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pubs.acs.org/NanoLett

Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications

Jinjun Shi,, Alexander R. Votruba, Omid C. Farokhzad,, and Robert Langer*,,
MIT-Harvard Center for Cancer Nanotechnology Excellence and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and Laboratory of Nanomedicine and Biomaterials, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts 02115
ABSTRACT The application of nanotechnology in medicine, referred to as nanomedicine, is offering numerous exciting possibilities in healthcare. Herein, we discuss two important aspects of nanomedicine, drug delivery and tissue engineering, highlighting the advances we have recently experienced, the challenges we are currently facing, and what we are likely to witness in the near future. KEYWORDS Nanotechnology, nanomedicine, drug delivery, tissue engineering

n pharmaceutical industries, a new molecular entity (NME) that demonstrates potent biological activity but poor water solubility, or a very short circulating halflife, will likely face signicant development challenges or be deemed undevelopable. On the other hand, less active but pharmaceutically optimal compounds may become more suitable candidates for development. In either case, there is always a degree of compromise, and such tradeoffs may inevitably result in the production of less-ideal drugs. However, with the emerging trends and recent advances in nanotechnology, it has become increasingly possible to address some of the shortcomings associated with potential NMEs. By using nanoscale delivery vehicles, the pharmacological properties (e.g., solubility and circulating half-life) of such NMEs can be drastically improved, essentially leading to the discovery of optimally safe and effective drug candidates. This is just one example that demonstrates the degree to which nanotechnology may revolutionize the rules and possibilities of drug discovery and change the landscape of pharmaceutical industries. Indeed, current nanotechnology-based therapeutic products have been validated through the improvement of previously approved drugs, and many novel classes of nanotherapeutics are now underway.1-3 Drug discovery is only one of the many areas in healthcare that nanotechnology is now beneting. The current and promising applications of nanomedicine include, but are not limited to, drug delivery, in vitro diagnostics, in vivo imaging, therapy techniques, biomaterials, and tissue engineering. Summarized in Table 1 are some important opportunities that nanotechnology may afford in each research area. Some of these opportunities are becoming realities or are actually being used today, while others are generating promise in their early phases of development
* To whom correspondence should be addressed. E-mail: rlanger@mit.edu. Published on Web: 08/20/2010

Nanotechnology may revolutionize the rules and possibilities of drug discovery and change the landscape of pharmaceutical industries.

and are expected to experience vigorous growth in the foreseeable future. As recognition of the importance of this exciting eld, it is expected that the global market of nanoscale applications in the medical eld could grow to $70-160 billion by 2015.4,5 In this perspective, we discuss the applications of nanomedicine with specic focus on drug delivery and tissue engineering. Drug Delivery. Since liposomes were rst described in the 1960s and proposed as carriers of proteins and drugs for disease treatment,6 nanotechnology has made a signicant impact on the development of drug delivery systems. A variety of organic/inorganic nanomaterials and devices have been used as delivery vehicles to develop effective therapeutic modalities (Figure 1). So far, there are over two dozen nanotechnology-based therapeutic products approved by Food and Drug Administration (FDA) for clinical use, and more are in clinical trials.1-3 Of these products, the majority are composed of a nontargeted delivery system (e.g., liposomes and polymers) and a drug, and are therefore considered rst generation nanotherapeutics.7 Compared to conventional drug delivery, the rst generation nanosystems provide a number of advantages. In particular, they can enhance the therapeutic activity by
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TABLE 1. Nanoscale Application in Medicine

prolonging drug half-life, improving solubility of hydrophobic drugs, reducing potential immunogenicity, and/or releasing drugs in a sustained or stimuli-triggered fashion. Thus, the toxic side effects of drugs can be reduced, as well as the administration frequency. In addition, nanoscale particles can passively accumulate in specic tissues (e.g., tumors) through the enhanced permeability and retention (EPR) effect.8 Beyond these clinically efcacious nanosystems, nanotechnology has been utilized to enable new therapies and to develop next generation nanosystems for smart drug delivery. Below are several areas, from our perspective, that will generate medical breakthroughs in the near future, and some of them could inspire the derivation of the next Killer Applications. New Therapeutics Delivery. Gene therapy and RNA interference (RNAi), the two most recent and notable therapies, hold great promise as treatment and prevention methods for various diseases.9,10 However, the systemic administration of these new therapeutics (e.g., DNA and siRNA) is affected by several barriers such as enzymatic degradation, uptake by reticuloendothelial system, kidney ltration, and limited intracellular entry. Cationic nonviral nanocarriers have, therefore, been widely used to encapsulate and make these new therapeutics more efcient. Unfortunately, a substantial number of these materials can produce severe problems
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associated with toxicity, immune or inammatory responses, and serum instability, making them unsuitable for clinical applications. Consequently, safe and effective delivery materials have become the bottleneck for the widespread use of gene therapy and RNAi. Recent and exciting developments are now paving the way for the clinical application of these new therapeutics. For example, high throughput screening platform technologies have been described and proof-of-concept has been demonstrated by identifying cationic polymers and lipid-like-materials suitable for systemic gene and RNAi delivery.11,12 On the other hand, rational design approaches are also showing great potential in creating successful delivery materials (e.g., DLin-KC2-DMA13 and cyclodextrin-containing polymer14). Nevertheless, it would also be favorable to use FDA-approved materials for new therapeutics delivery, as they offer specic benets such as safety and sustained release. One such material being studied is poly(lactic-co-glycolic acid) (PLGA), a specic polymer that can be applied to form nanoparticles densely loaded with siRNA for sustained gene silencing.15 Beyond assuring the safety and efciency of delivery materials, more progress is needed to screen other factors, including the physicochemical properties of nanocarriers, targeting ligands, and
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FIGURE 1. Timeline of nanotechnology-based drug delivery. Here, we highlight some delivery systems that serve as important milestones throughout the history of drug delivery.

formulation methods, all of which can affect the delivery of new therapeutics in vivo. Targeted Delivery. It is widely believed that active targeting, through the modication of nanoparticles with ligands, has the potential to enhance the therapeutic efcacy and reduce the side effects relative to conventional therapeutics.16 The ability to actively target specic cells rather than tissues also allows ligandconjugated nanocarriers to outperform rst generation, nontargeted nanosystems. While the necessity of targeted delivery depends on various factors (e.g., delivery vehicles, drugs, and diseases), a myriad of important benets have been demonstrated.3,16-19 In cancer therapy, the presence of targeting ligands can greatly enhance the retention and cellular uptake of nanoparticles via receptor-mediated endocytosis, even though tumor accumulation is largely determined by the physicochemical properties of nanoparticles.16,17 This can then lead to higher intracellular drug concentration and increase therapeutic activity, which is particularly important for bioactive macromolecules (e.g., DNA and siRNA) that require intracellular delivery for bioactivity.16 In the case of endothelial targeting for cardiovascular diseases or immunological tissue targeting, nanoparticle localization is guided by ligand-receptor interactions rather than EPR.18 Similarly, ligand-mediated targeting is of importance for the transcytosis of nanodrugs across tight epithelial and endothelial barriers (e.g., blood-brain barrier).19 Additionally, targeted delivery has been applied, in some instances, to combat multidrug resistance (MDR).3 It is also envisioned that longcirculating targeted nanoparitcles may be able to locate and ght migrating cancer cells.
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Despite three targeted nanoparticle systems now in phase I/II clinical trials,3 the clinical translation of targeted delivery is not as smooth as we expect. One possible barrier stems from the complexity behind manufacturing viable targeted nanoparticles. Targeted nanoparticle fabrication usually requires multiple steps, including biomaterial assembly, ligand coupling/insertion, and purication, which could cause batch-to-batch variation and quality concerns. The recent development of singlestep synthesis of targeted nanoparticles by selfassembling prefunctionalized biomaterials provides a simple and scalable manufacturing strategy.14,20 Another important consideration is targeting ligands. Among others, some variables that must be considered include ligand biocompatibility, cell specicity, binding afnity, mass production, and purity.21 For example, to achieve maximal specicity, the ideal ligand would be able to recognize the most overexpressed receptors on target cells relative to healthy ones. Other factors that could also affect cell targeting include ligand surface density and arrangement, as well as spacer type and length dividing ligand molecules and nanoparticles.22 Nevertheless, with advances in ligand engineering and screening, and nanoparticle optimization, targeted delivery will become a mainstay in the next generation of drug therapy. Co-delivery. Combination therapy has shown several potential advantages (e.g., synergistic effects and reversal of drug resistance) and may prove more effective than single drug therapy.23 However, due to the distinct pharmacokinetic proles of individual drugs, the synergistic drug ratio optimized in vitro will undoubtedly change after the conventional administration of drug cocktails, an outcome that could in turn lead to
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insufcient therapeutic results in vivo. To this end, lipidand/or polymer-based nanoscale systems, previously developed for single drug delivery, have been applied to facilitate co-delivery. For some drug combinations, we can successfully tune the relative dosage of various drugs in single particle levels, and simultaneously deliver them to target sites with a maintained drug ratio.24 For other combinations, we need to develop novel delivery vehicles with desired functionalities that enable co-encapsulation of hydrophobic and hydrophilic drugs, active targeting, and/or temporally controlled release.25,26 Such features are especially essential for the co-delivery of drugs and nucleic acids, which requires intracellular delivery to elicit bioactivity.27,28 For example, in the case of co-delivering chemotherapy and RNAi therapy to treat multidrug resistant cancers, the ideal nanoparticle would be expected to rst release siRNA to reduce the expression of MDR transporters, followed by the release of anticancer drugs. Another exciting advancement in co-delivery is the ability to combine targeted imaging and therapeutic agents within the same particle, allowing us to visualize sites of targeted drug delivery and deliver therapeutics simultaneously (theranostics).29 This technology is innovative in concept and holds signicant promise for making large medical impacts within the next few decades. It could provide us with critical information on intracellular targets, ensure that therapeutic agents are efciently reaching their target sites, and enable the effective early detection and treatment of diseases. Current research is primarily focused on the design of such multifunctional nanosystems and proof-of-concept tests,30-33 but more systematic in vivo studies are needed. Future research in this arena will also likely help us trace the absorption, distribution, metabolism, and excretion of nanoparticles in vivo. It is important that we understand the pharmacokinetics of a given drug delivery system to improve upon formulations, estimate clinical doses, and guarantee safety.34 Currently, radionuclide labeling is the only technique that can be used to provide in situ quantitative information; but radio emitters may be too unstable to conjugate with nanomaterials. With the help of recently developed in vivo imaging probes like magnetic nanoparticles,7 quantum dots,35 gold nanoparticles,36 and carbon nanotubes,37 more imaging modalities may become available to track the distribution of nanotherapeutics in the body. MEM/NEM Devices for Drug Delivery. Parallel to the development of particulate delivery systems, signicant headway has also been made in the eld of micro/nanoelectromechanical (MEM/NEM) device-based drug delivery over the past decade. In particular, implantable microchips containing nanosized reservoirs have been developed to deliver drugs for long time
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periods in a precisely controlled manner; microneedles are being tested in painless transdermal drug delivery; and the incorporation of nanofeatures (e.g., nanopores, nanochannels, and nanoparticles) in microfabricated systems are perfecting drug delivery and immunoisolation techniques.38-41 Intriguingly, these devices can be further modied to deliver new therapeutics, achieve targeted delivery, and co-deliver multiple agents.41,42 Substantial efforts are also being put into creating intelligent devices that could potentially sense when and how much dose is needed and then automatically release it from reservoirs.42 To do this, one feat that must be met is the continuous and stable monitoring of physical and biochemical conditions in situ. The recent development of nanotechnology-based sensors (e.g., nanowire and nanotube) may offer new ways to address this concern and could even facilitate device miniaturization.43 In addition to drug delivery, micro- and nanofabricated devices have shown potential in developing nanocarriers with controlled physicochemical properties (e.g., size, shape, and surface chemistries). By using peruoropolyether molds, fabricated by traditional topdown approaches, polymeric particles at the submicrometer scale can be replicated with variable shapes and controllable surface chemistries.44 Compared to bulk synthesis, microuidic devices have also recently been used for nanoprecipitation synthesis of smaller and more homogeneous PLGA-PEG nanoparticles.45 Nonetheless, micro- and nanotechnologies, which can be universally used to control the biophysicochemical properties of various nanosystems, are still in great demand. Beyond the aforementioned opportunities and challenges, the following are also essential for the development of next generation drug delivery systems: (1) detailed physicochemical characterization of nanosystems (which will require sophisticated and stateof-art techniques); (2) restriction of undesired uptake by nontarget organs (e.g., liver and spleen); (3) improvement of stimuli-triggered or programmable drug release systems (e.g., pH, temperature, light, enzyme, ultrasound, magnetic eld, and electric current); (4) furthering the means by which we can understand the biological principles of disease and its microenvironment, the biological barriers that hinder drug delivery, and endosomal trafcking pathways; and (5) identication of biological markers attributable to diseased cells. With continual advancement in these areas, we can expect that the eld of drug delivery will benet greatly from the emergence of nely engineered nanomaterials and devices. Tissue Engineering. Tissue engineering is an evolving interdisciplinary eld integrating biology, engineering, materials science, and medicine, that focuses on the development of biological substitutes to restore, replace,
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maintain, or enhance tissue and organ function.46 Over the past few decades, continued progress in this specic eld has led to the creation of implantable tissues, some of which are already used in humans (e.g., skin and cartilage) or have entered clinical trials (e.g., bladder and blood vessels).47 Nevertheless, most tissue engineering strategies rely on the principle that under appropriate bioreactor conditions, cells seeded or recruited into threedimensional (3D) biocompatible scaffolds are able to reassemble into functional structures resembling native tissues. Early articial scaffolds were designed to provide cells structural integrity on a macroscopic level, but only achieved moderate success. It is now widely accepted that to recapitulate proper tissue functionality, scaffolds should also establish a tissue specic microenvironment to maintain and regulate cell behavior and function.48 Within tissues, cells are surrounded by extracellular matrix (ECM) which is characterized by a natural web of hierarchically organized nanobers.49 This integral nanoarchitecture is important because it provides cell support and directs cell behavior via cell-ECM interactions. Furthermore, ECM plays a vital role in storing, releasing, and activating a wide range of biological factors, along with aiding cell-cell and cell-soluble factor interactions.50 Thus, the ability to engineer biomaterials that closely emulate the complexity and functionality of ECM is pivotal for successful regeneration of tissues. Recent advances in nanotechnology, however, have enabled the design and fabrication of biomimetic microenvironment at the nanoscale, providing an analog to native ECM.48 Notably, these technologies have been applied to create nanotopographic surfaces and nanofeatured scaffolds, and to encapsulate and control the spatiotemporal release of drugs (e.g., growth factors). In turn, these nanodevices offer a means to direct cellular behaviors that range from cell adhesion to gene expression. Cell-Nanotopography Interactions. Living cells are highly sensitive to local nanoscale topographic patterns within ECM.49 In the pursuit to control cell function by underlying nanotopographic cues, engineered substrates with different nanofeatures have become rapidly adopted (Figure 2). Top-down lithographic techniques are now utilized to create various nanopatterns, such as gratings, pillars, and pits, in a precisely controlled manner.51 Techniques like micelle lithography, anodization, and electrospinning can also be used to create an array of nanospheres, vertical nanotubes, and nanobers.52-54 Additionally, less-ordered nanotopographies are now being fabricated by polymer demixing, chemical etching, electrospinning, and phase separation processes.55 These advances in the design of nanoscale substrates have enabled investigators to explore cell-nanotopography interactions and have allowed for the manipulation of cell morphology, signaling, orientation, adhesion, migration, proliferation, and differentiation. In particular, it has been
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FIGURE 2. Schematic of fabricated nanotopographic features used to guide cell behaviors via cell-nanotopography interactions.

determined that nanogratings and aligned nanobers can govern the alignment and elongation of many different cell types;54,56-59 the differentiation of mesenchymal stem cells can be regulated by polymer nanogratings,58 disordered nanopits,60 or vertically aligned TiO2 nanotubes;53,61 endothelial cells cultured on nanogratings can be organized into multicellular band structures, forming aligned capillary-like tubes;56 and cell adhesion strength and apopotosis can be controlled by the combination of cell signaling epitopes and nanotopography.52,62 In the near future, we can expect the emergence of more striking results from different combinations of cell type, topography geometry and scale, and substrate material. Nonetheless, the design and fabrication of next-generation nanotopographic substrates will be guided by a greater understanding of the mechanisms by which cells respond to and sense nanofeatures. Nanofabricated Scaffolds. While critical insights into 2D cell-nanotopography interactions are now enabling us to direct cell behavior, considerable efforts have been made to develop 3D articial scaffolds at the nanoscale for tissue engineering applications. Nanobrous scaffolds are now under wide investigation as they exhibit a very similar physical structure to protein nanobers in ECM.48 Among the three dominant nanofabrication methods, electrospinning is a very simple and practical technique, suitable for the creation of aligned and complex 3D structures; self-assembly technology emulates the process of ECM assembly and can thus produce very thin nanobers; and phase separation allows for continuous ber network fabrication with tunable pore structure and the formation of sponge-like scaffolding.63 On the other hand, nanocomposite-based scaffolds (e.g., nanohydroxyapatite/collagen) are very popular in hardtissue engineering, particularly for the reconstruction of bone tissue.64 Beyond nanobers and nanocomposites, carbon nanotubes have also attracted attention due to
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and multiple-layer assembly70 could be combined with nanotopographic cues to exponentially improve scaffold design. Controlled Release. Achieving localized and controlled delivery of biological factors in 3D scaffolds represents another key for tissue regeneration and growth. For example, the controlled release of angiogenic factors (e.g., vascular endothelial growth factors and basic broblast growth factors) can specically enhance vascularization essential for maintaining continuous blood supply to developing tissues.71 The strategy of biomacromolecule encapsulation by direct entrapment or chemical conjugation to scaffolds can provide sustained release characteristics; however, the ability to control release kinetics with these methods is limited. Therefore, polymeric micro/nanoparticles, preloaded with growth factors, have been incorporated into porous scaffolds and hydrogels.72 Using PLGA microspheres or nanospheres, single or multiple biological factors can be released in a spatiotemporally controlled manner.73,74 Furthermore, individual biological factors can be provided with distinct release properties by tuning particle formulation and composition, a modication that could help drive tissue growth to completion. In addition to polymeric carriers, biological factors can be incorporated with nanobrous scaffolds by either modied electrospinning or self-assembly techniques.75,76 Guided by this principle, nanobers with core-shell structures can now be prepared by coaxial electrospinning and internally loaded with growth factors.75 To further enhance the release kinetics of growth factors from these particular scaffolds, adjustments can also be made to control the thickness and porosity of the polymer shell. Despite these efforts, the application of nanotechnology to control the release of biological factors from scaffolds is still in its infancy if compared to the great achievements of nanoparticle-based drug delivery.72 Indeed, many other nanoscale systems including lipidand dendrimer-based nanocarriers and inorganic nanomaterials, could also help to control the delivery of growth factors from articial scaffolds. Some of these nanocarriers even have the unique ability to co-encapsulate multiple drugs and control the release of each agent in a temporal fashion (e.g., lipid-polymer hybrid nanoparticle25), or to trigger drug release by responding to environmental changes, such as pH, temperature, light, and mechanical stress. With modications like cell specic ligands or signaling molecules, targeting nanoparticles immobilized on a scaffolds surface may be able to enhance cell adhesion and guide cell migration. Additionally, these controlledrelease nanotechnologies can be applied to deliver other biological molecules (e.g., DNA and siRNA) to cells to regulate cell behavior, an idea that has been conrmed
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FIGURE 3. Nanotechnology applications in engineering complex tissues. Cells seeded into biocompatible and nanostructured scaffolds are able to reassemble into functional structures that resemble native tissues under the stimulation of growth factors spatiotemporally delivered by nanoparticles. Complex tissues, like this lobule of the liver, could be engineered with the help of devices that are equipped with nanotechnology.

their mechanical strength and electrical conductivity, and because they can be readily incorporated into 3D architectures.65 The potential of nanobrous and nanocomposite scaffolds for the regeneration of various tissues (e.g., nerve, bone, cardiac/skeletal muscle, blood vessels, and liver) is now under extensive investigation (Figure 3). Notwithstanding the great achievements behind the fabrication of nanoscale scaffolds, there is still plenty of room for improvement. For example, the integration of ne nanofeatures into microfabricated 3D scaffolds could provide better control of cell function via cell-nanotopography interactions. Microscale scaffolds with controlled features (e.g., pore size, geometry, network interconnectivity, and mechanical strength) have been created by a set of microfabrication technologies.66 However, in conjunction with nanofabrication technologies, scaffolds could be further decorated with nanotopographic patterns, such as grooves and ridges, to better match the nanoarchitecture of ECM. A particular case is the E-beam and photolithography modications recently applied to fabricate tubular scaffolds with multiple nanofeatures for vascular tissue engineering.67 Another example that denes the benets of nanotopographic patterning is the addition of chemically etched, nanoscale roughness to the surface of porous PLGA scaffolds, a method that has been shown to enhance cell adhesion and growth, as well as the expression of matrix components.68 Moreover, several advanced techniques like multiphoton polymerization69
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following the very recent development of poly(-amino esters)-DNA nanoparticles used to genetically engineering stem cells for enhanced angiogenesis.77 Aside from the benets discussed above, nanotechnology is also expected to play an important role in creating novel tissue regeneration strategies (e.g., cell sheet engineering78) and in surmounting other important obstacles in tissue engineering, such as the development and characterization of new biomaterials and stem cell engineering. For example, high throughput assays based on nanoliter-scale synthesis have emerged for the cellbased screening of biomaterials.79 Despite the ongoing challenges, we can imagine that the achievement of functional, articial tissues/organs will have extremely strong impact on regenerative medicine, as well as other medical elds. One exciting opportunity that lies ahead is the idea of organ-on-a-chip80 that, in the future, could replace the expensive and life-costing animal testing used for drug development and for evaluation/optimization of nanoparticulate systems for drug delivery. Acknowledgment. This work was supported by National Institutes of Health Grants U54-CA119349, DE013023, DE016516, EB000244, and EB006365; and the Koch-Prostate Cancer Foundation Award in Nanotherapeutics. Notes O.C.F. and R.L. have nancial interest in BIND Biosciences and Selecta Biosciences.
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One exciting opportunity is the idea of organ-on-a-chip

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that

could replace the expensive and life-costing animal testing used for drug development and for evaluation/ optimization of nanoparticulate systems for drug delivery.

Summary. Nanotechnology is becoming the driving force behind a variety of evolutionary and revolutionary changes in the medical eld. The impact of nanotechnology on drug delivery has helped to improve the efcacy of available therapeutics and will likely enable the creation of entirely new therapeutic entities. For tissue engineering, nanotechnology has also opened the door to new approaches that could stimulate the reconstruction of complex tissue architectures. We are optimistic about the future of nanomedicine, given the wide array of innovative nanoscale materials and technologies that stand on the horizon. With the clarication of nanotechnology-specic medical regulations and a continued inux of investments and time, we believe that nanomedicine will not only improve conventional therapies, but also bridge the shortcomings of conventional medicine to help people on both global and individual levels.
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(50) Taipale, J.; Keski-Oja, J. FASEB J. 1997, 11, 5159. (51) Bettinger, C. J.; Langer, R.; Borenstein, J. T. Angew. Chem., Int. Ed. 2009, 48, 54065415. (52) Huang, J.; Grater, S. V.; Corbellini, F.; Rinck, S.; Bock, E.; Kemkemer, R.; Kessler, H.; Ding, J.; Spatz, J. P. Nano Lett. 2009, 9, 11111116. (53) Park, J.; Bauer, S.; von der Mark, K.; Schmuki, P. Nano Lett. 2007, 7, 16861691. (54) Xu, C. Y.; Inai, R.; Kotaki, M.; Ramakrishna, S. Biomaterials 2004, 25, 877886. (55) Norman, J. J.; Desai, T. A. Ann. Biomed. Eng. 2006, 34, 89101. (56) Bettinger, C. J.; Zhang, Z.; Gerecht, S.; Borenstein, J. T.; Langer, R. Adv. Mater. 2008, 20, 99103. (57) Gerecht, S.; Bettinger, C. J.; Zhang, Z.; Borenstein, J. T.; VunjakNovakovic, G.; Langer, R. Biomaterials 2007, 28, 40684077. (58) Yim, E. K.; Pang, S. W.; Leong, K. W. Exp. Cell Res. 2007, 313, 18201829. (59) Kim, D. H.; Lipke, E. A.; Kim, P.; Cheong, R.; Thompson, S.; Delannoy, M.; Suh, K. Y.; Tung, L.; Levchenko, A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 565570. (60) Dalby, M. J.; Gadegaard, N.; Tare, R.; Andar, A.; Riehle, M. O.; Herzyk, P.; Wilkinson, C. D.; Oreffo, R. O. Nat. Mater. 2007, 6, 9971003. (61) Oh, S.; Brammer, K. S.; Li, Y. S.; Teng, D.; Engler, A. J.; Chien, S.; Jin, S. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 21302135. (62) Ranzinger, J.; Krippner-Heidenreich, A.; Haraszti, T.; Bock, E.; Tepperink, J.; Spatz, J. P.; Scheurich, P. Nano Lett. 2009, 9, 4240 4245. (63) Madurantakam, P. A.; Cost, C. P.; Simpson, D. G.; Bowlin, G. L. Nanomedicine 2009, 4, 193206. (64) Murugan, R.; Ramakrishna, S. Compos. Sci. Technol. 2005, 65, 23852406. (65) Edwards, S. L.; Werkmeister, J. A.; Ramshaw, J. A. Expert Rev. Med. Devices 2009, 6, 499505. (66) Borenstein, J. T.; Weinberg, E. J.; Orrick, B. K.; Sundback, C.; Kaazempur-Mofrad, M. R.; Vacanti, J. P. Tissue Eng. 2007, 13, 18371844. (67) Seunarine, K.; Meredith, D. O.; Riehle, M. O.; Wilkinson, C. D. W.; Gadegaard, N. Microelectron. Eng. 2008, 85, 13501354. 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DOI: 10.1021/nl102184c | Nano Lett. 2010, 10, 3223-3230

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Impact of Nanotechnology on Drug Delivery

Omid C. Farokhzad,,* and Robert Langer,,*

Laboratory of Nanomedicine and Biomaterials and Department of Anesthesiology, Brigham and Womens Hospital and Harvard Medical School, Boston, Massachusetts 02115, MITHarvard Center for Cancer Nanotechnology Excellence, and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

ABSTRACT Nanotechnology is the engineering and manufacturing of materials at the atomic and molecular scale. In its strictest denition from the National Nanotechnology Initiative, nanotechnology refers to structures roughly in the 1100 nm size regime in at least one dimension. Despite this size restriction, nanotechnology commonly refers to structures that are up to several hundred nanometers in size and that are developed by topdown or bottom-up engineering of individual components. Herein, we focus on the application of nanotechnology to drug delivery and highlight several areas of opportunity where current and emerging nanotechnologies could enable entirely novel classes of therapeutics.

*Address correspondence to ofarokhzad@partners.org, rlanger@mit.edu. Published online January 27, 2009. 10.1021/nn900002m CCC: $40.75
2009 American Chemical Society

he application of nanotechnology to drug delivery is widely expected to change the landscape of pharmaceutical and biotechnology industries for the foreseeable future.17 The pipelines of pharmaceutical companies are believed to be drying up in many cases, and a number of blockbuster drugs will come off patent in the near-term.8 There has also been a concurrent increase in the utilization of the HatchWaxman Act by generic drug companies, which allows them to challenge the patents of branded drugs, further deteriorating the potential revenues of pharmaceutical companies.8 The development of nanotechnology products may play an important role in adding a new armamentarium of therapeutics to the pipelines of pharmaceutical companies. Using nanotechnology, it may be possible to achieve (1) improved delivery of poorly water-soluble drugs; (2) targeted delivery of drugs in a cell- or tissue-specic manner; (3) transcytosis of drugs across tight epithelial and endothelial barriers; (4) delivery of large macromolecule drugs to intracellular sites of action; (5) co-delivery of two or more drugs or therapeutic modality for combination therapy; (6) visualization of sites of drug delivery by combining therapeutic agents with imaging modalities;9 and (7) real-time read on the in vivo efcacy of a therapeutic agent.3 Additionally, the manufacturing complexity of nanotechnology therapeutics may also create a signicant hurdle for generic drug companies to develop equivalent therapeutics readily. These are just a few of the many compelling reasons that nanotechnology holds enormous promise for drug delivery. Nanotechnology: Both Evolutionary and Revolutionary. Among the rst nanotechnology drug delivery systems were lipid vesicles, which were described in the 1960s and later became known as liposomes.10

Subsequently, a variety of other organic and inorganic biomaterials for drug delivery were developed. The rst controlledrelease polymer system for delivery of macromolecules was described in 1976.11 More complex drug delivery systems capable of responding to changes in pH to trigger drug release,12 as well as the rst example of cellspecic targeting of liposomes,13,14 were rst described in 1980. The rst longcirculating liposome was described in 1987, and the concept was later named stealth liposomes.15 Subsequently, the use of polyethylene glycol (PEG) was shown to increase circulation times for liposomes16 and polymeric nanoparticles17 in 1990 and 1994, respectively, paving the road for the development and subsequent approval of Doxil (doxorubicin liposome) in 1995, for the treatment of AIDS-associated Kaposis Sarcoma. There are over two dozen nanotechnology therapeutic products that have been approved for clinical use to date.18 Among these rst-generation products, liposomal drugs and polymerdrug conjugates are two dominant classes. The majority of these therapeutic products improve the pharmaceutical efcacy or dosing of clinically approved drugs, which in some cases also provides life-cycle extension of drugs after patent expiration. There have been signicantly fewer clinical examples where nanotechnology has enabled entirely new therapeutics that would otherwise not exist; we see this as an important area of promise for nanotechnology in the future. With nanotechnology therapeutic products now validated through the improvement of previously approved drugs, increasing interest is expected among academic and industry investigators to revisit pharmaceutically suboptimal but biologically active new molecular entities (NMEs) that were previously considered undevelopable through conwww.acsnano.org

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The emergence of nanotechnology platforms can enable development and commercialization of entirely new classes of bioactive macromolecules that need precise intracellular delivery for bioactivity.
ventional approaches. Indeed, we expect the emergence of nanotechnology platforms to enable development and commercialization of entirely new classes of bioactive macromolecules such as those involved in RNA interference pathways (e.g., siRNA or microRNA) that need precise intracellular delivery for bioactivity. Nearly all of the major pharmaceutical companies now have a RNAi franchise, and the obstacle to their broad clinical translation is the development of robust delivery platforms, an area where nanotechnology can make signicant strides.19 Targeting: Necessity or Luxury? The current clinically approved nanotechnology products are relatively simple and generally lack active targeting or triggered drug release components. Interestingly, the products that are currently under clinical development also lack complexity. In fact, nearly 29 years after the rst examples of targeted liposomes were described in the literature,13,14 this technology has not made a signicant clinical impact on human health; the question is why? The answer is complex and needs to be explored on a case-bywww.acsnano.org

case basis while considering at least erties of nontargeted drug delivery the following points: (1) Delivery vehicles such as ordered striations of vehicleOwere the combination of functional groups24 as well as their biomaterials and the processes to shape and size25 have also been develop targeted drug delivery sys- shown to enhance particle uptake tem optimal for product develop(Figure 1). ment? (2) DrugsOwere the properDrugs. The choice of therapeutic ties of the therapeutics as well as for targeted delivery needs careful their site and mode of action suited consideration. The delivery of therafor targeting to confer an advanpeutics with intracellular sites of actage? (3) Diseases and tion for which cellular uptake is inefindicationsOwere the diseases for cient may be best achieved with which targeted drug delivery systargeted delivery vehicles. An extems were previously explored the ample would be RNAi or antisense correct killer apps for targeting to therapeutics. Conversely, if a theraconfer an advantage? peutic requires intracellular delivery Delivery Vehicle. There are a number for bioactivity, then therapeutic efof parameters that are important for cacy may require homogeneous tisthe successful development and sue penetration and cellular uptake manufacturing of targeted drug deof the targeted drug delivery velivery vehicles.20 These include (a) the hicle, which is difcult to achieve.26 use of biocompatible materials with In some cases, it is believed that tarsimple robust processes for biomate- geting may anchor drug delivery rial assembly, conjugation chemistry, systems and decrease the efciency and purication steps; (b) the ability of diffusion and uniform tissue disto optimize in parallel the myriad of tribution. The optimization of the biophysicochemical parameters of ligand density on the drug delivery targeted drug delivery vehicles imsurface can facilitate the balance portant for pharmacokinetic properbetween tissue penetration and celties and possible cell uptake; and (c) lular uptake, resulting in optimal developing scalable unit operations therapeutic efcacy. The targeting amenable to manufacturing large of cell surface receptors that particiquantities of targeted drug delivery pate in membrane recycling pathsystems needed for clinical translaways facilitates the uptake of tartion. It has been shown that the degeted drug delivery systems velopment of targeted drug delivery through receptor-mediated envehicles by self-assembly of prefunc- docytosis. Understanding endosotionalized biomaterials simplies the mal trafcking pathways, which are optimization and the potential complex and can vary among remanufacturing of these ceptors, can also facilitate the engisystems.2023 The biophysicochemical properties of the vehicle, such as size, charge, surface hydrophilicity, and the nature and density of the ligands on their surface, can all impact the circulating half-life of the particles as well as their biodistribution.20,21 The presence of targeting ligands can increase the interaction of the drug delivery system with a subset of cells in the target tissue, which can potentially enFigure 1. Efcacy of nanoparticles as delivery vehicles is highly size- and shape-dependent. The size of the nanoparhance cellular uptake by ticles affects their movement in and out of the vasculature, receptor-mediated endocytowhereas the margination of particles to vessel wall is imsis. More recently, surface prop- pacted by their shape.
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ery systems,29 the difference in cellular cytotoxicity is more pronounced.20,30,34 In the case of vascular endothelial targeting for oncology or cardiovascular indications, ligand-mediated targeting is of critical importance as tissue accumulation is not a function of EPR.35 Similarly, in the case of immunological tissue targeting, such as targeted drug delivery systems as vaccine where particles are transported through the lymphatic vessels to draining Figure 2. Passive vs active targeting. (Right) Particles tend to passively extravasate through the leaky lymph nodes, size-mediated vasculature, which is characteristic of solid tumors and inamed tissue, and preferentially accumulate targeting has been shown to through the EPR effect. In this case, the drug may be released in the extracellular matrix and diffuse be important for efcient throughout the tissue for bioactivity. (Middle) Once particles have extravasated in the target tissue, the presence of ligands on the particle surface can result in active targeting of particles to receptors that are antigen presentation to cells present on target cell or tissue resulting in enhanced accumulation and cell uptake through receptorin the lymph nodes.36 mediated endocytosis. This process, referred to as active targeting, can enhance the therapeutic efNanotherapeutics are Gaining cacy of drugs, especially those which do not readily permeate the cell membrane and require an intracellular site of action for bioactivity. (Left) The particles can be engineered for vascular targeting by Traction. With recent scientic incorporating ligands that bind to endothelial cell-surface receptors. While the presence of leaky vasculaadvances, it will be increasture is not required for vascular targeting, when present as is the case in tumors and inamed, this stratingly feasible to engineer taregy may potentially work synergistically for drug delivery to target both the vascular tissue and target cells within the diseased tissue for enhanced therapeutic. geted or multifunctional nanotechnology products for lating half-life to facilitate timeneering of suitable targeted delivtherapeutic applications. With the dependent extravasations of drug ery systems. correct combination of an optimally delivery systems through the leaky Diseases and Indications. There has engineered vehicle, a suitable drug, tumor microvasculature and accubeen increasing effort to identify and a killer app disease, the benet new disease biomarkers and associ- mulation of drugs in the tumor tisof a targeted drug delivery system 32 sue. This process is largely mediated ligands for use in targeted over the equivalent nontargeted sysated by the biophysicochemical drug delivery applications. While tem is expected to be substantial. A targeted drug delivery systems have properties of the nanoparticles and case in hand is the recently anbeen developed for a myriad of im- not by active targeting.32 Therefore, nounced completion of phase I tolereven in the absence of targeting portant diseases, the thrust of reability evaluation of CALAA-01,37 a search has been focused on solid tu- ligands, drug delivery systems can transferrin-targeted RNAibe engineered to better target a mors, cardiovascular diseases, and nanotherapeutic for delivering siRNA particular tissue, or nonspecically immunological diseases. The curto reduce the expression of the M2 absorbed by cells, by optimizing rently approved nanotechnology subunit of ribonucleotide reductase their biophysicochemical therapeutic products for cancer (R2) for solid tumor therapy. properties.24,25 However, once partherapy function by accumulating In the near- and medium-term, ticles extravasate out of the vascula- we can expect the emergence of in tumor tissue through the enture into the tumor tissue, their rehanced permeability and retention many nanotechnology platforms for 27 tention and specic uptake by (EPR) effect and releasing their drug delivery applications. While payload in the extravascular tumor cancer cells is facilitated by active both organic and inorganic techtissue for antitumor efcacy. While targeting and receptor-mediated nologies are under development, these nontargeted drug delivery endocytosis (Figure 2).30 This procontrolled-release polymer techcess can result in higher intracellusystems have been clinically efcanologies and liposomes will likely lar drug concentration and incious, there have been contradictcontinue to have the greatest clinicreased cellular cytotoxicity. While ing data regarding the added bencal impact for the foreseeable futhere is relatively modest improveet for the inclusion of targeting ture. These are exciting times for molecules to these systems.20,2831 ment in tumor tissue accumulation nanotechnology research, and the Tumor tissue accumulation is a pas- of targeted drug delivery systems pace of scientic discovery in this area is gaining momentum. It is sive process requiring a long circurelative to nontargeted drug delivVOL. 3 NO. 1 FAROKHZAD AND LANGER www.acsnano.org

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While both organic and inorganic technologies are under development, controlled-release polymer technologies and liposomes will likely continue to have the greatest clinical impact for the foreseeable future.
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