-Roussel, F., P. Breton, et al. (1996). "Immunochemical characterization of antibody-coated nanoparticles." Experientia 52(8): 803-6. A new method using surface plasmon resonance (SPR) through the BIAcore was used to demonstrate the specific interaction between an anti-CD4 monoclonal antibody (IOT4a), adsorbed on poly(methylidene malonate 2.1.2) (PMM 2.1.2) nanoparticles, and the CD4 molecule. The results obtained were compared with the interaction of the same immunonanoparticles with rabbit anti-mouse Fc antibodies. The molar ratio (Fc)/(Fab) was 1, suggesting that the same number of epitopes on the Fc and the Fab fragments were accessible after IOT4a adsorption onto nanoparticles. Comparing the observed association rates of free antibody and antibody adsorbed on nanoparticles, the number of molecules of IOT4a antibody on PMM 2.1.2 nanoparticles was estimated as

between 2.6 and 3 per nanoparticle. The properties of the antibody-coated nanoparticles are compatible with their use as antibody-targeted pharmacophores. Venier-Julienne, M. C., I. Vouldoukis, et al. (1995). "In vitro study of the anti-leishmanial activity of biodegradable nanoparticles." Journal of Drug Targeting 3(1): 23-9. Leishmania are obligate intracellular parasites, responsible for leishmaniasis. Leishmaniasis are transmitted via insect vector to vertebrate hosts including humans. The infection was reproduced in vitro with promastigotes which can infect murine resident peritoneal cells. Amphotericin B was incorporated into poly(D, L-lactide-coglycolide) nanoparticles, biodegradable drug carriers, to allow specific targeting inside the cell. The interaction of the drug with infected cells was determined by exposing macrophage cultures to drug carriers. The toxic effects of polymeric drug carriers were defined prior to exposing cells to drug-loaded nanoparticles. For contact times up to 4h, cells tolerated polymer concentrations of 0.01%. The viability of parasites after treatment was determined. Infected macrophages were incubated at 26 degrees C (which allows the transformation of amastigote to promastigote) along with loaded and unloaded nanoparticles, as well as the free drug alone, and a count of the parasites in the medium was recorded. Anti-leishmanial activity was observed with drug-free nanoparticles. This activity may arise through the release of hydrogen peroxide following the activation of macrophages. The incorporation of amphotericin B did not enhance this effect. Interestingly, trehalose, a cryoprotector of the freezedried nanoparticles, altered parasite growth and activated macrophages. Venier-Julienne, M. C. and J. P. Benoit (1996). "Preparation, purification and morphology of polymeric nanoparticles as drug carriers." Pharmaceutica Acta Helvetiae 71(2): 121-8. The aim of this work was to prepare biodegradable poly(D,L-lactic acid-co-glycolic acid) copolymer (PLAGA) nanoparticles by the solvent evaporation process and to incorporate an antifungal antibiotic, amphotericin B. Blank nanoparticles obtained were 130 +/- 27 nm in diameter. When amphotericin B was added in the organic phase, the final suspension showed two populations due to unbound drug. Free amphotericin B was removed by contacting the nanoparticle suspension with an adsorbent polymer. Amberlite XAD16, and subsequently ultrafiltering the medium. The drug payload was between 0.7 and 1.3%. To gain more insight in the cause of this low loading, we studied progesterone-loaded nanoparticles using PLAGA and polystyrene as models because progesterone and these polymers exhibit a degree of miscibility. In the case of polystyrene, nanoparticle drug content reached 8%. Venugopalan, P., A. Sapre, et al. (2001). "Pelleted bioadhesive polymeric nanoparticles for buccal delivery of insulin: preparation and characterization." Pharmazie 56(3): 217-9. The study was an attempt to develop an alternative buccal delivery system for insulin. Insulin bearing nanoparticles were prepared by the emulsion internal phase evaporation method. The effect of some formulation variables viz., polymer/drug ratio and emulsifier concentration was studied on particle size and entrapment efficiency. Nanoparticles were pelleted to impart three-dimensional structural conformity and coherence thereby facilitating buccal application. Solid lateral and horizontal sedimentaton in the pellet can be avoided by nanoparticulation and ensuring uniform drug distribution throughout the pellet. The in vitro studies of the pellets included bioadhesion and drug release profile. In vivo studies were performed on diabetic rats. A significant hypoglycemic response was observed after 7 h, without any detectable fluctuation in blood glucose profile and risk of hypoglycemia. Verdun, C., F. Brasseur, et al. (1990). "Tissue distribution of doxorubicin associated with polyisohexylcyanoacrylate nanoparticles." Cancer Chemotherapy and Pharmacology 26(1): 13-8. The body distribution of i.v. doxorubicin depends mainly on the physicochemical characteristics of the molecule. However, entrapment of that cytostatic drug inside polyalkylcyanoacrylate nanoparticles has been shown to modify its distribution profoundly in the mouse. Polysiohexylcyanoacrylate nanoparticles loaded with [14C]doxorubicin were studied in comparison with free drug, with emphasis on their distribution pattern in mouse tissue after i.v. administration. An autoradiographic study showed that most of the radioactivity was found in the reticuloendothelial system as soon as a few minutes after i.v. administration of the doxorubicin-loaded nanoparticles. Quantitative determinations by liquid scintillation counting in fresh tissue (spleen, heart, kidneys, liver, lungs, bone marrow) and blood samples confirmed these observations. When the drug was linked to nanoparticles, doxorubicin blood clearance was reduced during the first few minutes after administration, whereas heart and kidney concentrations were substantially decreased. Assays of doxorubicin and doxorubicinol by a specific HPLC analytical method gave results very similar to those obtained by scintillation counting. Verma, P., G. Irmer, et al. (2000). "Hyper-Rayleigh scattering of CdS nanoparticles with different surfaces in solution." Proceedings of SPIE the International Society for Optical Engineering 3937: 123-31. Large third-order susceptibilities, chi /sup (3)/ or gamma , have been observed for II-VI semiconductor nanoparticles. However, there are only few studies on the second-order susceptibilities because it is usually believed that the centrosymmetry or near-centrosymmetry of the particles eliminate the beta to zero or very small

value. Here the hyper-Rayleigh scattering (HRS) technique is used to measure the second-order NLO response of nanoscale CdS colloids with different surfaces in solution, which are denoted by CdS/Cd/sup 2+/, CdS/S/sup 2/, CdS/SC(NH/sub 2/)/sub 2/ CdS/AOT/sup -/ and CdS/Py. The result shows that the "per particle" beta values for CdS nanoparticles are very large. And the beta values are different for CdS nanoparticles with different surfaces. Time dependent experiment show that the HRS signal decreases remarkably as time goes by. Further studies reveal that it has multi-photon fluorescence (MPF) emission under the radiation of 1064 nm for newly made samples, but for aged stable sample the MPF is rather weak. All these experiments show that the HRS and MPF signals are very sensitive to the changes of the nanoparticle surface or the nanoparticle/solution interface. They also give the evidences proving that the surface termination of the crystalline lattice that creates a condition of non-centrosymmetry is contributing to the large beta values for CdS nanoparticles. (24 References). Verrecchia, T., P. Huve, et al. (1993). "Adsorption/desorption of human serum albumin at the surface of poly(lactic acid) nanoparticles prepared by a solvent evaporation process." Journal of Biomedical Materials Research 27(8): 1019-28. Biocompatible and biodegradable nanoparticles of poly(lactic acid) (100% L-lactic units = PLA) were prepared by an emulsion, microfluidization, and solvent evaporation method using human serum albumin (HSA) as a surface agent. A radiolabeling technique was employed to quantify the serum albumin bound to the nanoparticles and to measure its desorption kinetics in various media at 22 degrees C and 37 degrees C (phosphate buffer pH 7.4, serum albumin 40 g/L in phosphate buffer pH 7.4 and fetal calf serum). The amount of serum albumin bound to the nanoparticles was found to be a linear function of 1/D (where D is the nanoparticle mean diameter) and was related to the total developed area of the nanoparticles. The adsorption/desorption behavior of serum albumin at the surface of the nanoparticles suggested a multilayer adsorption model. Moreover, a part of the serum albumin molecules was irreversibly bound regardless of the incubation conditions. Consequently, the classical Langmuirian theories of equilibria could not be applied. Vert, M. (1986). "Polyvalent polymeric drug carriers." Critical Reviews in Therapeutic Drug Carrier Systems 2(3): 291-327. A number of drug-carrier systems have been considered, so far, for time-controlled delivery, targeting, and decrease of toxicity of biologically active compounds. Many of these drug carriers are based on synthetic polymers. Prerequisites for polymeric drug carriers and the need for polyvalent systems capable of carrying different drugs are examined from the viewpoint of effective pharmaceutical uses. The cases of microcapsules, microspheres, nanoparticles, and emulsions based on polymers are recalled. Of particular interest are copolymers, such as amphiphilic block-copolymers and partially quaternized polytertiary amines, that can form hydrophobic microdomains in aqueous media. Discussions are focused on the capability of the corresponding microphases to solubilize, carry, and release lipophilic drugs. The present state of the art is illustrated by recent examples. Vijaya Sarathy, K., K. S. Narayan, et al. (2000). "Novel fluorescence and morphological structures in gold nanoparticlepolyoctylthiophene based thin films." Chemical Physics Letters 318(6): 543-8. Thin films, obtained from a homogeneous solution of Au nanoparticles and polyoctylthiophene (P30T), exhibit novel structures. Fluorescence centers of ~1 mu m diameter containing the pure polymer, interspersed with Au nanoparticles are observed throughout the film. Conventional photoluminescence (PL) and spatially resolved near-field scanning optical microscope (NSOM) techniques are used to study these emission centers. The PL results are interpreted in terms of ordered polymer regions and distinct blue-shifted amorphous regions. The results are correlated with the nanoparticle distribution which has a higher density in the vicinity of the amorphous regions. (13 References). Violante, M. R. (1990). "Potential of microparticles for diagnostic tracer imaging." Acta Radiologica Supplementum 374(3): 153-6. The development of tracer imaging agents with sufficiently high label activity can lead to problems of poor aqueous solubility of the labeled tracer, causing formulation difficulty, inadvertent accumulation by phagocytic cells, or inadequate signal to noise. Our approach to solving these problems is to administer the tracer in the form of monodispersed nanoparticles which can safely be administered intravenously. Since the phagocytosis of these particles can be controlled or avoided in a predictable manner by altering particle size and surface characteristics, imaging tracers can be designed for a variety of intended applications. This paper summarizes the results and ideas for several applications involving computed tomography, ultrasound, magnetic resonance imaging, and radioisotope imaging modalities. Vittaz, M., D. Bazile, et al. (1996). "Effect of PEO surface density on long-circulating PLA-PEO nanoparticles which are very low complement activators." Biomaterials 17(16): 1575-81. The rapid uptake of injected nanoparticles by cells of the mononuclear phagocytes system (MPS) is a major obstacle when a long blood circulation time is needed. Whereas nanoparticles made from PLA and stabilized by surfactants (PLA-F68) are rapidly phagocytized, the rate of phagocytosis is strongly reduced in case of nanoparticles made from a diblock copolymer (PLA-PEO). Because of the role of the complement system in

opsonization, this difference of phagocytosis was hypothesized to be related to this system. An important complement consumption was obtained in 5 min in the presence of PLA-F68 particles. In the presence of a higher surface area of PLA-PEO particles possessing a high PEO surface density, the consumption remained very low. When the average PEO surface density was decreased on such particles below a given threshold, a fast and strong complement consumption occurred again. These experimental data support the concept of steric repulsion towards proteins, by surfaces covered with terminally attached PEO chains and emphasize the prime importance of PEO surface density in such an effect. The major, but probably not exclusive, role of complement as an opsonin capable of inducing a fast phagocytosis by MPS should be taken into account concerning the in vitro evaluation of nanoparticles as candidates for a long blood circulation. Vlckova, B., P. Smejkal, et al. (2000). "Surface-enhanced resonance Raman spectroscopy of porphyrin and metalloporphyrin species in systems with Ag nanoparticles and their assemblies." Journal of Inorganic Biochemistry. [ print.] 79(1-4): 295-300. The advantages of systems with Ag nanoparticles and their assemblies for surface-enhanced resonance Raman scattering (SERRS) spectral investigation, detection and determination of porphyrin species are demonstrated. SERRS spectral detection limits of the testing porphyrin species (including porphyrin aggregates) in these systems are shown to be, on average, 102-103 lower than detection limits by resonance Raman scattering (RRS). Systems with Ag nanoparticles modified by anionic organosulfur spacers enable us to obtain SERRS spectra of unperturbed cationic porphyrin species. In the case of thiopheneacetate-modified Ag particles prepared by laser ablation, no negative effect of the spacer on the spectral detection limit of the porphyrin was observed. Systems with isolated Ag nanoparticles allow for obtaining SERRS spectra of porphyrin species upon excitation into the Soret electronic absorption band which leads to at least a 10-fold decrease in the detection limit. Voisin, C., D. Christofilos, et al. (2000). "Size-dependent electron-electron interactions in metal nanoparticles." Physical Review Letters 85(10): 2200-3. The internal thermalization dynamics of the conduction electrons is investigated in silver nanoparticles with radius ranging from 13 to 1.6 nm using a femtosecond IR pump-UV probe absorption saturation technique. A sharp increase of the electron energy exchange rate is demonstrated for nanoparticles smaller than 5 nm. The results are consistent with electron-electron scattering acceleration due to surface induced reduction of the Coulomb interaction screening by the conduction and core electrons. Vollath, D. and D. V. Szab (1999). "Coated nanoparticles: a new way to improved nanocomposites." Journal of Nanoparticle Research 1: 235-242. Vyas, S. P. and A. Malaiya (1989). "In vivo characterization of indomethacin magnetic polymethyl methacrylate nanoparticles." Journal of Microencapsulation 6(4): 493-9. The in vivo magnet responsiveness and kinetics of distribution of indomethacin entrapped in a magnetic and plain carrier were characterized by rat tail model and periodic monitoring of drug concentration in various visceral organs after intraarterial and intravenous administration respectively. Up to 60 min post injection time 60-fold higher concentrations could be achieved in tail target segment which resulted in considerably reduced drug concentration in other organs as evinced by data from control rats. Following normal administration (no magnetic field applied) the drug concentration was higher in the liver and spleen where endocytosis and phagocytosis occur. The magnetic nanoparticle of indomethacin holds promise for selective targeting under magnetic field of 8000 Oe strength. Wajnberg, E., D. Acosta-Avalos, et al. (2000). "Electron paramagnetic resonance study of the migratory ant Pachycondyla marginata abdomens." Biophys J 78(2): 1018-23. Electron paramagnetic resonance was used to investigate the magnetic material present in abdomens of Pachycondyla marginata ants. A g congruent with 4.3 resonance of high-spin ferric ions and a very narrow g congruent with 2 line are observed. Two principal resonance broad lines, one with g &gt; 4.5 (LF) and the other in the region of g congruent with 2 (HF), were associated with the biomineralization process. The resonance field shift between these two lines, HF and LF, associated with magnetic nanoparticles indicates the presence of cluster structures containing on average three single units of magnetite-based nanoparticles. Analysis of the temperature dependence of the HF resonance linewidths supports the model picture of isolated magnetite nanostructures of approximately 13 nm in diameter with a magnetic energy of 544 K. These particles are shown to present a superparamagnetic behavior at room temperature. The use of these superparamagnetic particle properties for the magnetoreception process of the ants is suggested. Walsh, T. J., M. A. Viviani, et al. (2000). "New targets and delivery systems for antifungal therapy." Medical Mycology 38(Suppl 1): 335-47. Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence

factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium. Walter, J. (2000). "Quasi-two-dimensional or hcp palladium nanoparticles with host-guest interaction prepared at room temperature." Philosophical Magazine Letters 80(4): 257-62. Quasi-two-dimensional palladium nanoparticles with an average lateral dimension of 7 nm have been prepared by reduction of a PdCl/sub 2/ graphite intercalation compound precursor by lithium-diphenylide in tetrahydrofuran at room temperature. Selected-area electron diffraction patterns provide evidence that the palladium nanoparticles are hcp single-crystal particles. Owing to the template effect of the graphite lattice, the lattice parameter of palladium was found to have a strong relation with the graphite, and a 3a/sub graphite/ superstructure was inferred. The palladium structure is rotated by 30 degrees with regard to the carbon host lattice. Raman spectroscopy on this sample showed that a charge transfer between carbon and palladium occurs. The sample can be considered as a common Pd-graphite intercalation compound with palladium nanoparticles as guest. This behaviour is different from palladium nanoparticles prepared by hydrogen reduction at higher temperatures from the same precursor material. These particles may represent an early stage of nanoparticle formation. (16 References). Walter, J. and H. Shioyama (2000). "Se atoms and Se6 molecules as guests in Se-carbons-prepared by reduction of a SeCl4-graphite precursor." Journal of Physics Condensed Matter 12(4): 367-74. A SeCl/sub 4/-graphite intercalation compound precursor was reduced by a solution of lithium diphenylide in tetrahydrofuran at room temperature. X-ray diffraction measurements gave two distinguishable stages. One stage represented a Se-atom intercalation the other represented an intercalation of Se/sub 6/ molecules. The in-plane diffraction patterns were estimated by selected-area electron diffraction, the existence of two different guest species (atoms and molecules) could be proved. The Se/sub 6/-molecule phase shows an incommensurate lattice with regard to the host lattice, but they are in the same orientation. The lattice parameter of intercalated Se/sub 6/ is a/sub Se6-geust/=1158+or-36 pm, c/sub Se6-guest/=483+or-38 pm, which fits with the lattice parameter of nonintercalated Se/sub 6/ molecules. Se atom domains show a 2*a/sub graphite/ superlattice with respect to the host lattice, which is a commensurate superstructure. Raman scattering data showed the occurrence of an acceptortype graphite intercalation compound. Three different types of spectra could be obtained, two kinds of spectra consists of doublets at 1588 cm/sup -1/ and 1608 cm/sup -1/, with different intensity ratios. These two kinds of spectra are certainly attributed to Se-atom domains, with different stages. A third type of spectrum show bands at higher wavenumbers (1646 cm/sup -1/ and 1653 cm/sup -1/). These bands are probably correlated to Se/sub 6/molecule domains. They represent maybe very early stages of nanoparticle formation. (32 References). Wang, N. and X. S. Wu (1997). "Preparation and characterization of agarose hydrogel nanoparticles for protein and peptide drug delivery." Pharmaceutical Development and Technology 2(2): 135-42. The purpose of this work was to develop and characterize a protein and peptide injectable drug delivery system in agarose hydrogel nanoparticles. The nanoparticles were prepared by using a new emulsion-converted-tosuspension in situ method. This is an emulsifier-free method that has advantages for protein and peptide drug encapsulations. Ovalbumin, used as a model protein drug, was successfully encapsulated into nearly spherical agarose hydrogel nanoparticles under mild conditions. The nanoparticles possessed a log-normal size distribution with an average size of 504 nm. They imbibed a large amount of water (66.85% to 84.33%) and the water content was a function of temperature; the water content increased with increase in temperature. Release studies of the ovalbumin from the agarose hydrogel nanoparticles revealed a diffusion-controlled release mechanism with a temperature dependence; the ovalbumin release rate was higher at 37 degrees C than that at room temperature. The great biocompatibility of agarose hydrogel, plus the mild conditions for drug encapsulation, make the agarose hydrogel nanoparticles a potential system for protein and peptide drug delivery. Wang, J., B. Zou, et al. (2000). "Photoinduced vibrational absorptions from poly(3-octylthiophene)/Fe2O3 nanoparticle composite, a time-resolved FTIR study." Synthetic Metals 113(3): 223-6. Photoinduced vibrational bands of poly(3-octylthiophene), P3OT, have been studied at room temperature by using time-resolved FTIR spectroscopy (TR-FTIRS) in the nanosecond to microsecond time domain. A photobleach occurs in the deformation band of =C--S--C= at 1463-1419 cm/sup -1/, and a few transient absorption

bands occur at lower frequency (e.g. ~1290 cm/sup -1/). The transient absorption band at 1290 cm/sup -1/ shows a signal exponential formation occurring in <200 ns, and a double exponential decay process, with lifetimes of 53 and 788 mu s. Adding Fe/sub 2/O/sub 3/ nanoparticle into the polymer composite significantly enhances the photoinduced signal, indicating the interaction between polymer and nanoparticle. The dynamics of these photoinduced species on the nanosecond to microsecond time scale are discussed. (18 References). Wang, R., J. Yang, et al. (2001). "Dendron-controlled nucleation and growth of gold nanoparticles." Angewandte Chemistry International Edition English 40(3): 549-552. Weber, A. P., M. Seipenbusch, et al. (1999). "Aerosol catalysis on nickel nanoparticles." Journal of Nanoparticle Research 1: 253-26. Weber, C., S. Reiss, et al. (2000). "Preparation of surface modified protein nanoparticles by introduction of sulfhydryl groups." International Journal of Pharmacy 211(1-2): 67-78. The objective of the present study was to establish several methods for the introduction of thiol groups onto the surface of human serum albumin (HSA) nanoparticles. Besides the varepsilon-amino groups of lysine, the carboxyl groups of asparaginic and glutaminic acid, and the carbonyl groups of the cross-linker glutaraldehyde, sulfhydryl groups are possible targets for the covalent linkage of drugs to particle surfaces. In principle, the thiol groups were introduced by the reaction with dithiotreitol (DDT) or 2-iminothiolane, by quenching reactive aldehyde residues with cystaminiumdichloride or by coupling L-cysteine and cystaminiumdichloride by the aqueous carbodiimide reaction. The resulting nanoparticulate systems were characterised concerning the number of available sulfhydryl groups, particle size and particle density. It was shown, that by variation of the reaction conditions, e.g., the concentration of the coupling reagent or the sulfhydryl containing component as well as the reaction time, the proposed methods enabled the preparation of HSA nanoparticles with a well defined surface characteristic. Stability studies showed that the introduced thiol groups were relatively stable and lost their reactivity with a half-life of 28.2 days independently of the method used for the sulfhydryl group introduction. Besides the quantification of free sulfhydryl groups the covalent attachment of cystaminiumdichloride by the carbodiimide reaction was used to calculate the amount of free carboxyl groups on the surface of the nanoparticles. The toxicity of the modified nanoparticles was evaluated in cell culture experiments. Weber, C., J. Kreuter, et al. (2000). "Desolvation process and surface characteristics of HSA-nanoparticles." International Journal of Pharmacy 196(2): 197-200. The objective of the present study was to characterise and optimise the desolvation process of human serum albumin (HSA) for the preparation of nanoparticles. Following the desolvation of the protein, the resulting nanoparticles were stabilised by the addition of varying amounts of glutaraldehyde. The particle size and the number of available amino groups on the surface of the nanoparticles were determined. The results indicated that the particle size depended mainly on the amount of desolvating agent added, but not on the amount of crosslinker. Increasing volumes of glutaraldehyde reduced the number of amino groups on the surface of HSA nanoparticles. Weber, C., C. Coester, et al. (2000). "Desolvation process and surface characterisation of protein nanoparticles." International Journal of Pharmacy 194(1): 91-102. The objective of the present study was to characterise and optimise the desolvation process of human serum albumin (HSA) for the preparation of nanoparticles and to characterise the resulting colloidal system. Following the desolvation of the protein, the resulting nanoparticles were stabilised by the addition of varying amounts of glutaraldehyde or by heat denaturation. The particle size, zeta potential, and the number of available amino groups on the surface of the nanoparticles were determined. The amino groups were quantified by a spectrophotometric method using 2,4, 6-trinitrobenzenesulfonic acid (TNBS). The results indicated that the particle size depended mainly on the amount of desolvating agent added, but not on the amount of cross-linker or the kind of cross-linking procedure. Increasing amounts of glutaraldehyde reduced the number of amino groups on the surface of HSA nanoparticles and also decreased the zeta potential of the carrier system. The temperature and heat denaturation time only had an influence on the stability of the nanoparticles but not on the amount of amino groups or the particle size. It was shown that heat denatured HSA nanoparticles possessed the greatest number of amino groups on their surface. Additional experiments for the characterisation of gelatin A and B nanoparticles were performed. Weeber, J. C., J. R. Krenn, et al. (2000). "Optical near-field properties of lithographically designed metallic nanoparticles." Semiconductor Quantum Dots. Symposium. 571: 95-100. We report on the experimental observation of localized surface plasmons sustained by small metallic particles using a photon scanning tunneling microscope (PSTM). The surface plasmons are excited in gold nanostructures tailored by electron beam lithography. The constant height operation of the PSTM allowed a direct comparison with theoretical computations of the distribution of the optical near-field intensity. Plasmon coupling above a chain

of Au particles and electromagnetic energy transfer from a resonantly excited nanoparticle to a nanowire are demonstrated. Our experimental results appear to be in good agreement with theoretical computations based on Green's dyadic technique. (10 References). Wei, M., A. J. Ruys, et al. (1999). "Solution ripening of hydroxyapatite nanoparticles: effects on electrophoretic deposition." Journal of Biomedical Materials Research 45(1): 11-9. Electrophoretic deposition is a low-cost, simple, and flexible coating method for producing hydroxyapatite (Hap) coatings on metal implants. However, densification requires heating the coated metal to high temperatures, which, for commercial HAp powders, generally means at least 1200 degrees C. At such temperatures, the metal tends to react with the HAp coating, inducing decomposition, and the strength of titanium and stainless steel implants is severely degraded. With the use of raw uncalcined nanoparticulate Hap, densification can occur at 900 degrees -1050 degrees C; however, such coatings are prone to cracking due to the high drying shrinkage. This problem was solved by precipitating nanoparticulate HAp by the metathesis process [10Ca(NO3)2 + 6NH4H2PO4 + 8NH4OH] and optimizing the approximately 30 nm of nanoprecipitates by an Ostwald ripening approach, that is, by boiling and/or ambient aging in the mother liquor. While the as-precipitated nanoparticles produced severely cracked coatings, 2 h of boiling or 10 days of ambient aging ripened the &quot;gel-like&quot; mass into unagglomerated nanoparticles, which produced crack-free coatings. Since boiling enhanced particle size but ambient aging did not, crack elimination probably was due to the transition from the highly agglomerated gel-like state to the dispersed nanoparticulate state rather than to particle growth. Furthermore, boiling only reduced the amount of cracking whereas aging completely eliminated cracking. Weitz, A., J. Worrall, et al. (2000). "A facile nanoparticle synthesis within a polar polysulfone active matrix." Advanced Materials 12(2): 106-9. A novel and simple synthesis of semiconducting and metallic nanoparticles is described that involves the in-situ formation of particles in a high dielectric-constant polymeric matrix that stabilizes the nanoparticles and also enables easy processing into films and fibers at ambient conditions. The procedure is applied to an array of different metal and semiconducting particles such as the CuS particles. (18 References). Wern, H. and C. Funk (2000). "New method to obtain GRIN-lenses through numerical modeling." Proceedings of SPIE the International Society for Optical Engineering 3984: 228-33. A new technique to produce a radial gradient in the refractive index in organic-inorganic nanocomposite materials using sol-gel techniques in combination with electrophoretically induced concentration profiles of oxide nanoparticles is presented. Electric charges of the ZrO/sub 2/ nanoparticle surface force the particles to diffuse in the gel state in the presence of an electric field employed by appropriate electrodes. In a previous study it has been shown that there exists a linear relation between the refractive index and the concentration of the oxide particles. In this paper the emphasis is focused to the development of appropriate electrodes through numerical modeling. The underlying time dependent parabolic partial differential equation is solved numerically using implicit methods. For the electric potential, a parametric model is assumed from which the spatial dependent electric field follows by gradient expansion. The parameters of the model are optimized using an iterative modified LevenbergMarquardt algorithm to match with the prescribed refractive index. The results of this new approach are discussed. (6 References). Wernsdorfer, W., D. Mailly, et al. (2000). "Single nanoparticle measurement techniques." Journal of Applied Physics 87(9): 1-3. Various single particle measuring techniques are briefly reviewed and the basic concepts of a new microsuperconducting quantum interference device technique are discussed. It allows measurements of the magnetization reversal of single nanometer-sized particles at low temperature. The influence of the measuring technique on the system of interest is discussed. (24 References). Wisner, E. R., R. W. Katzberg, et al. (1994). "Iodinated nanoparticles for indirect computed tomography lymphography of the craniocervical and thoracic lymph nodes in normal dogs." Academic Radiology 1(4): 377-84. RATIONALE AND OBJECTIVES: We evaluated the imaging characteristics of an interstitially or intraperitoneally delivered iodinated particulate contrast agent for computed tomography (CT) lymphography of the craniocervical and thoracic lymph nodes. METHODS: We injected 2-4 ml of 15% wt/vol iodinated nanoparticle suspension subcutaneously, submucosally, or intraperitoneally in eight normal dogs. CT and plain radiographic images were obtained prior to contrast administration and 4 hr, 24 hr, and 7 days after injection. Correlation was made to detailed postmortem assessment. RESULTS: CT images showed enhancement of regional nodes draining injection sites. Mean attenuation of opacified nodes was 313 +/- 297 (mean +/- standard deviation), 536 +/- 453, and 492 +/- 372 Hounsfield units at 4 hr, 24 hr, and 7 days postinjection, respectively. Lymph node opacification on CT images correlated well with node location found at postmortem. CONCLUSION: Craniocervical and thoracic lymph nodes can be effectively opacified from interstitial or intraperitoneal delivery of this iodinated nanoparticulate contrast agent.

Wisner, E. R., R. W. Katzberg, et al. (1995). "Indirect computed tomography lymphography using iodinated nanoparticles: time and dose response in normal canine lymph nodes." Academic Radiology 2(11): 985-93. RATIONALE AND OBJECTIVES: We evaluated the effect of time and dose on lymph node iodine uptake after subcutaneous or submucosal administration of iodinated nanoparticles used for computed tomography lymphography. METHODS: We injected 0.1-6 ml of a 15% wt/vol iodinated nanoparticle suspension into the distal extremities subcutaneously (n = 5) or into the buccal submucosa (n = 7) of normal dogs. Precontrast and 4, 12, 24, and 48 hr after contrast administration, CT scans of opacified lymph nodes were obtained. Iodine concentration, node volume, and total iodine uptake were estimated for each node. RESULTS: All estimated parameters increased between 4 and 12 hr postcontrast (p &lt; .05), with no significant increase thereafter. At 24 hr postcontrast, iodine concentration ranged from 0.01 to 16.1 mg/ml (47-568 Hounsfield units). The average iodine concentration and total iodine uptake increased with contrast dose (p &lt; .05) for all lymph node groups evaluated. Node opacification also revealed internal architectural detail. CONCLUSION: Subcutaneous and submucosal injections of iodinated nanoparticles result in a dose-dependent iodine uptake in targeted lymph nodes. In addition, architectural detail within opacified nodes can be visualized. Wisner, E. R., R. W. Katzberg, et al. (1995). "Indirect computed tomography lymphography of subdiaphragmatic lymph nodes using iodinated nanoparticles in normal dogs." Academic Radiology 2(5): 405-12. RATIONALE AND OBJECTIVES: We evaluated the imaging characteristics of an iodinated particulate contrast agent for indirect computed tomography (CT) lymphography of normal subdiaphragmatic lymph nodes in dogs. METHODS: Four milliliters of a 15% (wt/vol) iodinated nanoparticle suspension was injected into the gastric, colonic, rectal, or cervical submucosa, loose paraprostatic fascia, or metatarsal subcutaneous tissues in 10 healthy beagles. Endoscopic, CT, or ultrasound guidance was used when necessary to facilitate contrast agent delivery. CT and radiographic images were obtained prior to contrast administration and at 4 hr, 24 hr, and 7 days postcontrast injection. Postmortem examinations were then conducted. RESULTS: CT images showed enhancement of regional lymph nodes draining the various injection sites. The mean attenuation of opacified nodes was 678 +/- 463 Hounsfield units 24 hr after injection and remained elevated 7 days later. Lymph node opacification on CT images correlated well with the node location observed on postmortem examinations. CONCLUSION: Subdiaphragmatic lymph nodes can be effectively opacified using an iodinated nanoparticle contrast agent for indirect CT lymphography. Wisner, E. R., R. W. Katzberg, et al. (1996). "Characterization of normal and cancerous lymph nodes on indirect computed tomography lymphographic studies after interstitial injection of iodinated nanoparticles." Academic Radiology 3 Suppl 2(5): S257-60. Wisner, E. R., R. W. Katzberg, et al. (1996). "Indirect computed tomography lymphography using iodinated nanoparticles to detect cancerous lymph nodes in a cutaneous melanoma model." Academic Radiology 3(1): 40-8. RATIONALE AND OBJECTIVES: To evaluate differences in contrast uptake in normal and cancerous lymph nodes on indirect computed tomography (CT) in swine, we conducted lymphographic examinations after subcutaneous injection of a lymphotropic iodinated nanoparticle suspension. METHODS: Perilesional subcutaneous contrast injections (2 ml per lesion) of a 15% wt/vol iodinated nanoparticle suspension were made in immature Sinclair miniature swine (n = 5) with cutaneous melanomas. Average attenuation, iodine concentration, node volume, and total iodine uptake were estimated on the CT scans for each opacified lymph node 24 hr after injection. Nodes were classified as normal or cancerous microscopically, and the percentage of tumor replacement was estimated in cancerous nodes. RESULTS: Average attenuation and iodine concentration were higher in normal nodes, and total iodine uptake was higher in cancerous nodes with greater than 25% replacement (p &lt; .05). Architectural alterations in opacified cancerous nodes included medullary filling defects, expansile cortical lesions, and disruption of corticomedullary junctions. CONCLUSION: Quantitative and qualitative differences in iodinated nanoparticle enhancement characteristics are useful in distinguishing between normal and cancerous lymph nodes on indirect CT lymphography examinations. Wisner, E. R., A. Theon, et al. (1998). "Contrast-enhancement properties of irradiated normal lymph nodes: initial experience with interstitially delivered iodinated nanoparticles." Academic Radiology 5 Suppl 1(3): S180-2; discussion S183-4. Wisner, E. R., J. A. Seibert, et al. (1998). "Quantitative methods for indirect CT lymphography." Veterinary Radiology and Ultrasound 39(2): 110-6. In this investigation, we applied quantitative CT methods to characterize contrast enhanced lymph nodes opacified using iodinated contrast media for indirect CT lymphography. Iodinated nanoparticles were injected into the buccal submucosa and SQ into the metatarsus and metacarpus of four normal swine (1.0-4.0 ml/site, 76 mg I/ml). Attenuation (HU), volume (cm3), iodine concentration (mg I/cm3), total iodine uptake (mg I), contrast-tonoise ratio (CNR), and percent injected dose (%ID) were estimated in opacified inguinal, cervical and

parotid/mandibular lymph nodes using manual image segmentation techniques on 24 hour post-contrast CT images. Lymph node volumes estimated by multiple slice ROI analysis were compared with estimates obtained by post-excisional weight measurements. HU and iodine concentration increased 5-20 fold in opacified nodes (p &lt; 0.01) and CNR increased more than four-fold (p &lt; 0.001). %ID ranged between 3.5 and 11.9% and did not appear dose related. ROI estimated lymph node volumes approximated volumes calculated from weight measurements. (R2 = 0.94, p &lt; 0.0001). We conclude that interstitially injected iodinated nanoparticles increase attenuation and conspicuity of targeted nodes on CT images. Quantitative methods could play an important clinical role in more accurate metastasis detection. Wisner, E. R., A. Theon, et al. (2000). "Long-term effect of irradiation on lymph node uptake of interstitially delivered nanoparticulate contrast media." Investigative Radiology 35(3): 199-204. RATIONALE AND OBJECTIVES: To characterize the long-term effects of therapeutic doses of ionizing radiation on the uptake and distribution of percutaneously delivered particulate contrast media in normal lymph nodes. METHODS: Two milliliters of an iodinated nanoparticle suspension (76 mg I/mL) was injected subcutaneously or submucosally into nine normal adult beagles. Region of interest analysis was used to estimate the volume, attenuation, and iodine concentration of opacified targeted lymph nodes and nonopacifled contralateral nodes on 24-hour postinjection CT images. All lymph nodes were then irradiated with 50 Gy in 25 fractions of 2 Gy/d. Contrast-enhanced quantitative CT was repeated 12 months after irradiation. RESULTS: Contrast-enhanced nodes averaged 2.3+/-0.8 times the volume of nonenhanced contralateral nodes before irradiation. The mean attenuation of contrast-enhanced nodes increased to 305 to 380 Hounsfield units from a pre-enhancement value of approximately 25 Hounsfield units. Opacified node volumes after irradiation averaged 61% to 86% of preirradiation volumes but were generally not statistically different. Contrast uptake assessed by average attenuation and iodine concentration decreased significantly by an average of 17% to 22% after irradiation and was significantly less than preirradiation uptake. Qualitatively, irradiated nodes generally appeared smaller than nonirradiated nodes, but the distribution pattern of contrast media did not appear to be appreciably altered. CONCLUSIONS: Lymph node irradiation resulted in only minimal decreases in contrast media uptake and node volume at 12 months. These effects presumably would not appreciably alter the potential clinical value of indirect lymphography for evaluating patients undergoing radiation therapy. Wood, R. F., J. N. LeBoeuf, et al. (2000). "Aspects of nanoparticle formation during pulsed laser ablation." Proceedings of SPIE the International Society for Optical Engineering 3935: 57-65. Laser ablation is one of the most effective ways of making single-wall carbon nanotubes. Although the process is poorly understood, the importance of nanoparticle formation to initiate tube growth is evident. While some groups have concluded that nanoparticles can form in vacuum, we have argued that this is unlikely because the expansion of the plume is so rapid that the "freezing limit" is reached too rapidly for nucleation and growth to the observed size. A background gas changes the dynamics completely. Calculations show that in a few microseconds the ablated plume is dramatically slowed by the "snowplowing" of the background gas into a peak whose density is much greater than its initial density. The ablated material is trapped within this peak. The question then arises as to how this peak dissipates by diffusion. A simple calculation shows that it is at this point that a drastic change in the timescale of the process occurs so that there is ample time (milliseconds) for nanoparticles to nucleate and grow. (17 References). Wright, D. L., R. McGraw, et al. (2001). "Bivariate extension of the quadrature method of moments for modeling simultaneous coagulation and sintering of particle populations." Journal of Colloid and Interface Science 236(2): 242-251. We extendthe application of moment methods to multivariate suspended particle population problems-those for which size alone is insufficient to specify the state of a particle in the population. Specifically, a bivariate extension of the quadrature method of moments (QMOM) (R. McGraw, Aerosol Sci. Technol. 27, 255 (1997)) is presented for efficiently modeling the dynamics of a population of inorganic nanoparticles undergoing simultaneous coagulation and particle sintering. Continuum regime calculations are presented for the Koch-FriedlanderTandon-Rosner model, which includes coagulation by Brownian diffusion (evaluated for particle fractal dimensions, D(f), in the range 1.8-3) and simultaneous sintering of the resulting aggregates (P. Tandon and D. E. Rosner, J. Colloid Interface Sci. 213, 273 (1999)). For evaluation purposes, and to demonstrate the computational efficiency of the bivariate QMOM, benchmark calculations are carried out using a high-resolution discrete method to evolve the particle distribution function n(nu, a) for short to intermediate times (where nu and a are particle volume and surface area, respectively). Time evolution of a selected set of 36 low-order mixed moments is obtained by integration of the full bivariate distribution and compared with the corresponding moments obtained directly using two different extensions of the QMOM. With the more extensive treatment, errors of less than 1% are obtained over substantial aerosol evolution, while requiring only a few minutes (rather than days) of CPU time. Longer time QMOM simulations lend support to the earlier finding of a self-preserving limit for the dimensionless joint (nu, a) particle distribution function under simultaneous coagulation and sintering (Tandon and Rosner, 1999; D. E. Rosner and S. Yu, AIChE J., 47 (2001)). We demonstrate that, even in the bivariate case, it is possible to use the QMOM to rapidly model the approach to asymptotic behavior, allowing an immediate assessment of when

previously established asymptotic results can be applied to dynamical situations of current/future interest. Copyright 2001 Academic Press. Wu, J., D. Bratko, et al. (1998). "Interaction between like-charged colloidal spheres in electrolyte solutions." Proceedings of the National Academy of Sciences U S A 95(26): 15169-72. How colloidal particles interact with each other is one of the key issues that determines our ability to interpret experimental results for phase transitions in colloidal dispersions and our ability to apply colloid science to various industrial processes. The long-accepted theories for answering this question have been challenged by results from recent experiments. Herein we show from Monte-Carlo simulations that there is a short-range attractive force between identical macroions in electrolyte solutions containing divalent counterions. Complementing some recent and related results by others, we present strong evidence of attraction between a pair of spherical macroions in the presence of added salt ions for the conditions where the interacting macroion pair is not affected by any other macroions that may be in the solution. This attractive force follows from the internal-energy contribution of counterion mediation. Contrary to conventional expectations, for charged macroions in an electrolyte solution, the entropic force is repulsive at most solution conditions because of localization of small ions in the vicinity of macroions. Both Derjaguin-Landau-Verwey-Overbeek theory and Sogami-Ise theory fail to describe the attractive interactions found in our simulations; the former predicts only repulsive interaction and the latter predicts a longrange attraction that is too weak and occurs at macroion separations that are too large. Our simulations provide fundamental &quot;data&quot; toward an improved theory for the potential of mean force as required for optimum design of new materials including those containing nanoparticles. Wu, X. and Y. Hong (2000). "Rapidly solidified morphology and microstructure of 18-8 stainless steel with ZrO2 coating by pulsed laser." Chin Shu Hsueh Pao: Acta Metallurgica Sinica 36(3): 239-42. A coating was synthesized on an austenite stainless steel surface by laser alloying of nanoparticle using a pulsed laser. The rapidly solidified morphology, microstructure, hardness, and modulus were investigated. The existence of Zr-alloying, with non-uniform distribution of Zr composition, was seen in a scope of 15 mu m just below the surface. The rapidly solidified sub-grain, i.e., is refined significantly and cell of austenite, is refined significantly due to the ultra-high temperature gradient and high cooling rate. In addition, two fine structures, i.e., cellular dislocation and paling twins, were observed. However, the grain in laser remelted zones is not fined because of epitaxial growth. The effect of laser radiation on hardness and modulus was analyzed. (9 References). Wu, X., L. Zou, et al. (2001). "Structural characterizations of organo-capped barium titanate nanoparticles prepared by the wet chemical route." Journal of Colloid and Interface Science 239(2): 369-373. In the present study, nanoscale barium titanate particles were chemically prepared with organic shells on their surfaces. Their chemical and physical structures were characterized by FT-IR, FT-Raman, XRD, and XPS. Based on the results of characterizations, it can be concluded that the presence of organic ligands greatly influences the nucleation and surface chemistry of BaTiO(3) nanoparticles. Surface Ti(4+) tends to bond to stearate ions instead of the previous Ba(2+) in the starting materials. The usual preferable orientation growths of lattice, i.e., (101), (111), and (200), were significantly restrained due to surface coordination. Although poor crystallinity was observed, a tetragonal phase of BaTiO(3) nuclei could be inferred from both XRD and Raman patterns. Finally, the formation mechanism and structural model of organo-capped nanoparticles are discussed. Copyright 2001 Academic Press. Xiang Ling, J., L. Bin, et al. (2000). "Luminescent properties of organic-inorganic hybrid monoliths containing rare-earth complexes." Journal of Non Crystalline Solids 275: 1-2. Transparent organic-inorganic hybrid monoliths containing rare-earth complexes (Eu(TTA)/sub 3/Phen, Tb(Sal)/sub 3/) were prepared via the sol-gel technique. It could be observed by transmission electron microscopy that the fluorescent particles are distributed in the matrix at the microscopic level. The matrix is composed of organic-inorganic semi-interpenetrating networks, i.e., the PHEMA-SiO/sub 2/ system. The fluorescence emission spectra of samples are similar to those from corresponding powdered Eu(III) and Tb(III) complexes, and the halfwidths of the strongest bands are less than 10 nm, which indicates that the monolith exhibits high fluorescence intensity and color purity. Furthermore, the fluorescence spectra exhibit no obvious change with decreasing nanoparticle size of the rare-earth complex. The fluorescence lifetimes of samples are longer than pure Eu(III), Tb(III) complexes, respectively. Samples irradiated with an UV lamp (365 nm) are still transparent but become bright red and green in color due to fluorescence of Eu(III) and Tb(III) complexes. (10 References). Xiangcheng, S., M. J. Yacaman, et al. (2000). "Microstructural and magnetic properties on graphitic encapsulated Ni nanocrystals and pure Ni nanoparticles with NiO layer." Nanophase and Nanocomposite Materials III. Symposium 581: 535-40. Two kinds of different nickel nanoparticles with distinct morphological properties, Ni(C) and Ni(O), are studied. Magnetization measurements for the assembly of two kinds of Ni nanoparticles show, a larger coercivity and remanence as well as the deviation between the zero field cooling (ZFC) and the field cooling (FC) magnetization

have been observed in the Ni(O) particles. This deviation may be explained as a typical cluster glass-like behavior due to ferromagnetic interaction among the assembly of Ni(O) particles. However, Ni(C) particles exhibit superparamagnetism at room temperature. The average blocking temperature (T/sub B/) is determined to around 115 K. We also observe gradual decrease in saturation magnetization, which is attributed to the nanocrystalline nature of the encapsulated particles. (12 References). Xin, Y., S. Sheng-Kwei, et al. (2000). "Intra- and intermonolayer hydrogen bonding in amide-functionalized alkanethiol self-assembled monolayers on gold nanoparticles." Langmuir 16(24): 9527-32. We have synthesized a series of monolayer-protected gold clusters (gold MPCs) featuring amide functionality within the monolayer chains. Spectroscopic investigation of these MPCs using IR and /sup 1/H NMR spectroscopy reveal that intramonolayer hydrogen bonding is highly dependent on the distance of the amide from the nanoparticle core. Additionally, intermonolayer hydrogen bonding with concomitant nanoparticle aggregation was observed when the amide functionality was placed near the monolayer surface. (31 References). Xin, W., Z. Yu, et al. (2000). "Electronic and optical properties of chemically modified metal nanoparticles and molecularly bridged nanoparticle arrays." Journal of Physical Chemistry B 104(38): 8925-30. Nanometer-sized metal particles (e.g., gold and silver) are certain to be important fundamental building blocks of future nanoscale electronic and optical devices. However, there are numerous challenges and questions which must be addressed before nanoparticle technologies can be implemented successfully. For example, basic capping ligand chemistry-nanoparticle electronic function relationships must be addressed in greater detail. New methods for assembling nanoparticles together into higher-order arrays with more complex electronic functions are also required. This review highlights our recent progress toward characterizing electron transport in gold nanoparticles as a function of capping ligand charge state. These studies have shown that single electron tunneling energies can be manipulated predictably via pH-induced charge changes of surface-bound thiol capping ligands. We also show that rigid phenylacetylene molecules are useful bridges for assembling gold and silver nanoparticles into arrays of two, three, and four particles with pseudo D/sub infinity h/, D/sub 3h/ and T/sub d/ symmetries. These nanoparticle "molecules" interact electromagnetically in a manner qualitatively consistent with dipole coupling models. (19 References). Xu, W. (2000). "Thick film microsensors based on nanosized titania sol-gel powder." Inst. Electron. Technol., Warszawa. Electron Technology 33: 1-2. Thick films of nanostructured TiO/sub 2/ and tantalum-doped TiO/sub 2/ have been fabricated by screen-printing technology starting from pure titania and tantalum-doped titania powders prepared by the sol-gel method. The titania powders, obtained via sol gel, show crystalline anatase structure and the particles are homogeneous and nanosized (30+50 nm). Two series of films, each one composed of pure and Ta-doped titania samples, have been obtained by firing the pastes in air atmosphere at 650 degrees C and 850 degrees C, respectively. SEM observations and electrical characterizations showed that the firing temperature strongly influences the nanostructure and the gas response of the pure titania samples. The addition of tantalum inhibits the grain sintering at the higher temperature. Moreover the electrical data show that the tantalum addition (10 at.%) does not affect the conductance of the films at all while significantly enhancing the CO response and leaves almost unaltered or enhances its ability to sense NO/sub 2/ depending on the thermal treatments. (10 References). Yalabik-Kas, H. S., J. Kreuter, et al. (1986). "Sorption of 5-fluorouracil from aqueous solutions onto methyl methacrylate nanoparticles." Journal of Microencapsulation 3(2): 71-5. The sorption of 5-fluorouracil from aqueous solutions onto poly(methyl methacrylate) was investigated. Linear sorption isotherms were obtained and no crystallinity of the nanoparticles after sorption was detectable by X-ray analysis indicating a partitioning of the drug into the polymer particles-forming a solid solution. Standard enthalpy, standard entropy and standard free energy of sorption were -36.9 kJ mol-1, -85.0 J mol-1 K-1 and -12.0 kJ mol-1, respectively. Yang, S., J. Zhu, et al. (1999). "Body distribution of camptothecin solid lipid nanoparticles after oral administration." Pharmacetical Research 16(5): 751-7. PURPOSE: The aim of this study was to investigate the specific changes in body distribution of camptothecin (CA) through incorporation into solid lipid nanoparticles (SLN) by peroral route. METHODS: Camptothecin loaded solid lipid nanoparticles (CA-SLN) coated with poloxamer 188 were produced by high pressure homogenization. The CA-SLN were characterized by transmission electron microscopy and electrophoretic mobility measurement. In vitro release characteristics of camptothecin from CA-SLN were studied at different pH media. The concentration of camptothecin in organs was determined using reversed-phase high-performance liquid chromatography with a fluorescence detector after oral administration of CA-SLN and a camptothecin control solution (CA-SOL). RESULTS: Our results showed that CA-SLN had an average diameter 196.8 nm with Zeta potential of -69.3 mV. The encapsulation efficiency of camptothecin was 99.6%, and in vitro drug release was achieved up to a week. There were two peaks in the camptothecin concentration-time curves in plasma and

tested organs after oral administration of CA-SLN. The first peak was the result of free drug and the second peak was indicative of gut uptake of CA-SLN after 3 hours. In tested organs, the area under curve (AUC) and mean residence time (MRT) of CA-SLN increased significantly as compared with CA-SOL, and the increase of brain AUC was the highest among all tested organs. CONCLUSIONS: The results indicate SLN could be a promising sustained release and targeting system for camptothecin or other lipophilic antitumor drugs after oral administration. Yang, S. C., L. F. Lu, et al. (1999). "Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain." Journal of Controlled Release 59(3): 299-307. The objective of the present study was to investigate the specific drug targeting of anticarcinogenic drugs, such as camptothecin (CA), after intravenous (i.v.) injection by incorporation into solid lipid nanoparticles (SLN). A CA loaded SLN suspension consisted of 0.1% (w/w) camptothecin, 2.0% (w/w) stearic acid, 1.5% (w/w) soybean lecithin and 0.5% (w/w) polyoxyethylene-polyoxypropylene copolymer (Poloxamer 188) was prepared by high pressure homogenization. In vitro drug release was investigated in pH 7.4 phosphate-buffered saline at 37 degrees C. The concentrations of camptothecin in various organs were determined using reversed-phase highperformance liquid chromatography with a fluorescence detector after i.v. administration of CA-SLN and a camptothecin control solution (CA-Sol). The results showed that the CA-SLN had an average diameter 196.8 nm with a Zeta potential of -69.3 mV and in vitro drug release was achieved for up to a week. In tested organs, the AUC/dose and the mean residence times (MRT) of CA-SLN were much higher than those of CA-Sol, especially in brain, heart and reticuloendothelial cells containing organs. The brain AUC ratio of CA-SLN to CA-Sol was the highest among the tested organs. These results indicate that SLN are a promising sustained release and drug targeting system for lipophilic antitumour drugs, and may also allow a reduction in dosage and a decrease in systemic toxicity. Yao, Y. and A. Tholen (2000). "TEM investigation on stress contrast and interfaces of contacting particles." Materials Characterization 44: 4-5. An investigation on nanoparticle contacting using convergent beam electron diffraction (CBED) and highresolution electron microscopy (HREM) is reported. Cobalt particles (5-200 nm) from a solution-treated Cu2(w/o)Co alloy were extracted and allowed to contact without pressure. The contacting stress field due to adhesion was clearly observed, and the stress field had a dipole character. Free particles were observed to contact along low-index zone axes and with specific orientation relationships. Fourier transformation of the HREM micrographs revealed a highly distorted area along the contacting boundary containing dislocations. Electron diffraction contrast from the stress fields between contacting particles was simulated, and agreed well with the experiments. (17 References). Yatsui, K., T. Yukawa, et al. (2000). "Synthesis of ultrafine g-Al2O3 powders by pulsed laser ablation." Journal of Nanoparticle Research 2: 75-83. Yoo, H. S., J. E. Oh, et al. (1999). "Biodegradable nanoparticles containing doxorubicin-PLGA conjugate for sustained release." Pharmacetical Research 16(7): 1114-8. PURPOSE: Doxorubicin was chemically conjugated to a terminal end group of poly(D,L-lactic-co-glycolic acid) [PLGA] and the doxorubicin-PLGA conjugate was formulated into nanoparticles to sustain the release of doxorubicin. METHODS: A hydroxyl terminal group of PLGA was activated by p-nitrophenyl chloroformate and reacted with a primary amine group of doxorubicin for conjugation. The conjugates were fabricated into ca. 300 nm size nanoparticles by a spontaneous emulsion-solvent diffusion method. The amount of released doxorubicin and its PLGA oligomer conjugates was quantitated as a function of time. The cytotoxicity of the released species was determined using a HepG2 cell line. RESULTS: Loading efficiency and loading percentage of doxorubicinPLGA conjugate within the nanoparticles were 96.6% and 3.45 (w/w) %, respectively while those for unconjugated doxorubicin were 6.7% and 0.26 (w/w) %, respectively. Both formulation parameters increased dramatically due to the hydrophobically modified doxorubicin by the conjugation of PLGA. The nanoparticles consisting of the conjugate exhibited sustained release over 25 days, whereas those containing unconjugated free doxorubicin showed rapid doxorubicin release in 5 days. A mixture of doxorubicin and its PLGA oligomer conjugates released from the nanoparticles had comparable IC50 value in a HepG2 cell line compared to that of free doxorubicin. Sustained drug release was attributed to the chemical degradation of conjugated PLGA backbone, which permitted water solubilization and subsequent release of doxorubicin conjugated PLGA oligomers into the medium. CONCLUSIONS: The conjugation approach of doxorubicin to PLGA was potentially useful for nanoparticle formulations that require high drug loading and sustained release. The doxorubicin-PLGA oligomer conjugate released in the medium demonstrated a slightly lower cytotoxic activity than free doxorubicin in a HepG2 cell line. Yoo, H. S., K. H. Lee, et al. (2000). "In vitro and in vivo anti-tumor activities of nanoparticles based on doxorubicin-PLGA conjugates." Journal of Controlled Release 68(3): 419-31.

Doxorubicin was chemically conjugated to a terminal end group of poly(D,L-lactic-co-glycolic acid) [PLGA] by an ester linkage and the doxorubicin-PLGA conjugate was formulated into nanoparticles. A carboxylic acid end group of PLGA was conjugated to a primary hydroxyl group of doxorubicin. The primary amine group of doxorubicin was protected during the conjugation process and then deprotected. The nanoparticles containing the conjugate exhibited sustained doxorubicin release profiles over a 1-month period, whereas those containing unconjugated free doxorubicin showed a rapid doxorubicin release within 5 days. Doxorubicin release patterns could be controlled by conjugating doxorubicin to PLGA having different molecular weights. The conjugated doxorubicin nanoparticles showed increased uptake within a HepG2 cell line, which was quantitated by a flow cytometry and visualized by confocal microscopy. The nanoparticles exhibited slightly lower IC(50) value against the HepG2 cell line compared to that of free doxorubicin. In vivo anti-tumor activity assay also showed that a single injection of the nanoparticles had comparable activity to that of free doxorubicin administered by daily injection. The conjugation approach of doxorubicin to PLGA was potentially useful for the formulation of nanoparticles that requires targeting for cancer cells as well as sustained release at the site. Yoo, H. S., H. K. Choi, et al. (2001). "Protein-fatty acid complex for enhanced loading and stability within biodegradable nanoparticles." Journal of Pharmacological Science 90(2): 194-201. Lysozyme was hydrophobically modified with a fatty acid, sodium oleate, via an ion-pairing mechanism. Ionic binding between an anionic carboxylic group of sodium oleate and basic amino groups in lysozyme was primarily utilized to form lysozyme-oleate complex. The complex formation was pH dependent. The lysozyme-oleate complex dissolved in an organic solvent exhibited much higher conformational stability at elevated temperature compared with free lysozyme in the same solvent. The complex was formulated into biodegradable nanoparticles by a spontaneous emulsion and solvent diffusion method. The resultant formulation showed near 100% encapsulation efficiency of lysozyme within nanoparticles with < 100 nm in diameter with a narrow size distribution. Lysozyme could be loaded into the nanoparticles up to 18.6% (w/w) with concomitantly increased particle sizes. This study demonstrates a new formulation method of biodegradable nanoparticles with highly efficient encapsulation of proteins, which are potentially useful for oral protein delivery including mucosal vaccination. Young-Hag, K., K. Hae-Won, et al. (2000). "Microstructural evolution and mechanical properties of Si3N4-SiC (nanoparticle)-Si3N4 (whisker) composites." Journal of Materials Research 15(2): 364-8. The effects of SiC-nanoparticle and Si/sub 3/N/sub 4/-whisker additions on the microstructural evolution and mechanical properties of Si/sub 3/N/sub 4/ were investigated. The addition of SiC nanoparticles suppressed Si/sub 3/N/sub 4/ grain growth, leading to an improvement in the flexural strength. On the other hand, Si/sub 3/N/sub 4/ whiskers in the specimen promoted the formation of large elongated grains, which were found to be beneficial to the fracture toughness of the material. When both SiC nanoparticles and Si/sub 3/N/sub 4/ whiskers were added concurrently, large grains were formed in fine matrix grains. The microstructure of Si/sub 3/N/sub 4/ was controlled by adjusting the relative concentrations of SiC nanoparticles and the Si/sub 3/N/sub 4/ whiskers added. These compositional and microstructural variations of the Si/sub 3/N/sub 4/ had significant influence on the mechanical properties, such as strength, fracture toughness, R-curve behavior, and high-temperature strength. (19 References). Youssef, M., E. Fattal, et al. (1988). "Effectiveness of nanoparticle-bound ampicillin in the treatment of Listeria monocytogenes infection in athymic nude mice." Antimicrob Agents Chemother 32(8): 1204-7. The effectiveness of nanoparticle-bound ampicillin was tested in the treatment of experimental Listeria monocytogenes infection in congenitally athymic nude mice. Nanoparticles of polyisohexylcyanoacrylate (PIHCA) 187 +/- 13 nm in diameter were bound to ampicillin at an ampicillin/PIHCA ratio of 0.2:1. The proportion of ampicillin bound was 90% +/- 3%. After adsorption onto nanoparticles, the therapeutic activity of ampicillin increased dramatically over that in the free state. Thus, 2.4 mg of nanoparticle-bound ampicillin (three doses of 0.8 mg each) had a greater therapeutic effect than 48 mg of free ampicillin (three doses of 16 mg each). These results might provide an incentive for further development of intracellular targeting of antibiotics on biodegradable polymeric carriers. Yu, O., I. J. Namer, et al. (1995). "Susceptibility-based MRI contrast of the CSF by intravascular superparamagnetic nanoparticles." Magma 3(3-4): 169-72. Endorem, a suspension of superparamagnetic iron oxide dextran nanoparticles (NP), have been injected intravenously to healthy anesthetized rats for the purpose of contrast enhancement of brain in gradient-echo imaging at 200 MHz. Not only gray and white matter but also particular regions of the cerebrospinal fluid (CSF) were contrasted in sagittal and transverse images, although samples of this fluid did not contain NP. The selected contrast in the CSF would result form the ability of dense vascular beds containing highly magnetized particles to induce a remote susceptibility effect far beyond the vascular walls into a large fraction of extravascular water. Yu, X., S.-K. Song, et al. (2000). "Molecular imaging of human thrombus using a novel fibrin-targeted MR imaging agent."

Circulation. [ print] 102(18 Supplement): 375. Yu, X., S.-K. Song, et al. (2000). "High-resolution MRI characterization of human thrombus using a novel fibrin-targeted paramagnetic nanoparticle contrast agent." Magnetic Resonance in Medicine. [ print] 44(6): 867-872. In this study, the sensitivity of a novel fibrin-targeted contrast agent for fibrin detection was defined in vitro on human thrombus. The contrast agent was a lipid-encapsulated perfluorocarbon nanoparticle with numerous GdDTPA complexes incorporated into the outer surface. After binding to fibrin clots, scanning electron microscopy of treated clots revealed dense accumulation of nanoparticles on the clot surfaces. Fibrin clots with sizes ranging from 0.5-7.0 mm were imaged at 4.7 T with or without treatment with the targeted contrast agent. Regardless of sizes, untreated clots were not detectable by T1-weighted MRI, while targeted contrast agent dramatically improved the detectability of all clots. Decreases in T1 and T2 relaxation times (20-40%) were measured relative to the surrounding media and the control clots. These results suggest the potential for sensitive and specific detection of microthrombi that form on the intimal surfaces of unstable atherosclerotic plaque. Yu, L., P. Zhang, et al. (2000). "Tribological behavior and structural change of the LB film of MoS 2 nanoparticles coated with dialkyldithiophosphate." Surface and Coatings Technology 130(1): 110-15. The LB film of MoS/sub 2/ nanoparticles coated with dialkyldithiophosphate (DDP) was prepared on a coppercoated glass substrate. The tribological behavior of the surface-modified MoS/sub 2/ nanoparticle LB film against GCr15 bearing steel (SAE 52100) was evaluated with a one-way reciprocating friction tester, and the structural change of the LB film during rubbing process was investigated with a Fourier transform infrared (FTIR) microscope and X-ray photoelectron spectroscope (XPS). It has been found that MoS/sub 2/ nanoparticle LB film shows a considerably decreased friction coefficient and increased wear resistance in sliding against steel. Tribochemical changes were involved during the friction process of the LB film against GCr15 bearing steel, including the disordering and partial or even complete decomposition of the modifier DDP at sliding cycles above 5000. However, the inorganic nanocores of MoS/sub 2/ kept unchanged after sliding even for 5000 cycles, though they experienced oxidation when heated to 300 degrees C in air. Thus, the improved tribological behavior of DDP coated-MoS/sub 2/ nanoparticles is attributed to the lubricity of DDP modifier at low sliding cycles and the loadcarrying capacity and lubricity of MoS/sub 2/ nanocores at increased sliding cycles. (24 References). Yu, X., S. K. Song, et al. (2000). "High-resolution MRI characterization of human thrombus using a novel fibrin-targeted paramagnetic nanoparticle contrast agent." Magn Reson Med 44(6): 867-72. In this study, the sensitivity of a novel fibrin-targeted contrast agent for fibrin detection was defined in vitro on human thrombus. The contrast agent was a lipid-encapsulated perfluorocarbon nanoparticle with numerous GdDTPA complexes incorporated into the outer surface. After binding to fibrin clots, scanning electron microscopy of treated clots revealed dense accumulation of nanoparticles on the clot surfaces. Fibrin clots with sizes ranging from 0.5-7.0 mm were imaged at 4.7 T with or without treatment with the targeted contrast agent. Regardless of sizes, untreated clots were not detectable by T(1)-weighted MRI, while targeted contrast agent dramatically improved the detectability of all clots. Decreases in T(1) and T(2) relaxation times (20-40%) were measured relative to the surrounding media and the control clots. These results suggest the potential for sensitive and specific detection of microthrombi that form on the intimal surfaces of unstable atherosclerotic plaque. Yuan, F. (1998). "Transvascular drug delivery in solid tumors." Semin Radiat Oncol 8(3): 164-75. The microvessel wall is a barrier for the delivery of various therapeutic agents to tumor cells. Tumor microvessels are, in general, more permeable to macromolecules than normal vessels. The hyperpermeability is presumably due to the existence of large pore structures in the vessel wall, induced by various cytokines. The cutoff pore size is tumor dependent, as determined by transport studies of nanoparticles. The vascular permeability is heterogeneous in tumors and dependent on physicochemical properties of molecules as well as the ultrastructure of the vessel wall. The ultrastructure is dynamic and can be modulated by the tumor microenvironment. The microenvironment itself can be altered by the transvascular transport because the transport may facilitate angiogenesis, reduce blood flow, and induce interstitial hypertension in tumors. Future studies of transport need to address mechanisms of the barrier formation and emphasize development of novel strategies for circumventing or exploiting the vascular barrier. Zambaux, M. F., F. Bonneaux, et al. (1998). "Influence of experimental parameters on the characteristics of poly(lactic acid) nanoparticles prepared by a double emulsion method." Journal of Controlled Release 50(1-3): 31-40. Nanoparticles were prepared by the double emulsion method (w/o/w), using methylene chloride as an organic solvent and polyvinyl alcohol (PVA) or human serum albumin (HSA) as a surfactant. Experimental parameters such as the preparation temperature, the solvent evaporation methods, the internal aqueous phase volume, the surfactant concentration and the polymer molecular weight were investigated for particle size, the zeta potential, the residual surfactant percentage and the polydispersity index. Preparation parameters leading to particles with well-defined characteristics such as an average size around 200 nm and a polydispersity index lower than 0.1 were identified. The conditions were optimized to ensure protein encapsulation: a cool temperature, a short

processing time, a sufficient internal aqueous phase and careful washing. It appeared that the higher the surfactant concentration in the external aqueous phase was, the smaller the particles, the lower the polydispersity index and the higher the residual amount of surfactant were. For PVA or HSA, the agreement between the convenient surfactant concentration and its critical aggregation concentration could be emphasized. Otherwise, an increased polymer molecular weight led both to a slightly decreased particle size and to a lower polydispersity index. Moreover, multilayer absorption of PVA which does not depend on Poly(lactic-acid) molecular weight was exhibited. Finally, the zeta potential resulted from the polymer molecular weight and the residual PVA. Zambaux, M. F., F. Bonneaux, et al. (1999). "Preparation and characterization of protein C-loaded PLA nanoparticles." Journal of Controlled Release 60(2-3): 179-88. This paper deals with the preparation and the characterization of poly(lactic acid) (PLA) nanoparticles containing protein C, a plasma inhibitor. Nanoparticles were prepared by the double emulsion method (w/o/w), using methylene chloride as an organic solvent and polyvinyl alcohol (PVA) or human serum albumin (HSA) as a surfactant. The influence of experimental constraints such as sonication and organic solvent on protein C activity was evaluated. It appears that a short time of sonication as well as the addition of acetone to methylene chloride (1/1) limited the lost of protein C activity. The study of protein C adsorption on blank PLA nanoparticles gave evidence to hydrophobic interactions between these two entities. The increase in PLA molecular weight on the characteristics of the protein C-loaded nanoparticles led to both a slightly decreased particle size and a lower polydispersity index, whereas the entrapment efficiency of protein C was not affected. The use of HSA as a surfactant allowed the increase in the entrapment efficiency of protein C but prevented its release. Finally, the evaluation of the activity of released protein C clearly illustrates that it was disturbed during the nanoparticle preparation. Thus, the obtained results emphasize the potential of protein C-loaded biodegradable nanoparticles for protein progressive delivery in plasma. Zambaux, M. F., F. Bonneaux, et al. (1999). "MPEO-PLA nanoparticles: effect of MPEO content on some of their surface properties." Journal of Biomedical Materials Research 44(1): 109-15. Nanoparticles of poly(lactic acid) (PLA) and of blends of PLA and monomethoxypoly(ethylene oxyde) (MPEOPLA) were prepared by the double emulsion method. Sucrose was added to overcome nanoparticle aggregation with freeze-drying. Whereas PLA nanoparticles rapidly are phagocytosed by the mononuclear phagocyte system cells, the uptake of MPEO-PLA nanoparticles is delayed. Opsonization is one of the steps of phagocytosis, and serum complement is a major component of the opsonin system. The in vitro complement consumption of the prepared nanoparticles was evaluated as a function of time and of their surface area. To avoid the aggregation of MPEO-PLA nanoparticles due to MPEO crystallization, sucrose was necessary, and its concentration was dependent on MPEO proportion in the nanoparticle suspension. As expected, the complement consumption for PLA nanoparticles is faster and more important than for PLA/MPEO-PLA blends. The complement consumption decreases with the increase in MPEO surface density. Complement is less consumed with the lower surface density provided by a higher molecular weight than by the higher surface density provi ded by a lower molecular weight MPEO. The complement consumption seems to be dependent on the number of nanoparticles in contact with human serum. Finally, the model of steric repulsion of MPEO towards proteins and the importance of the surface density of MPEO were emphasized. Zambaux, M. F., B. Faivre-Fiorina, et al. (2000). "Involvement of neutrophilic granulocytes in the uptake of biodegradable non-stealth and stealth nanoparticles in guinea pig." Biomaterials 21(10): 975-80. The in vivo behavior of monomethoxypoly(ethylene oxide)-poly(lactic acid) (MPEO20-PLA45/PLA (75/25)) nanoparticles in comparison with PLA ones was studied in guinea pig. Indeed, the aim of this study was to bring to the fore the in vivo stealth character of these copolymer nanoparticles and to identify the phagocytic circulating cells involved in their uptake. After the intravascular administration of fluorescent nanoparticles (rubrene), their phagocytosis by granulocytes and monocytes was assayed by flow cytometry. At the same time, the evolution of the number of these phagocytic cells was realized in order to identify their function in the nanoparticle uptake. Finally, a histological study of the spleen (30 h after the nanoparticle administration) was investigated to highlight the splenic trapping of these stealth nanoparticles. This study has shown that the phagocytic circulating cells involved in the nanoparticle uptake were mainly neutrophilic granulocytes and some of them were found in the spleen. Zambaux, M.-F., B. Faivre-Fiorina, et al. (2000). "Involvement of neutrophilic granulocytes in the uptake of biodegradable non-stealth and stealth nanoparticles in guinea pig." Biomaterials 21(10): 975-980. The in vivo behavior of monomethoxypoly(ethylene oxide)-poly(lactic acid) (MPEO20-PLA45/PLA (75/25)) nanoparticles in comparison with PLA ones was studied in guinea pig. Indeed, the aim of this study was to bring to the fore the in vivo stealth character of these copolymer nanoparticles and to identify the phagocytic circulating cells involved in their uptake. After the intravascular administration of fluorescent nanoparticles (rubrene), their phagocytosis by granulocytes and monocytes was assayed by flow cytometry. At the same time, the evolution of the number of these phagocytic cells was realized in order to identify their function in the nanoparticle uptake.

Finally, a histological study of the spleen (30 h after the nanoparticle administration) was investigated to highlight the splenic trapping of these stealth nanoparticles. This study has shown that the phagocytic circulating cells involved in the nanoparticle uptake were mainly neutrophilic granulocytes and some of them were found in the spleen. Zambaux, M. F., F. Bonneaux, et al. (2001). "Protein C-loaded monomethoxypoly (ethylene oxide)-poly(lactic acid) nanoparticles." International Journal of Pharmacology 212(1): 1-9. This paper deals with the preparation and characterization of monomethoxypoly(ethylene oxide)-poly(lactic acid) (MPEO-PLA) nanoparticles containing protein C, a plasma inhibitor which regulates the mechanism of blood coagulation. Protein C was entrapped in MPEO-PLA nanoparticles using the double emulsion method. The influence of MPEO-PLA copolymers on the different parameters was evaluated: characteristics of protein Cloaded nanoparticles, in vitro release of the protein, evolution of the particle size with incubation time and MPEO release. The nanoparticle size does not depend on copolymer characteristics (MPEO and/or PLA block molecular weight). On the other hand, the efficiency of protein C entrapment is affected by the copolymer characteristics. The burst effect during the protein C release is increased with the hydrophilic character of the copolymer. Moreover, protein C adsorption on the particle surface during its release may be related to MPEO release. Only 25% of the released protein C is active, which clearly illustrates that it is altered during its encapsulation. The optimization of the experimental parameters which disturbed entrapped protein C activity, i.e. sonication time and organic solvent was investigated and has led to a preservation of protein C activity. Then, to optimize its entrapment efficiency, a blend PLA/MPEO-PLA (25/75) was used to prepare nanoparticles. This blend limited burst effect of protein C and its adsorption. However, protein C is only partially released which implicates further investigation for a potential therapeutic use. Zarur, A. J. and J. Y. Ying (2000). "Reverse microemulsion synthesis of nanostructured complex oxides for catalytic combustion." Nature 403(6765): 65-7. Catalysts play an important role in many industrial processes, but their use in high-temperature applications-such as energy generation through natural gas combustion, steam reforming and the partial oxidation of hydrocarbons to produce feedstock chemicals--is problematic. The need for catalytic materials that remain stable and active over long periods at high operation temperatures, often in the presence of deactivating or even poisoning compounds, presents a challenge. For example, catalytic methane combustion, which generates power with reduced greenhouse-gas and nitrogen-oxide emissions, is limited by the availability of catalysts that are sufficiently active at low temperatures for start-up and are then able to sustain activity and mechanical integrity at flame temperatures as high as 1,300 degrees C. Here we use sol-gel processing in reverse microemulsions to produce discrete barium hexa-aluminate nanoparticles that display excellent methane combustion activity, owing to their high surface area, high thermal stability and the ultrahigh dispersion of cerium oxide on the their surfaces. Our synthesis method provides a general route to the production of a wide range of thermally stable nanostructured composite materials with large surface-to-volume ratios and an ultrahigh component dispersion that gives rise to synergistic chemical and electronic effects, thus paving the way to the development of catalysts suitable for high-temperature industrial applications. Zhan, J. H., X. G. Yang, et al. (2000). "Light scattering microscopy from monolayers and nanoparticles at the air/water interface." Colloids and Surfaces A Physicochemical and Engineering Aspects 171: 1-3. Light scattering microscopy (LSM) is introduced here as a versatile technique for the study of interfacial films at the air/water interface. Laser light scattered from the interface is collected by a microscope objective and imaged onto a CCD camera. LSM allows determination of the spatial distribution of submicron particles, phase transitions in two-dimensions, and defects. The power of LSM, especially if conducted simultaneously with fluorescence microscopy or Brewster angle microscopy (BAM), is illustrated in three examples. (a) Visualization of the spatial distribution of nanoscale particles with respect to monolayer phases: calcium oxalate crystals were grown underneath dipalmitoyl phosphatidyl choline (DPPC) and dimyristoyl phosphatidyl serine (DMPS) monolayers in the liquid expanded/liquid condensed (LE/LC) phase coexistence. The density of light scatterers was considerably higher in the respective LE than the LC phase, and a gradual migration of particles was observed towards the domain boundaries. A similar behavior was observed for nanocrystals injected underneath lipid monolayers. (b) Probing two-dimensional (2D) protein crystallization processes underneath functionalized lipid monolayers and the spatial distribution of crystal defects: streptavidin was crystallized as a model protein in 2D through coordination of exposed histidines on the protein surface to the monolayer-anchored metal chelator, Cu-DO-IDA. Vacancies were formed within the 2D protein crystals after injection of the soluble metal chelator EDTA, and the spatial distribution of vacancies was probed by LSM. (c) Detection of monolayer topographic transitions, corrugation and nanoscale budding: The phases of DPPC monolayers were studied under isothermal compression. New nanoscale topographic transitions are observed by LSM if DPPC is compressed into the liquid condensed (LC) state far below the collapse pressure. (45 References). Zhang, Z., G. Liao, et al. (1993). "[Pharmacokinetics model for targeted drug delivery systems]." Hua Xi Yi Ke Da Xue Xue

Bao 24(1): 49-53. Analyzing the observed phenomena and the data collected in research, we developed a multi-compartment linear recirculation model for targeted drug delivery systems and figured out the function formulas of the drug concentration-time in blood and target organ by computing. According to this model, the drug concentration-time curve for the target organ can be plotted with reference to the data on blood; the pharmacokinetics parameters of the target organ can also be obtained. We further detected the practicability of the model by using the curves of drug concentration-time in blood and target organ (liver) of liver-targeting nanoparticles obtained from animal tests. Based on the liver drug concentration-time curve calculated by the function formula of target organ and the statistical moment, the pharmacokinetics behaviour of the target organ (liver) was analysed and the pharmacokinetics parameters of liver were obtained. We suggest that the &quot;relative targeting index&quot; be used for quantitative evaluation of the targeted drug delivery system. Zhang, Q., G. Liao, et al. (1995). "[Physicochemical characteristics of gentamicin polybutylcyanoacrylate nanoparticles]." Hua Xi Yi Ke Da Xue Xue Bao 26(2): 172-6. Several formulations of gentamicin nanoparticle (GM-NP) colloids were prepared by the emulsion polymerization technique using the polybutylcyanoacrylate as the carrier. Various kinds of physicochemical characteristics, such as particle size and size distribution, drug loading and associating ratio, surface zeta potential, surface tension, turbidity, relative density, viscosity, refractive index and acidity were observed, determinated and compared. The results of the experiments have contributed to a full understanding of the physicochemical characteristics of gentamicin nanoparticles and also provided a basis for the establishment of the quality evaluation methods. Zhang, Q. and G. T. Liao (1995). "[Studies on in vitro release kinetics of gentamicin sulfate polybutylcyanoacrylate nanoparticles]." Yao Xue Xue Bao 30(6): 459-65. The in vitro release characteristics of gentamicin sulfate polybutylcyanoacrylate nanoparticles were studied using a dialysis system comprising dialysis bag and receptor chamber. The whole apparatus was placed in a water bath shaker thermostated at 37 degrees C, and shaken at 50 cpm. The concentration of gentamicin in the receptor chamber was periodically determined by first derivative spectrometry. The results showed that the in vitro release of gentamicin sulfate from polybutylcyanoacrylate nanoparticles is characteristically biphasic, with an initial fast release (the burst effect), followed by a much slower release. These release profiles can be well modelled using a biexponential function. The related parameters of release kinetics have been calculated according to the biexponential function, and some factors that may affect the release characteristics were studied. Zhang, Z. R., G. T. Liao, et al. (1995). "[Study on pharmacokinetics of mitoxantrone polycyanoacrylate nanoparticles freeze-dried injection by HPLC column switching technique]." Yao Xue Xue Bao 30(11): 843-7. The drug concentration--time curves of mitoxantrone polycyanoacrylate nanoparticles freeze-dried injection (DHAQ-PBCA-NP-FDIn) and mitoxantrone solution injection (DHAQ-SIn) in rabbit blood were determined by HPLC column switching technique, and the difference between the DHAQ-PBCA-NP-FDIn and DHAQ-SIn in vivo was observed. The pharmacokinetic parameters of DHAQ-PBCA-NP-FDIn and DHAQ-SIn were presented by statistical moment. The results showed that the MRT and T1/2 of DHAQ-PBCA-NP-FDIn were 2.15 times longer than that of DHAQ-SIn, and the Vss was 4.81 times bigger than that of DHAQ-SIn. This indicates that DHAQPBCA-NP-FDIn has targeting and prolonging effect on the action in vivo. Zhang, Q., G. Liao, et al. (1996). "[The electricity properties of polybutylcyanoacrylate nanoparticles]." Hua Xi Yi Ke Da Xue Xue Bao 27(4): 395-9. Electricity properties of polybutylcyanoacrylate nanoparticles (PBCA-NP) were studied by using a U-tube electrophoresis apparatus. It was proved that all the PBCA-NP is negatively charged. The surface potential of PBCA-NP is directly proportional to the concentration of stabilizer (Dextran 70) and the pH value of the medium, while it is inversely proportional to the concentration of butylcyanoacrylate and the model drug (gentamycin). The effect of ion strength on surface potential is obvious but not linear. The effect of stabilizers and surfactants used on the surface potential is evident while the effect of electrolytes is indistinct under the experimental conditions. Zhang, Q., G. T. Liao, et al. (1996). "[Increase of gentamicin uptake in cultured mouse peritoneal macrophage and rat hepatocytes when used in the form of nanoparticles]." Yao Xue Xue Bao 31(5): 375-80. The polybutylcyanoacrylate nanoparticles of 3H-labeled gentamicin were prepared in order to investigate the possibility of gentamicin nanoparticles as an intracellular drug delivery system for intracellular chemotherapy. The 3H-labeled gentamicin nanoparticles were incubated with mouse peritoneal macrophage (MPM) or rat hepatocytes (RH) for some period, then the cells were separated from the nanoparticles, and finally the radioactivity (cpm) of 3H in the cells were measured by a liquid scintillation counter. By comparison with the solution of 3H-labeled gentamicin, a 6.34 times increase of cpm value in MPM after 30 min incubation, and 27.74, 9.03 and 8.36 times increase of MPM values in RH after 1, 12, and 24 h incubation respectively, were observed by binding gentamicin with polybutylcyanoacrylate nanoparticles. The particle size, surfactant coating, stabilizer and the gentamicin concentration were found to have some effect on the uptake of nanoparticles by two kinds of

cells. This study provided a basis for the screening of intracellular drug delivery system. Zhang, Z., H. Tian, et al. (1998). "[Preparation of acyclovir-polybutylcyanoacrylate-nanoparticles by emulsion polymerization method]." Hua Xi Yi Ke Da Xue Xue Bao 29(3): 329-33. The aim of this study was to optimize the conditions and technology of preparing acyclovirpolybutylcyanoacrylate-nanoparticles (ACV-PBCA-NP) which has the diameter of about 100 nm and the shape of a sphere. The influential factors on sphericization were observed by single factor optimization. The preparation conditions and technology were optimized by the even design method. The contents of acyclovirin in acyclovir polybutyloganoacrylate nanoparticles were determined by HPLC. The optimum conditions and technology of preparing acyclovir polybutylcyanoacrylate nanoparticles were decided and put into use. The average diameter of the ACV-PBCA-NP thus prepared was 108.5 +/- 94.8 (n = 588). Its embedding ratio was 71.8%, and drug loading was 18.5%. The results suggest that the conditions and technology of preparing ACV-PBCA-NP presented in this paper are stable and practical. Zhang, Z. (1998). "High resolution transmission electron microscopic study of some low-dimensional nanostructures." Microsc Res Tech 40(3): 163-76. High-resolution transmission electron microscopy (HRTEM) study of some low-dimensional nanostructures, such as carbon nanotubules and silicon-based blue-light emitting beta-SiC nanoparticles will be reported. We have shown that nested hollow tubules formed by successive cylindrical graphite sheets are found, frequently, to be polyhedral or elliptical in cross-section, which are perpendicular to the tube-axis. Varied spacing between adjacent tube sheets is observed and edge-type dislocations can be distinguished in some tubules. These abnormal structural features are related to accommodations of various strains taking place simultaneously in tube sheets. Blue-light emitting porous beta-SiC formed by C+ implantation of a single crystal silicon wafer have also been investigated. Buried layer structures with different beta-SiC concentration were formed in the implanted silicon substrate. These beta-SiC nano-particles are 2-8 nm in size and formed epitaxially from the upper and lower damaged layers, respectively, but randomly in the middle layer. The structural characteristics of the layered structure may be responsible for the blue-light emitting effect of the porous beta-SiC material. Zhang, Z., J. C. Li, et al. (2000). "Reverse micellar synthesis of a nanoparticle/polymer composite." Langmuir 16(23): 8568-74. Cadmium sulfide nanoparticle/polymer composites have been produced using a one-system reverse micellar synthesis. A monomer, methyl methacrylate (MMA), was used as the oil and polymerized following formation of 23 nm CdS particles in the fluid medium. When Aerosol OT (AOT) was employed as the surfactant, opaque solids containing 20-80 nm aggregates of the CdS nanoparticles were obtained. The aggregates were fairly uniform in size, their diameter depending on the AOT concentration. With a 1:1 weight ratio of MMA and a polyethylene diacrylate, aggregation was eliminated but the solid remained opaque. Replacing the AOT by the polymerizable surfactant didecyldimethylammonium methacrylate with MMA as the oil led to the formation of a transparent solid matrix containing nonaggregated CdS particles. (63 References). Zhang, J. Z. (2000). "Interfacial charge carrier dynamics of colloidal semiconductor nanoparticles." Journal of Physical Chemistry B 104(31): 7239-53. Understanding the dynamic properties of charge carriers at the liquid-semiconductor interface is critical to many applications including photocatalysis, solar energy conversion and photoelectrochemistry. Dynamic properties of charge carriers, including trapping, recombination, and transfer, in a number of semiconductor nanoparticle systems have been studied using powerful time-resolved laser techniques. Several interesting features have been identified, including exciton-exciton annihilation upon trap state saturation at high excitation intensities for CdS, CdSe, TiO/sub 2/, ultrafast electron injection in dye sensitization of TiO/sub 2/, increased transient absorption over transient bleach with increasing intensity for Ag/sub 2/S and Cu/sub 2/S due to trap state saturation, surface dependence of electronic relaxation in PbI/sub 2/ and BiI/sub 3/, complex kinetics of the orange emission in Mndoped ZnS, and surface-independent relaxation for Fe/sub 2/O/sub 3/ and PbS. These observations provide new insight into the interfacial charge carrier properties in colloidal semiconductor nanoparticles, which is important for designing novel nanoarchitectures for emerging technologies. (194 References). Zhang, M., M. Yudasaka, et al. (2000). "Orientational melting of two-shell carbon nanoparticles: molecular dynamics study." Chemical Physics Letters 328: 4-6. The energetic characteristics of two-shell carbon nanoparticles (onions) with different shapes of second shell are calculated. The barriers of relative rotation of shells are found to be surprisingly small; therefore, free relative rotation of shells can take place at room temperature. The intershell orientational melting of the nanoparticle is studied by molecular dynamics. The parameters of the Arrhenius formula for jumprotational intershell diffusion are calculated. The rotation of shells can be observed beginning from a temperature of 70 K. (35 References). Zhang, Q., G. Yie, et al. (2000). "Studies on the cyclosporin A loaded stearic acid nanoparticles." International Journal of

Pharmacy 200(2): 153-9. Stearic acid nanoparticles were prepared in this study by melt-homogenization to investigate the possibility of them as a new kind of drug carrier system. Some physicochemical properties of stearic acid nanoparticles were studied and morphology examined by transmission electron microscope. Cyclosporin A as a model drug was then encapsulated into stearic acid nanoparticles. Following the establishment of high performance liquid chromatography assay for cyclosporin A analysis in stearic acid nanoparticles or blood samples, the encapsulation ratio of cyclosporin A to stearic acid nanoparticles was estimated and pharmacokinetics as well as bioavailability of cyclosporin A stearic acid nanoparticles after oral administration to Wistar rats were studied, using the Sandimmun Neoral(R) (an available microemulsion system of cyclosporin A) as a reference. The mean diameter of cyclosporin A stearic acid nanoparticles was 316.1 nm, while the encapsulation ratio of cyclosporin A to stearic acid nanoparticles reached to 88.36%. It was demonstrated by IR spectra and differential scanning calorimetry that there was no chemical reaction occurred between the cyclosporin A and stearic acid. The relative bioavailability of cyclosporin A stearic acid nanoparticles over reference was nearly 80%, and the time to reach maximum concentration (T(max)) of cyclosporin A after oral administration of cyclosporin A stearic acid nanoparticles was delayed significantly than the reference, suggesting an obvious sustained release effect. The stearic acid nanoparticles might be a very potential drug carrier. Zhang, Y., D. Fu, et al. (2000). "Synthesis and characterization of CdS nanoparticles with strong electrolyte behavior." Journal of Nanoparticle Research 2: 299-303. Zhang, Q., Z. Shen, et al. (2001). "Prolonged hypoglycemic effect of insulin-loaded polybutylcyanoacrylate nanoparticles after pulmonary administration to normal rats." International Journal of Pharmacology 218(1-2): 75-80. Insulin-loaded polybutylcyanoacrylate nanoparticles were prepared by emulsion polymerization. The mean diameter of the nanoparticles was 254.7 nm with a polydispersity of 0.064. The associating ratio of insulin to the nanoparticles reached 79.1%. Studies on in vitro release kinetics showed that release profiles can be modeled using a biexponential function and the burst effect was obvious. After various doses of insulin-loaded nanoparticles were intratracheally given to normal rats, significant decrease of glucose level was achieved at each dose group from 5 to 20 IU kg(-1). The minimum blood glucose concentration reached 46.9%, 30.4% and 13.6% of the initial level after pulmonary delivery of 5, 10 and 20 IU kg(-1) insulin-loaded nanoparticles to normal rats, respectively. The time to reach the minimum blood glucose level (T(min)) was 4, 4 and 8 h for three doses, respectively. The duration of glucose level below 80% of insulin-loaded nanoparticles was much longer than that of insulin solution at every dose. Relative pharmacological bioavailability of insulin-loaded nanoparticles by pulmonary administration was 57.2% over the same formulation by subcutaneous administration. Zhang, G., A. Niu, et al. (2001). "Formation of novel polymeric nanoparticles." Accounts of Chemical Research 34(3): 24956. We have found that not only block copolymers but also ionomers can self-assemble in a selective solvent to form surfactant-free nanoparticles. The self-assembly can be induced by chemical reaction, polymer-polymer complexation, and microphase inversion in addition to the temperature. A recently developed microwave method for the preparation of uniform surfactant-free polymeric nanoparticles is also reviewed. Our results have revealed that for a given dispersion, the particle surface area occupied per stabilizer (surfactant, polymer chains, and ionic groups) is close to a constant. Zheng, W., M. M. Maye, et al. (2000). "Imparting biomimetic ion-gating recognition properties to electrodes with a hydrogen-bonding structured core-shell nanoparticle network." Analytical Chemistry 72(10): 2190-9. This paper presents findings of the creation of biomimetic ion-gating properties with core-shell nanoparticle network architectures. The architectures were formed by hydrogen-bonding linkages via an exchange-crosslinking-precipitation reaction pathway using gold nanoparticles capped with thiolate shell and alkylthiols terminated with carboxylic groups as model building blocks. Such network assemblies have open frameworks in which void space is in the form of a channel or chamber with the nanometer-sized cores defining its size, the geometric arrangement defining its shape, and the shell structures defining its chemical specificity. The formation of the network linkages via head-to-head hydrogen-bonded carboxylic terminals and the reversible pH-tuned structural properties between neutral and ionic states were characterized using infrared reflectance spectroscopic technique. The biomimetic ion-gating properties were demonstrated by measuring the pH-tuned network &quot;open-close&quot; responses to charged redox probes. Such redox responses were shown to depend on the degree of protonation-deprotonation of carboxylic groups at the interparticle linkages, core sizes of the nanoparticles, and charges of the redox probes. Differences in structural networking, pH-tuning, and electrochemical gating properties were identified between the network films derived from nanoparticles of two different core sizes (2 and 5 nm). The mechanistic correlation of these structural properties was discussed. These findings have added a new pathway to the current approaches to biomimetic molecular recognition via design of core-shell nanoparticle architectures at both nanocrystal and molecular scales.

Zhengxin, L., L. Hao, et al. (2000). "Favored structure of Ag nanoparticles embedded in SiO2, by implantation: Single crystal with contracted (111) lattice." Journal of Materials Research 15(6): 1245-7. The structure of Ag nanoparticles, embedded in crystalline SiO/sub 2/ by high-dose implantation, was investigated. It was found that single crystal is favored over multiple-twinned particles. In addition, the contracted (111) lattice spacing of the Ag nanocrystals was measured by X-ray diffraction. (17 References). Zhi-Hong, W., J. Tian-Hao, et al. (2000). "Magnetoresistance of La0.5Sr0.5MnO3 nanoparticle compact." Journal of Applied Physics 87(9): 1-3. Magnetization, resistance, and current-voltage (I-V) measurements have been performed in La/sub 0.5/Sr/sub 0.5/MnO/sub 3/ compact prepared by pressing sol-gel nanoparticles (46 nm) at 723 K with a high pressure (4 GPa). The pressed compound orders ferromagnetically at 340 K (T/sub C/) and has a substantial drop in the thermomagnetic curve below 158 K (T/sub DP/). After undergoing a metal-to-semiconductor transition at 140 K (T/sub MS/), the compound reenters into a strong semiconducting state below 60 K, demonstrating a charge localized behavior induced by the small grain rather than the magnetic disorder which is related with the frozen spin clusters below T/sub DP/. Instead of showing a feature near T/sub MS/, the magnetoresistance (MR) ratio increases almost linearly with decreasing temperature. The large low field MR corresponding to the sharp rise of magnetization is obtained at 5 K and, evidenced as the spin polarized intergrain tunneling (SPIT) effect by the nolinear I-V curve. Although La/sub 0.5/Sr/sub 0.5/MnO/sub 3/ has a relatively high T/sub C/, the SPIT MR decays rapidly from 17.6% (5 K, 0.3 T) to 7.6% (150 K, 0.3 T), indicating that if trying to put the low field sensitivity of SPIT MR into application at room temperature, the selected compound having a higher T/sub C/ seems to be a prerequisite. (21 References). Zhiqiang, Q., K. Siegmann, et al. (2000). "Nanoparticle air pollution in major cities and its origin." Atmospheric Environment 34(3): 443-451. Suspended particles with a diameter below 1 mum act as vehicles transporting toxic chemicals into the human respiratory system. It is therefore of interest to record the intensity of these particles and to determine the source from which they were emitted. It is shown that this can be done by simultaneously measuring the light scattering (LS), the photoelectric charging (PC), and the diffusion charging (DC). Particles carrying polycyclic aromatic hydrocarbons (PPAH) are detected by their large PC and are generated in combustion of organic materials whereas particles from other sources only exhibit LS and DC. The fraction of particle mass due to PPAH is independent of location and weather conditions. As an example of an application, we study the nanoscale particles found on motorways in or near various large cities. The sources of the majority of these particles are Diesel motors or cars with defect catalysts. Promising strategies for improving the air quality emerge from these observations. Zhou, W., J. M. Thomas, et al. (1998). "Ordering of ruthenium cluster carbonyls in mesoporous silica." Science 280(5364): 705-8. The anionic ruthenium cluster carbonylates [Ru6C(CO)16]2- or [H2Ru10(CO)25]2- interspersed with bis(triphenylphosphino)iminium counterions (PPN+) are incorporated from solution into the pores of MCM-41 mesoporous silica (3 nanometers in diameter), where they form tightly packed arrays. These arrays were shown by high-resolution transmission electron microscopy, Fourier transform optical diffraction, and computer simulations to be well ordered both along and perpendicular to the axis of the cylindrical pores. In their denuded state produced by gentle thermolysis, the cluster carbonylates yield nanoparticles of ruthenium that are less well ordered than their assimilated precursors but show good activity as hydrogenation catalysts for hexene and cyclooctene. In both their as-prepared and denuded states, these encapsulated clusters are likely to exhibit interesting electronic and other properties. Zhou, W. L., E. E. Carpenter, et al. (2000). "Transmission electron microscopy study of gold-coated iron core-shell and Au/Fe/Au onion-like nanoparticles synthesized using reverse micelles." Nanophase and Nanocomposite Materials III. Symposium 581: 107-12. Gold-coated iron core-shell structure and Au/Fe/Au onion-like nanoparticles synthesized using reverse micelles were characterized by transmission electron microscopy (TEM). The average nanoparticle size of the core-shell structure is about 8 nm, with about 6 nm diameter core and 2 nm shell. The gold shell structure can be resolved from both high resolution electron microscopy (HREM) image and energy dispersive X-ray spectrum (EDS). Even though the gold and iron electron diffraction rings overlap a little bit, they can still be identified due to the slight mismatch of the diffraction rings. The Au/Fe/Au onion-like nanoparticles were also observed. The nanoparticles were formed with about 6 nm diameter gold core, 1 nm iron interlayer and 2 nm gold shell. The shell structure coated on the core appeared unhomogeneous, however, in both cases the iron core and interlayer iron shell stay air-stable. (9 References). Zhou, X. T., H. Y. Peng, et al. (2000). "Synthesis of MoS 2 nanostructures from nano-size powder by thermal annealing." Siberian Russian Student Workshops and Tutorials on Electron Devices and Materials.

It have been shown that the molybdenite could be the first inorganic fullerene-style molecular shell (MoS/sub 2/)n, of perhaps several materials, based on the transition metal chalcogenides, which could be allowed to create nanocages and nanotubes. We first describe in detail the attempt to produce nanostructures from nano-size MoS/sub 2/ powder by thermal annealing in vacuum conditions. We show the chemical synthesis process of nano-size MoS/sub 2/ powder and the technological regimes of thermal treatment of molybdenite nano-size powder. The TEM images of thermal treated molybdenite powder show the appearance of curvature of reflective planes (002), which could be considered as initial seeds for nanostructures. (11 References). Zhu, Y. and Q. Wu (1999). " Synthesis of magnetite nanoparticles by precipitation with forced mixing." Journal of Nanoparticle Research 1: 393-396. Zhu, Y., H. Wang, et al. (2000). "Charge diffusion noise in monocrystalline PbS nanoparticle films." Applied Physics Letters 77(21): 3421-2. Charge transport in monocrystalline lead sulfide (PbS) nanoparticle films is investigated by current noise measurements. Monocrystalline and single-sized PbS nanoparticles are synthesized via the gas phase and deposited electrostatically onto semiconducting (GaAs) and on isolating (SiN/sub x/) substrates with planar electrode contacts. The particles form inhomogeneous films. Low-frequency current noise of 1-ML-thick films are measured at various voltages, exhibiting diffusion noise characteristics, which indicates a random-walk (diffusion) phenomenon of electrons between the particles. (4 References). Zimmer, A., J. Kreuter, et al. (1991). "Studies on the transport pathway of PBCA nanoparticles in ocular tissues." Journal of Microencapsulation 8(4): 497-504. The transport pathway of PBCA nanoparticles through the rabbit cornea and conjunctiva was studied using fluorescence microscopy. Nanoparticles were produced by an emulsion-polymerization process, purified by a GPC procedure, and labelled with rhodamine 6G or propidium iodide as fluorescent laser dyes. The stability of the dye label, particle diameter, and zeta potential of the nanoparticles were determined. Freshly excised rabbit cornea and conjunctiva were incubated with a suspension of labelled nanoparticles for about 30 min in standard perfusion cells. After incubation the particles were visualized, due to their fluorescent character, using laser scanning confocal microscopy. The results show a fluorescence signal inside the cells. In particular conjunctival cells showed an uptake of nanoparticles. Fluorescent particles were visually observed inside the cells, in what appeared to be vesicles or granules. Thus, either endocytosis of the nanoparticles by conjunctival tissue or lysis of the cell wall by nanoparticle metabolic degradation products, are possible explanations of the data. A fluorescence signal was also observed within corneal cells. Only a transcellular pathway was observed. A possible penetration through tight junctions was not noticed; moreover, penetration was observed only into the first two cell layers and no full tissue penetration occurred. Zimmer, A., E. Mutschler, et al. (1994). "Pharmacokinetic and pharmacodynamic aspects of an ophthalmic pilocarpine nanoparticle-delivery-system." Pharmacetical Research 11(10): 1435-42. The regional pharmacokinetics as well as the pharmacodynamics of pilocarpine-loaded nanoparticles for the treatment of glaucoma were investigated and compared to a solution of this drug. Polybutylcyanoacrylate nanoparticles were prepared by an emulsion polymerization process. Formulations with different drug concentrations (2-6%) as well as different particle concentrations were investigated and analyzed for size and drug loading. Drug binding to the particles was achieved at a level of 10-18% of the total drug content. The colloidal nanoparticles were sufficiently small (diameter: 100-300 nm) for a non-irritating application to the eye. All preparations were applied to the eyes of New Zealand white rabbits which were treated with betamethasone before to create an elevated intraocular pressure (IOP). Pilocarpine concentrations, assayed from aqueous humor using gaschromatography, increased by 23% (AUC) for nanoparticle suspensions compared to aqueous reference solutions. Additionally, t1/2 was prolonged and the elimination coefficient was significantly decreased. Pharmacodynamic effects such as miosis and IOP reduction were investigated. tmax values of aqueous humor concentration were observed to be in a similar time range as miosis tmax readings. It was found that at lower drug contents a more pronounced prolongation of miosis was achieved with nanoparticles versus a standard solution. The IOP-reduction was significantly prolonged with nanoparticles preparations; whereas maximum reduction was obtained with a reference solution after 1-2 hours, it was reached with nanoparticles at about 2-3 hours. Differences between nanoparticles and aqueous solutions were most pronounced at lower drug concentrations. Zimmer, C., R. Weissleder, et al. (1995). "MR imaging of phagocytosis in experimental gliomas." Radiology 197(2): 533-8. PURPOSE: To determine whether phagocytosis can be observed in vivo in glioma cells. MATERIALS AND METHODS: Rat C6 glioma cells were studied in culture and after intracerebral implantation into 13 rats. Monocrystalline iron oxide nanoparticles (MION), a model marker of phagocytosis, was administered intravenously to tumor-bearing rats at 2-20 mg of iron per kilogram. Magnetic resonance (MR) imaging was performed at multiple time points. RESULTS: Glioma cells in culture showed uptake of MION in amounts of up to 10 ng of iron per 10(6) cells, corresponding to approximately 50,000 particles per cell. Fluorescently labeled

MION was found to be located primarily in tubular lysosomes. Intracerebral gliomas showed characteristic changes in signal intensity at MR imaging that peaked 12 hours after administration of MION and lasted up to 5 days; these changes corresponded to uptake and subsequent biodegradation of MION by tumor cells. CONCLUSION: Phagocytosis of glioma cells can be detected in vivo with iron oxide-enhanced MR imaging, and this may permit accurate delineation of tumor margins. Zimmer, C., R. Weissleder, et al. (1995). "Cerebral iron oxide distribution: in vivo mapping with MR imaging." Radiology 196(2): 521-7. PURPOSE: To map the distribution of an iron oxide label in the central nervous system with in vivo magnetic resonance (MR) imaging. MATERIALS AND METHODS: Unilateral osmotic disruption of the blood-brain barrier (BBB) in rats (n = 40) was followed by injection of monocrystalline iron oxide nanoparticles (MION) into the carotid artery. MR images (1.5 T) were obtained in and ex vivo, and results were correlated with histologic sectionmatched iron maps. RESULTS: A mean of 0.2% of the injected MION was found in the brain 24 hours after unilateral osmotic disruption of the BBB. The spatial distribution of iron oxide within the brain correlated with areas known to have high relative perfusion. Iron was found in cell bodies and dendrites of cortical neurons and astrocytes and in the interstitial space. The threshold in concentration for detection of MION in the brain was 62.2 ng Fe/mm2. CONCLUSION: MR imaging is well suited to noninvasive in vivo mapping of the intracerebral iron oxide distribution. Zimmer, A. (1999). "Antisense oligonucleotide delivery with polyhexylcyanoacrylate nanoparticles as carriers." Methods 18(3): 286-95, 322. Polyalkylcyanoacrylate nanoparticles are effective colloidal drug carriers and were prepared by an emulsion polymerization process. Antisense oligonucleotides were loaded on the particles by adsorption. A cationic polymer, DEAE-dextran, was incorporated into the particle matrix or a cationic hydrophobic detergent (CTAB) was used to form a lipophilic oligonucleotide ion pair. Enzymatic digestion of the oligonucleotides was almost quantitatively inhibited by this nanoparticle complex and cellular uptake by different cell lines was significantly enhanced. In vivo the biodistribution of the oligonucleotide nanoparticle complex resulted in targeting of oligonucleotides to the liver. Improvements in antisense treatments with nanoparticles were demonstrated for tumor therapy as well as for antiviral applications. Zimmermann, E., R. H. Muller, et al. (2000). "Influence of different parameters on reconstitution of lyophilized SLN." International Journal of Pharmacy 196(2): 211-3. Drug-loaded solid lipid nanoparticles (SLN) suitable for parenteral administration were freeze-dried. The lipid matrix Imwitor 900 (concentration, 2.5%) was stabilized with Lipoid E 80 and sodium glycocholate. The influence of different parameters of lyophilization like the protective effect of cryoprotectants, freezing velocity, and thermal treatment was investigated. The results of this study demonstrate that, by optimizing critical process parameters, i.v. -injectable SLN-dispersions can be freeze-dried, preserving their small particle size. Ziyi, Z., B. Gates, et al. (2000). "Soft lithographic approach to the fabrication of highly ordered 2D arrays of magnetic nanoparticles on the surfaces of silicon substrates." Langmuir 16(26): 10369-75. This paper describes a simple and convenient method that uses patterned monolayers as templates to fabricate highly ordered 2D arrays of magnetic particles (Co, Ni, or alpha -Fe, and ferrites such as MgFe/sub 2/O/sub 3/ or NiFe/sub 2/O/sub 3/) with lateral dimensions in the range of 70-460 nm. In this method, the hydrophilic, hydroxylterminated surface of a Si/SiO/sub 2/ wafer was patterned with a hydrophobic monolayer of octadecyltrichlorosilane using microcontact printing with an elastomeric stamp and subsequently used as template to define and deposit a regular 2D array of 2-propanol droplets that contained inorganic salts such as Co(NO/sub 3/)/sub 2/, Ni(NO/sub 3/)/sub 2/, and Fe(NO/sub 3/)/sub 3/, or a combination of these compounds. Evaporation of the solvent led to the formation of a 2D array of nitrate nanoparticles on the hydrophilic, bare regions of Si/SiO/sub 2/. Each nanoparticle could be well-positioned within the hydrophilic region by withdrawing the substrate from the nitrate solution and by letting the solvent evaporate with the wafer being held at a specified orientation relative to the gravitational field. The nitrate was subsequently converted into metal oxide (Co/sub 3/O/sub 4/, NiO, and alpha -Fe/sub 2/O/sub 3/) by thermal decomposition in air at 600 degrees C, and finally into a magnetic substance (that is, Co, Ni, and alpha -Fe) through the reduction by hydrogen gas at 400 degrees C. The dimensions of these particles could be controlled by changing the concentration of the nitrate solution and/or the area of the hydrophilic region. We have also shown that coprecipitation of two (or more) different nitrates within the liquid droplets could lead to the formation of highly ordered 2D arrays of magnetic ferrites such as MgFe/sub 2/O/sub 4/ or NiFe/sub 2/O/sub 4/. The magnetic properties of these 2D arrays of nanoparticles supported on silicon substrates were studied using magnetic force microscopy. (28 References). Ziyi, Z., C. Huayi, et al. (2000). "Catalytic growth of carbon nanoballs with and without cobalt encapsulation." Chemical Physics Letters 330: 1-2. Carbon nanoballs encapsulated with cobalt were prepared by decomposition of methane. After acid treatment, the

encapsulated cobalt can be removed to produce hollow carbon nanoballs. The content of hollow carbon nanoballs as high as 90 vol% in acid-treated carbon product can be obtained by increasing the content of cobalt from 50 to 75 mol% in the catalysts. However, under the same catalytic conditions, the main carbon products are multi walled carbon tubes (MWNTs) over Co/Al/sub 2/O/sub 3/, Co/La/sub 2/O/sub 3/, Co/CeO/sub 2/ and Ni/MgO catalysts by decomposition of CH/sub 4/, or by decomposition of CO over Co/MgO catalysts. These carbon nanoballs encapsulated with cobalt are novel magnetic materials. (23 References). Zobel, H. P., J. Kreuter, et al. (1997). "Cationic polyhexylcyanoacrylate nanoparticles as carriers for antisense oligonucleotides." Antisense Nucleic Acid Drug Development 7(5): 483-93. After antisense oligodeoxynucleotides (ODNs) were suggested for therapeutic use in 1978, major advances were made in developing modified oligonucleotides with increased nuclease resistance and improved cellular uptake. In the present report, positively charged nanoparticles prepared from diethylaminoethyl (DEAE)-dextran and polyhexylcyanoacrylate (PHCA) were evaluated as carriers for ODNs. The oligonucleotides were analyzed by anion-exchange HPLC. The nanoparticles exhibited a high loading capacity, with approximately 35 mumol ODNs adsorbed per gram of polymeric material. The adsorption efficacy was found to be dependent on the pH, on the ionic strength of the medium, and on the amount of DEAE-dextran. Highest loading for ODNs was achieved at pH 5.5, using a 10 mM phosphate buffer. Oligonucleotides adsorbed to the surface of the nanoparticles were nearly completely protected against degradation by the endonuclease DNase I and under in vitro cell culture conditions, whereas unprotected ODNs were totally digested under these conditions. Nanoparticles led to a 20-fold increase in cellular uptake of FITC-oligonucleotides. The internalized oligonucleotides were frequently localized as vesicular structures in the cytoplasmatic compartment. Because of their temperature-dependent uptake, we propose an active uptake mechanism, such as endocytosis, for the internalization of the ODN-nanoparticle formulations. Zobel, H. P., F. Stieneker, et al. (1999). "Evaluation of aminoalkylmethacrylate nanoparticles as colloidal drug carrier systems. Part II: characterization of antisense oligonucleotides loaded copolymer nanoparticles." European journal of Pharmacy Biopharm 48(1): 1-12. Aminoalkylmethacrylate methylmethacrylate copolymer nanoparticles were evaluated for their use as potential drug carrier systems. Their cytotoxicity, as well as the loading of antisense oligonucleotides that were employed as anionic model drugs depended on the substitution of the basic aminoalkyl copolymer. Toxic influences on the integrity of cell membranes depended on aminoalkyl groups located on the particle surfaces. Toxicity was observed either by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays using African green monkey kidney (AGMK) cells or by a hemolysis test, where the efflux of haemoglobin from disrupted erythrocytes was measured. The cytotoxic effects were increased by the elongation of the N-alkyl chain by four additional methylene groups. Lipophilic polymethylmethacrylate (PMMA) homopolymer nanoparticles showed a negative surface charge and, therefore, were not suitable for the adsorption of anionic drugs. The surface charge was changed to positive values by the incorporation of basic monomers. Consequently, the loading efficacy was increased by raising the basic copolymer portion. Additionally, a pH-dependent loading behaviour of oligonucleotides was observed. Substitution of the amino nitrogen protons by methyl groups led to a decreased oligonucleotide loading and to a reduced cytotoxicity. Nanoparticles with permanent positively charged quarternary ammonium groups showed a high pH-independent loading efficacy, but also possessed a high cytotoxic potential. In this study, cationic copolymer nanoparticles containing 30% (w/w) methylaminoethylmethacrylate (MMAEMC) were found to be optimal with regard to biocompatibility and carrier properties for hydrophilic anionic antisense oligonucleotides. A significant portion of adsorbed oligonucleotides were protected from enzymatic degradation. The cellular uptake of oligonucleotides into Vero cells was significantly enhanced by this methylaminoethyl-methacrylate derivative. Zobel, H. P., D. Werner, et al. (1999). "Effect of ultrasonication on the stability of oligonucleotides adsorbed on nanoparticles and liposomes." Journal of Microencapsulation 16(4): 501-9. In the present study, oligonucleotides were adsorbed onto the surface of cationic liposomes and nanoparticles at different ratios. As a result, the surface charges of the colloidal carriers were decreased with increasing oligonucleotide concentration. At a certain oligonucleotide concentration, complete charge neutralization led to the aggregation of the carrier systems. Further increasing oligonucleotide concentrations reversed the surface charge of liposomes and nanoparticles to a negative one. Ultrasonication was investigated as a possible means for the homogenization of the formed aggregates. However, the use of ultrasonication led to a time-dependent damage of oligonucleotides adsorbed onto AH-Chol liposomes and MMAEMC-nanoparticles, as well as of unbound oligonucleotides. Nearly 60% of the oligonucleotides adsorbed to MMAEMC-nanoparticles and 65% of ODNs adsorbed to the liposomes were degraded by the effect of cavitation produced by ultrasonication within 10 min. In contrast, the oligonucleotides were protected from degradation when DEAE-stabilized PHCA-nanoparticles were employed as ODN carriers. More than 80% of the oligonucleotides entangled in the surface matrix of these nanoparticles remained intact.

Zobel, H. P., A. Zimmer, et al. (1999). "Evaluation of aminoalkylmethacrylate nanoparticles as colloidal drug carrier systems. Part I: Synthesis of monomers, dependence of the physical properties on the polymerization methods." European journal of Pharmacy Biopharm 47(3): 203-13. Conventional nanoparticles based on acrylic compounds are lipophilic and possess a negative surface charge. This is due to their manufacturing process and to the chemical structure of the polymer. Hence, these particles are not suitable for the adsorption of hydrophilic anionic drugs. In the present investigation, positively charged copolymer nanoparticles prepared from aminoalkyl- and methylmethacrylates were evaluated, with regard to their physical properties. This report provides a detailed description of the synthesis of the non-commercially available monomers and their polymerization procedure. Various parameters were investigated, such as comonomer content, total amount of monomer, concentration of the radical initiator, and the composition of the polymerization medium. The resulting particle diameter and the surface charge were found to be strongly dependent on the polymerization conditions and on the pH. Optimization of the polymerization procedure yielded nanoparticles of about 200 nm exhibiting a positive surface charge. The charges of the different copolymer particles were then compared at different pH values. N-trimethylaminoethylmethacrylate (TMAEMC) nanoparticles with quaternary ammonium groups located at their surfaces, possessed a nearly constant positive zeta potential at various pH values and, consequently, pH-independent particle diameters. The physical characteristics of the other aminoalkyl copolymers correlated with the basicity of the monomers employed and were found to be strongly dependent on the pH of the dispersion medium. Aminoethylmethacrylate (AEMC), methylaminoethylmethacrylate (MMAEMC), and aminohexylmethacrylate (AHMC) as well as aminoethylmethacrylamide (AHMAC) copolymer nanoparticles exhibited a strong positively charged surface even at physiological pH and, therefore, are useful candidates for the adsorption of anionic drugs. Zobel, H. P., M. Junghans, et al. (2000). "Enhanced antisense efficacy of oligonucleotides adsorbed to monomethylaminoethylmethacrylate methylmethacrylate copolymer nanoparticles." European journal of Pharmacy Biopharm 49(3): 203-10. The purpose of this study was the investigation of cationic nanoparticles as drug delivery systems for antisense oligonucleotides. Cationic monomethylaminoethylmethacrylate (MMAEMA) copolymer nanoparticles were prepared from N-monomethylaminoethylmethacrylate hydrochloride and methylmethacrylate. Oligonucleotides were adsorbed onto MMAEMA nanoparticles. Cell penetration was investigated in vitro with fluorescently labeled oligonucleotides and nanoparticles. Antisense effects of oligonucleotides adsorbed to MMAEMA nanoparticles were evaluated by sequence specific inhibition of ecto-5'-nucleotidase expression. The amount of enzyme expressed in PC12 cells was detected and quantified by immunocytochemistry using fluorescein isothiocyanatelabeled antibodies. Oligonucleotides were adsorbed to MMAEMA nanoparticles by the formation of ion-pairs between the positively charged secondary amino groups located on the particle surface and the anionic phosphodiester or phosphorothioate backbones of the oligonucleotides. Adsorption to nanoparticles led to an increased cellular uptake of oligonucleotides and to a significantly enhanced antisense efficacy of unmodified phosphodiester oligonucleotides as well as phosphorothioates. The results of the cell penetration and the antisense assay demonstrated that MMAEMA nanoparticles are promising carriers for oligonucleotide administration. zum Felde, U., M. Haase, et al. (2000). "Control of the interparticle spacing in gold nanoparticle superlattices." Journal of Physical Chemistry B 104(40): 9475-86. We have investigated the formation of 2-D and 3-D superlattices of Au nanoclusters synthesized in nonionic inverse micelles, and capped with alkanethiol ligands, with alkane chains ranging from C/sub 6/ to C/sub 18/. The thiols are found to play a significant role in the ripening of these nanoclusters, and in the formation of superlattices. Image processing techniques were developed to reliably extract from transmission electron micrographs (TEMs) the particle size distribution, and information about the superlattice domains and their boundaries. The latter permits us to compute the intradomain vector pair correlation function, from which we can accurately determine the lattice spacing and the coherent domain size. From these data the gap between the particles in the coherent domains can be determined as a function of the thiol chain length, It is found that as the thiol chain length increases, the nanoclusters become more polydisperse and larger, and the gaps between particles within superlattice domains increase. Annealing studies at elevated temperatures confirm nanocluster ripening. Finally, the effect of the particle gaps on physical properties is illustrated by computing the effective dielectric constant, and it is shown that the gap size now accessible in superlattices is rather large for dielectric applications. (23 References). zur Muhlen, A., E. zur Muhlen, et al. (1996). "Atomic force microscopy studies of solid lipid nanoparticles." Pharmacetical Research 13(9): 1411-6. PURPOSE: Solid Lipid Nanoparticles (SLN) are an alternative carrier system for the controlled delivery of drugs. In most cases prednisolone loaded SLN show a biphasic release behaviour. The initial phase is characterised by a fast drug release, which is followed by a sustained drug release over several weeks. METHODS: The particles are produced by high pressure homogenisation of a lipid (e.g. compritol, cholesterol) dispersed in an aqueous

surfactant solution. In this study atomic force microscopy was used to image the original unaltered shape and surface properties of the particles. The crystallinity of the nanoparticles was investigated by differential scanning calorimetry. RESULTS: The AFM investigations revealed the disc like shape of the particles. From differential scanning calorimetry data it can be concluded that the particle core is in the crystalline state. Additionally it was proven that the particles are surrounded by a soft layer. CONCLUSIONS: Thus it is conceivable that the fast initial drug release during in vitro dissolution tests takes place by drug release of the outer noncrystalline layers of the particles. The following sustained drug release can be assigned to the predisolone release of the inner crystalline particle layers. zur Muhlen, A., C. Schwarz, et al. (1998). "Solid lipid nanoparticles (SLN) for controlled drug delivery--drug release and release mechanism." European journal of Pharmacy Biopharm 45(2): 149-55. Solid lipid nanoparticles (SLN) are particulate systems for parenteral drug administration with mean particle diameters ranging from 50 up to 1000 nm. The model drugs tetracaine, etomidate and prednisolone were incorporated (1, 5 and 10%) to study the drug load, effect of drug incorporation on the structure of the lipid matrix and the release profiles and mechanism. SLN were produced by high pressure homogenization of aqueous surfactant solutions containing the drug-loaded lipids in the melted or in the solid state (500/1500 bar, 3/10 cycles). In case of tetracaine and etomidate, high drug loadings up to 10% could be achieved when using Compritol 888 ATO and Dynasan 112 as matrix material. The melting behavior of the drug loaded particles revealed that little or no interactions between drug and lipid occurred. A burst drug release (100% release &lt; 1 min) was observed with tetracaine and etomidate SLN, which was attributed to the large surface area of the nanoparticles and drug enrichment in the outer shell of the particles. In contrast, prednisolone loaded SLN showed a distinctly prolonged release over a monitored period of 5 weeks. Depending on the chemical nature of the lipid matrix, 83.8 and 37.1% drug were released (cholesterol and compritol, respectively). These results demonstrate the principle suitability of SLN as a prolonged release formulation for lipophilic drugs.