Biotechnology Advances: Yu Gao, Jingjing Xie, Haijun Chen, Songen Gu, Rongli Zhao, Jingwei Shao, Lee Jia

JBA-06756; No of Pages 17
Biotechnology Advances xxx (2013) xxxxxx
Contents lists available at ScienceDirect
Biotechnology Advances
journal homepage: www.elsevier.com/locate/biotechadv
Research review paper
Nanotechnology-based intelligent drug design for cancer

metastasis treatment
Yu Gao a,1, Jingjing Xie a,1, Haijun Chen a,b, Songen Gu a, Rongli Zhao a, Jingwei Shao a, Lee Jia a,
a
b
Cancer Metastasis Alert and Prevention Institute, College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou 350002, China
Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Fuzhou University, Fujian 350108, China
a r t i c l e
i n f o
Available online xxxx

Keywords:
Nanotechnology
Nanomedicine
Targeted drug delivery system
Cancer metastasis therapy
Nanoparticle platform
a b s t r a c t
Traditional chemotherapy used today at clinics is mainly inherited from the thinking and designs made four decades ago when the Cancer War was declared. The potency of those chemotherapy drugs on in-vitro cancer cells
is clearly demonstrated at even nanomolar levels. However, due to their non-specic effects in the body on normal tissues, these drugs cause toxicity, deteriorate patient's life quality, weaken the host immunosurveillance
system, and result in an irreversible damage to human's own recovery power. Owing to their unique physical
and biological properties, nanotechnology-based chemotherapies seem to have an ability to specically and safely reach tumor foci with enhanced efcacy and low toxicity. Herein, we comprehensively examine the current
nanotechnology-based pharmaceutical platforms and strategies for intelligent design of new nanomedicines
based on targeted drug delivery system (TDDS) for cancer metastasis treatment, analyze the pros and cons of
nanomedicines versus traditional chemotherapy, and evaluate the importance that nanomaterials can bring in
to signicantly improve cancer metastasis treatment.
2013 Elsevier Inc. All rights reserved.
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Current established nanoparticle platforms as drug delivery systems for cancer therapy
2.1.
Lipid-based nanoparticle platforms . . . . . . . . . . . . . . . . . . . .
2.2.
Polymer-based nanoparticle platforms . . . . . . . . . . . . . . . . . . .
2.3.
Protein-based nanoparticle platforms . . . . . . . . . . . . . . . . . . .
2.4.
Inorganic nanoparticle platforms . . . . . . . . . . . . . . . . . . . . .
3.
Strategies in designing intelligent nanomedicine for enhanced cancer treatment . . .
3.1.
Active targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Combination drug delivery approaches . . . . . . . . . . . . . . . . . .
3.3.
Environment-response controlled release strategies . . . . . . . . . . . . .
3.4.
Multi-stage delivery nanovectors . . . . . . . . . . . . . . . . . . . . .
3.5.
Cancer nanotheranostics . . . . . . . . . . . . . . . . . . . . . . . . .
4.
Conclusions and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Cancer remains a leading cause of death worldwide (Ferlay et al.,
2010). Although years of intense biomedical research and billions of
Corresponding author. Tel./fax: +86 591 8357 6921.
E-mail address: pharmlink@gmail.com (L. Jia).
1
These authors contributed equally to this work.
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dollars in spending have increased our understanding of the underlying

mechanisms of tumorigenesis and biology of cancer, cancer mortality
surprisingly reached to the highest point as the top killer in the US population younger than 85 years old (Jemal et al., 2010). Among them,
cancer metastasis attributes to approximately 90% of cancer-related
deaths (Veiseh et al., 2011). Although immunotherapy, thermal therapy, phototherapy (Jia and Jia, 2012; Shao et al., 2013) and gene therapy
are available as cancer treatment modalities, surgery, radiation, and/or
0734-9750/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.biotechadv.2013.10.013
Please cite this article as: Gao Y, et al, Nanotechnology-based intelligent drug design for cancer metastasis treatment, Biotechnol Adv (2013),
Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx
chemotherapy continue to be the therapeutic options for most cancers

over decades, each with its own limitations. Surgery and radiation therapy could be effective for the primary tumor, however, they may not be
a good treatment choice for metastases. Chemotherapy with cytotoxic
agents is commonly used for the whole-body treatment of recurrent
disease. But the conventional anticancer drugs generally result in serious side effects in clinic (Sinha et al., 2006; Stortecky and Suter, 2010;
Tsuruo et al., 2003). The side effects are associated with the formulation
due to poor water solubility of the drug, non-specic distribution, severe toxicity to normal cells, inadequate drug concentrations at tumors
or cancerous cells, and the development of multidrug resistance. Therefore, researchers are continuously seeking for improved anti-cancer
therapies that can selectively target tumor cells with minimal side
effects on normal tissues (Wang et al., 2008).
Nanotechnology is the understanding of materials in the nano (109)
size range, and involves imaging, measuring, modeling, and manipulating materials within that framework. Since its advent, nanotechnology
has revolutionized a wide range of medical products, generic tools and
biotechnology equipment. Nanomedicine focuses on application of
nanotechnology in medicine for diagnosis, prevention, detection, and
treatment of the disease. In particular, it has been used to design and development of targeted drug delivery system (TDDS) which could safely
deliver therapeutic drugs to injury sites or specic cells. For formulations
intended for i.v. administration, effective TDDSs could retain therapeutic
drug in the vehicle, evade the reticuloendothelial system (RES) uptake,
target to intended sites of injury, and release drug at the intended sites
with required drug concentration (Mills and Needham, 1999). In
the eld of oncology, TDDS offers many potential benets such as
(1) avoiding the side effects of the clinical formulation for improving
solubility, (2) protecting the entrapped therapeutic drug from degradation, (3) modifying pharmacokinetic and tissue distribution prole to
increase drug distribution in tumor, (4) reducing toxicity to normal
cells, and (5) increasing cellular uptake and internalization in cancer
cells. In the past 20 years, many nanomedicines have been in preclinical
development and some of them have been approved for use in clinic including for cancer therapy (Davis et al., 2008; Jain and Stylianopoulos,
2010; Peer et al., 2007). Besides used as drug delivery systems (DDSs)
for cancer therapy, nanoparticles loaded with imaging agents were
also found useful in imaging techniques applied for tumor diagnosis.
Here we will focus on TDDS designed for i.v. administration and for
delivering anticancer drugs including chemotherapeutic drugs and
therapeutic genes.
In this review, we rst outline the different types of nanoparticle
platforms currently being established for cancer treatment. We then
present various strategies that have been employed in designing new
effective TDDSs.
2. Current established nanoparticle platforms as drug delivery
systems for cancer therapy
There are diverse types of nanocarriers that have been synthesized
for drug delivery including dendrimers, liposomes, solid lipid nanoparticles, polymersomes, polymer-drug conjugates, polymeric nanoparticles, peptide nanoparticles, micelles, nanoemulsions, nanospheres,
nanoshells, carbon nanotubes, and gold nanoparticles, etc. (Fig. 1). In
all these types, drugs can be entrapped inside, dissolved in the matrix,
covalently linked to the backbone, or absorbed on the surface. From
the aspect of the property, these nanocarriers could be divided into organic, inorganic, and organic/inorganic hybrid nanoparticles. From the
perspective of formulation type, they could be divided into liposomes,
micelles, emulsions, nanoparticles, etc (Jia, 2005). Ljubimova and Holler
also proposed the term nanopolymer meaning a single polymer molecule in the nanoscale range, to distinguish with nano-polymer composites such as micelles and other self-assembled or aggregated forms in
the point of whether they could dissociate in solutions (Ljubimova
and Holler, 2012). Here, we will categorize these current established
nanoparticle platforms based on the difference in composition including

lipid-based nanomedicine, polymer-based nanomedicine, peptidebased nanomedicine and inorganic nanomedicine for treating cancer.
Some examples of nanomedicines that are approved for commercial
use or still in clinical trials are listed in Table 1.
2.1. Lipid-based nanoparticle platforms
Lipid-based nanoparticles have attracted great attention as DDS due
to their attractive biological properties such as good biocompatibility,
biodegradability, low immunogenicity, and the ability to deliver hydrophilic and hydrophobic drugs. Liposomes are the most widely used and
studied examples (Jia et al., 2002), with bilayer membrane structures
composed of phospholipids for stabilizing drugs, directing their cargo
toward specic sites, and for overcoming barriers to cellular uptake.
Their aqueous reservoir and the hydrophobic membrane allow them
to encapsulate either hydrophilic or hydrophobic agents. The important
milestone that led to the development of clinically suitable liposome formulations could be the inclusion of PEGylated lipids in the liposomes to
protect liposomes from destruction by the RES, thus to increase circulation time and increase drug accumulation in the tumors. It is worthy to
mention that Doxil/caelyx, a PEGylated liposome formulation of the
anticancer drug doxorubicin (DOX), was the rst formulation approved
for application in the clinic (Barenholz, 2012). With the aim to sitespecic delivery of cancer drugs to the cancerous tissues, the surface of
liposomes can be modied with ligands or antibodies targeting those receptors overexpressed on cancer cell membranes (Gabizon et al., 2006).
For tumor site-specic triggering drug release, liposomes were designed
with responsive to changes in light (Leung and Romanowski, 2012),
temperature (Park et al., 2013), acid (Mamasheva et al., 2011) or enzymes (Andresen et al., 2005). Though the work on modication of liposomes has achieved great progress, the application of liposomes in the
clinic still poses several challenges including rapid clearance from the
bloodstream, instability of the carrier, high production cost, and fast
oxidation of some phospholipids.
Solid lipid nanoparticles (SLN) is an alternative to liposomes, the
matrix of which comprises of solid lipids. They exhibit major advantages
such as less cytotoxicity than polymeric counterparts; stable formulations, excellent reproducibility, avoidance degradation of incorporated,
controlled drug release, and potential application in intravenous, oral,
dermal or topical routes (Uner and Yener, 2007). However, some limitations still exist such as undesired particle growth by agglomeration or
coagulation, ineffective drug loading capacity, rapid drug expulsion during storage due to lipid crystallization and high water contents of the
dispersions. Thus, modied SLN, so-called nanostructured lipid carriers
(NLC) were developed to overcome these limitations and combine the
advantages associated with SLN. In contrast to SLN which are made
from solid lipids core containing triglycerides, glyceride mixtures, or
waxes, NLC were composed of liquid lipid and solid lipid (preferably
in a ratio of 30:70 up to 0.1:99.9) to form a nanosized solid particle matrix. The imperfect crystal or amorphous structure assures them to have
enhanced drug loading and less drug expulsion during storage (Iqbal
et al., 2012). Till now, SLN and NLC as colloidal drug carriers have
been successfully multi-functionalized to transport drugs to the
targeted cancer cells and achieve efcient drug release in a controlled
manner, which conrm their promising application in cancer therapy.
2.2. Polymer-based nanoparticle platforms
Polymer-based nanoparticle platforms show enormous potential for
treating disease or repairing damaged tissues especially for cancer treatment, which relies on their remarkable properties including small size,
excellent biocompatibility and biodegradability, prolonged circulation
time in the bloodstream, enhanced drug loading capacity, and easy
chemical modication or surface functionalization. The last two characters are the utmost important criteria for their clinical use. Generally
Fig. 1. Schematic illustration of representative nanoparticle platforms that have been synthesized for drug delivery for cancer therapy.
speaking, polymer-based nanomedicine can be categorized into three

groups based on drug-incorporation mechanisms including polymerdrug conjugates by covalent conjugation, polymeric micelles by hydrophobic interactions, and polyplexes or polymersomes by encapsulation.
Most of the polymers are approved by FDA as the commonly explored
carriers for targeted drug delivery.
Polymer-drug conjugates using water-soluble polymers as carriers
have produced expected results, including a water-soluble polymeric
carrier (natural or synthetic), a biodegradable linkage and an anticancer
agent. Because polymer-drug conjugates can passively target to tumor
cells by enhanced permeability and retention (EPR) effect (Matsumura
and Maeda, 1986), many polymer-drug conjugates were under clinical
evaluation. The most attractive representative of synthetic polymerdrug conjugates is poly (L-glutamic acid)-paclitaxel (CT-2103, Xyotax),
which has advanced to Phase III clinical trials (Bonomi, 2007). Polymerdrug conjugates have exhibited several superiorities such as enhanced
therapeutic efciency, fewer side effects, exible drug administration
and even increased patient compliance. However, many challenges still
exist in the development of new generation of polymer-drug conjugates,
including the design of novel polymers that have modulated degradation
characteristics, polymerization methods allowing for controlling the
weight distribution, and conjugation techniques available for sitespecic attachment.
Amphiphilic block copolymers can self-assemble into different kinds
of mesoscopic structures (micelles and vesicles), which is just up to the
control about the volume ratio of hydrophilic to hydrophobic blocks
(Antonietti and Frster, 2003; Zupancich et al., 2006). Polymersomes
are self-assembled polymer vesicles formed by amphiphilic copolymers
containing hydrophilic and hydrophobic segments, which are different
from liposomes formed by amphiphilic phospholipids. The hydrophilic
interior structure is suitable for encapsulating with water-soluble
agents such as DNAs or proteins while the hydrophobic exterior bilayer
membrane can be simultaneously entrapped with poorly water-soluble
drugs. Compared with liposomes, polymersome exhibited more
prominent features such as higher loading capabilities, greater stabilities, and longer circulation time. The improvement of storage abilities
is attributed to their own large hydrophic core and surface functionality
through chemical synthesis and modication (Ghoroghchian et al.,
2005, 2006).
Polymeric micelles are self-assembling monolayers formed spontaneously under certain conditions including the concentrations of amphiphilic surfactants, pH, temperatures and ionic strength with a
hydrophobic core and hydrophilic shell in the nanometer range. The
properties of polymeric micelles such as small size, hydrophilic shell
avoiding the uptake by the mononuclear phagocyte system (MPS),
and the high molecular weight evading renal excretion made them
effective passive targeting systems. Ligands such as small organic molecules, DNA/RNA aptamers, peptides, carbohydrates and monoclonal antibodies could be attached to the surface of micelles, not only increasing
the accumulation at tumor sites but also increasing the cellular uptake
in cancer cells via receptor-mediated endocytosis (Farokhzad et al.,
2006; Sethuraman and Bae, 2007; Torchilin et al., 2003; Yoo and Park,
2004).
Dendrimers are kinds of nanomaterials with super biological characteristics: small size (115 nm), high water solubility, regularly
and highly branched three-dimensional architecture, nearly perfect
monodispersibility in nature, and high payload. All these facilitate
their applications in cancer or disease prevention and therapy.
Polyamidoamine (PAMAM) dendrimer was one of the most studied
dendrimers. It possesses multiple amine surface groups, and the number of the groups could be precisely controlled. Therefore, the multivalent conjugation could be achieved by attachment of targeting ligands,
therapeutics agents, drugs, imaging contrast agents, genes or even
chemical sensors to their terminal functional groups. M.H. Li et al.
(2012) prepared the G5 PAMAM dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting. The
study demonstrated that re-engineering dendrimer conjugates not
only target KB cancer cells, but also inhibited dihydrofolate reductase.
Table 1
Examples of current established nanoparticle platforms approved for commercial use or undergoing clinical investigation for cancer therapy.
Product
Nanoparticle platform
Drug
Current stage of development
Type of cancer
Doxil/caelyx
PEGylated liposomes
Doxorubicin
Approved by FDA
Myocet
Non-PEGylated liposomes
Doxorubicin
Approved in Europe and Canada
DaunoXome
Abraxane
ALN-VSP
CRLX101
CALAA-01
Liposomes
Albumin-bound nanoparticles
Lipid nanoparticles
Cyclodextrin nanoparticles
Cyclodextrin-containing linear polymer,
decorated with PEG and transferrin
Polymer micelle
PSMA-targeted polymeric nanoparticles
Pegylated colloidal gold nanoparticles
Heat-activated liposome
Liposomes
Daunorubicin
Paclitaxel
siRNA
Camptothecin
siRNA
Approved in the USA

Approved by FDA
Phase I
Phase II
Phase I
Refractory Kaposi's sarcoma, recurrent breast cancer,

ovarian cancer
Combinational therapy of metastatic breast cancer,
ovarian cancer, Kaposi's sarcoma
Advanced HIV-associated Kaposi's sarcoma
Various cancers
Liver cancer
Various cancers
Solid melanoma tumors
Doxorubicin
Docetaxel
TNFi
Doxorubicin
Irinotecan and oxuridine
Phase I
Phase I
Phase II
Phase III
Phase II
Various cancers
Advanced solid tumor cancers
Solid tumors
Hepatocellular carcinoma
Advanced solid tumors
NK-911
BIND-014
Aurimune
ThermoDox
CPX-1
Thomas and his co-workers used antibody-conjugated dendrimers to

bind antigen-expressing cells. The conjugates specically bound to the
antigen-expressing cells in a dose-and time-dependent manner with afnity similar to that of the free antibody (Thomas et al., 2008).
2.3. Protein-based nanoparticle platforms
Protein-based nanomedicine platforms as one of the representatives
have been paid serious attention owing to their biocompatibility, biodegradability as well as low toxicity. Protein-based nanomedicine platforms are usually consisted of naturally protein subunits of the same
protein or the combination of natural or synthetic protein, and different
types of drug molecules. There are a variety of proteins used and characterized for DDSs such as the plant-derived viral capsids (Liepold et al.,
2007; Suci et al., 2007), the small Heat shock protein (sHsp) cage
(Flenniken et al., 2005, 2006), albumin (Kratz, 2008; W. Lu et al.,
2007), soy and whey protein (Chen et al., 2008; Gunasekaran et al.,
2006), casein (Latha et al., 2000), collagen (Metzmacher et al., 2007)
and the ferritin/apoferritin protein cage (Wu et al., 2008a, 2008b). The
protein cage with hierarchical architectures derived from viruses has
its various advantages on the cage's uniform nanometer size for drug
loading and for avoidance of macromolecular aggregation, multifunctional groups on the surface available for conjugation with drugs, and
superior biological characteristics benecial for pharmacokinetics
study. Albumin as a versatile protein carrier for improving drug targeting
and pharmacokinetic properties is playing a vital role in the development
of protein-based nanoparticles. It demonstrates prominent features of
stability in a broad range of pH (49) and temperature (4 C60 C),
preferential uptake by tumor, and non-toxicity. Methotrexate-albumin
conjugate, albumin-binding prodrug of DOX and albumin PTX nanoparticle (Abraxane) have been designed and now are under clinical trials
(Miele et al., 2009).
2.4. Inorganic nanoparticle platforms
Organic nanoparticles such as liposomes, dendrimers, polymeric micelles have made great advances in cancer diagnosis and therapy
(Khemtong et al., 2009; Ljubimova et al., 2008). In contrast, inorganic
nanoparticles such as gold nanoparticles (AuNPs), carbon nanotubes
(CNTs), silica nanotubes, quantum dots (QDs), and super-paramagnetic
iron oxide nanoparticles (SPIOs) have also been extensively developed
and studied for biomedical applications due to their intrinsic unparallel
physical and biological properties such as optical, electrochemical, magnetic characteristics.
The biomedical applications of CNTs have been gradually proposed
and recognized through preliminary studies in vitro and in vivo and
even clinical tests, which is ascribed to their prominent physical and
chemical properties. In general, CNTs can be classied to two categories:
single-walled carbon nanotubes (SWNTs, 0.42.0 nm in diameters,

201000 nm in lengths) and multi-walled carbon nanotubes (MWNTs,
1.4100 nm in diameters, 1 m in lengths). MWNTs provide potential
platforms for large biomolecules delivery such as plasmids into cells,
which is mainly due to the multiple layers of grapheme and larger diameters (Gao et al., 2006; Liu et al., 2005). SWNTs exhibit more attractive optical properties suitable for biological imaging (Cherukuri et al.,
2004; O'Connell et al., 2002; Welsher et al., 2008). Functionalized
SWNTs by covalent binding, adsorption, and electrostatic interaction
can serve as novel drug delivery carriers in cancer therapy owing to
their biocompatibility, little toxicity and enhanced water solubility
(Feazell et al., 2007; Liu et al., 2007). Liu et al. (2008) prepared the
SWNT-PTX conjugate by coupling PTX to the branched PEG chains on
SWNTs and studied its antitumor effects in a xenograft murine 4T1
breast cancer model. They showed that SWNT delivery of PTX into
xenograft tumors could have 10-fold higher tumor suppression efcacy
than the clinical drug formulation Taxol.
Distinction from other nanomaterials, mesoporous silica nanoparticles (MSNs) showed unique properties such as tunable particle size
from 50 to 300 nm convenient for cell endocytosis; stable and rigid
framework resistant to degradations induced by pH, heat, and mechanical stress; uniform and tunable pore size adjusted between 2 and 6 nm
for the loading of different drug molecules; high surface area and large
pore volume allowing for high drug loading; internal and external functional surfaces available for selective modication. MSNs could be functionalized through co-condensation, grafting, and imprint coating
methods (Burleigh et al., 2001; Chen et al., 2006). The different surface
functionalization of MSNs has great effects on the cellular uptake mechanism and the internalization efciency of MSNs as well as the ability to
escape the endolysosomes (Slowing et al., 2006). MSNs were reported
having better biocompatibility compared with other silica-based materials. The viability of mammalian cells wasn't affected by the internalization of MSNs at concentrations below 100 g/ml (Slowing et al., 2008).
Similar results were found that injecting MSNs to the animals didn't
pose any toxic side effects for 42 days (Kortesuo et al., 2000). Therefore,
MSNs were widely employed as promising intracellular controlled release drug delivery carriers in cancer treatment (Slowing et al., 2007;
Trewyn et al., 2007; Vallet-Regi et al., 2007). J. Lu et al. (2007) incorporated the hydrophobic anticancer drug camptothecin (CPT) into the
pores of the prepared uorescent mesoporous silica nanoparticles
(FMSNs) and successfully achieved the controlled drug release to
human cancer cells and induced tumor cell death.
Magnetic nanoparticles (MNPs) have their own unique physical and
biological features including controllable size distribution ranging from
nanometers to micrometers, high magnetic ux density with the intrinsic penetrability for drug targeting, the ability to convert magnetic to
heat, non-toxicity, biocompatibility, and injectability (Ito et al., 2005;
Pankhurst et al., 2003). The magnetic nanoparticle-based DDSs could
be constructed by loading drug onto the particle coat via physical means
such as electrostatic interaction instead of covalent conjugation (Kievit
et al., 2011; Medarova et al., 2007). The physical, hydrodynamic, and
physiological parameters have great effects on the drug delivery efciencies of magnetic nanoparticles. Among the MNPs, SPIOs with the diameter of 5100 nm, which show high magnetization in an external
magnetic eld, have demonstrated attractive possibilities in biomedical
application. They could serve as good nanotheranostics for both
targeted drug delivery and magnetic resonance imaging of tumor cells
(Lee et al., 2013; Mouli et al., 2013; Yang et al., 2008; Zou et al., 2010).
Usually, SPIOs are loaded with small-molecule-based therapeutics into
polymer-based matrices (Quan et al., 2011).
Great interest has been paid to gold nanoparticles (AuNPs) in recent
years for their attractive properties including the strong and attractive
optical properties in the near-infrared (NIR) region from 700 to
900 nm (Jain, 2009; Xia et al., 2011), easy modication with functional
groups through formation of stable gold-thiolate bonds (Au\S) by
reacting with disulde (S\S) or thiol (\SH) groups (Huang et al.,
2013), controllable particle size, shape and geometry (Kim et al.,
2009), and diversely multi-functionalization with desired targeting ligands, specic antibodies or drugs. The routine applications of AuNPs
in cancer therapy were photothermal therapy and radiation therapy, respectively, for their strong absorption cross-sections and X-ray emission
characteristics (Sperling et al., 2008). AuNPs were also used as
nanocarriers for drug delivery. Several strategies have been used to improve AuNPs accumulation in tumor cells specically and efcient intracellular drug release, including the conjugation of AuNPs with
appropriate surface ligands (membrane-translocating peptides) or specic antibodies (Huang et al., 2008), the coupling drugs of AuNPs
through non-covalent (available for drug release) or covalent binding
(requiring for second release), the external triggering methods such as
glutathione (Hong et al., 2006), light or photothermal-mediated release
(Agasti et al., 2009; Bikram et al., 2007), and the surface modication
with amphiphilic reagents (PEG). Though advances have been made
in the research eld of AuNPs as TDDS for cancer therapy, more challenges are still confronted. The suitable types of AuNPs used as drug delivery (Cai et al., 2008; Chithrani et al., 2006), the delivery efciency, the
accuracy of targeting as well as the toxicity (Pan et al., 2009) were under
re-evaluation and optimization prior to clinical application.
3. Strategies in designing intelligent nanomedicine for enhanced
cancer treatment
3.1. Active targeting
Active targeting utilizes targeting moieties to peripherally conjugate
to nanoparticle systems for specically targeting to tumor tissue, specific cancer cells, or even cellular organelles (Fig. 2). The most common
used active targeting strategy involves the attachment of the targeting
ligands such as folic acid, antibodies, aptamers, or proteins to the nanoparticles which recognizes receptors over-expressed on cancer cells
(Ruoslahti et al., 2010). For example, in FR positive KB cells, uptake of
folate-targeted liposomal arsenic PEGylated liposomes inserted with a
small amount of DSPE-PEG3350-folate (0.3 mol%) was three to six
times higher than that of nontargeted liposomal arsenic, leading to a
28-fold increase in cytotoxicity (H. Chen et al., 2009).
Various antibodies that target receptors over-expressed on the surface of cancer cells such as vascular endothelial growth factor (VEGF),
human epidermal receptor-2 (HER-2), tumor necrosis factor- (TNF), and epidermal growth factor receptor (EGFR) have been attached
to nanoparticulate materials to achieve selective cancer cell targeting
(Fay and Scott, 2011). When developing the antibody-conjugated nanoparticles, the afnity and the conguration of the antibodies, as well
as the method to attach to the nanoparticles, are all key design factors
that should be taken into consideration (Cheng and Allen, 2008; Firer
and Gellerman, 2012; Rizk et al., 2009; Rudnick et al., 2011). The
characteristics of the antibodies will have great effects on the circulation

time, cellular uptake, tolerability, and efcacy of the nanoparticulate systems. In a recent study, two gold nanoparticles with the surface partiallycovered and surface fully-covered by EGFR antibody cetuximab were
designed to determine the cellular uptake mechanism of cetuximabconjugated nanoparticles. The endocytosis mechanism could be
switched from a Cdc42-dependent pinocytosis/phagocytosis to original
Dyn-2-dependent caveolar pathway when the nanoparticles were fully
coated with cetuximab (Bhattacharyya et al., 2012). Compared with antibodies, antibody fragments such as Fab' and scFv are more widely used
for active targeting because they have a smaller size easy to conjugate
into nanoparticles. More importantly, they could keep their targeting
specicity while reducing nonspecic antigen binding from Fc (Ansell
et al., 2000; Chapman, 2002; Rothdiener et al., 2010; Sapra et al.,
2004). Conjugation of the antibody on nanoparticles can be carried
out by coupling the carboxylic acid groups or primary amine groups of
the amino acid in the antibody to the primary amine groups or the carboxylic acid groups on the surface of the nanoparticles (Chapman,
2002). The interaction between biotin and avidin or streptavidin has
also been exploited for designing antibody-conjugated nanoparticles.
Wartlick et al. covalently modied the nanoparticles based on gelatin
and HSA with the biotin-binding protein NeutrAvidin followed by
the biotinylated herceptin conjugation to the surface of the nanoparticles. These nanoparticles could effectively internalize into HER-2overexpressing cells via receptor-mediated endocytosis observed by
confocal laser scanning microscopy (Wartlick et al., 2004).
Aptamers are kinds of oligonucleotides that are capable of binding to
a large number of targets with high afnity and specicity. Since the advent of aptamer technology (Ellington and Szostak, 1990; Tuerk and
Gold, 1990), aptamers have represented an interesting class of modern
pharmaceuticals for therapy and diagnostics. Known as chemical
antibodies, aptamers show many similar properties to traditional antibodies, however, they demonstrated a number of advantages over antibodies such as low immunogenic potential, easier to synthesize and
modify, structural exibility, higher afnity and specicity, and good
stability (Majumder et al., 2009). Recently, aptamers have been conjugated to many types of molecules such as siRNAs, miRNA, proteins,
and nanoparticles to improve their targeting efciency, stability, and
biodistribution prole (Kanwar et al., 2011). The chimeric aptamernanoparticle conjugates can bind to the target cells by the interaction
of aptamerreceptor interaction, and nally enter into the target cells,
resulting in release of the entrapped drugs (Estevez et al., 2010). In a
study, branched PEI-PEG polyplexes modied with an anti-prostatespecic membrane antigens (PSMA) aptamer were used to co-deliver
DOX and Bcl-xL-specic shRNA. The polyplexes could induce a synergistic and selective cancer cell death in PSMA-overexpressing prostate cancer cells (E. Kim et al., 2010).
With the development of different kinds of biomolecular ligands,
more and more new molecular-targeted nanoparticles are designed to
target different receptors. Considering that one kind of ligand is commonly specic to only one or a limited few target receptors, and conjugation of large targeting molecules to nanoparticles can change their
behaviors in vivo, pre-targeting strategy has been utilized to avoid
development of multiple nanoparticle formulations with different
targeting ligands and accommodate different targeting ligands without
alternating pharmacokinetic prole of the nanoparticles. Pre-targeting
is a multi-step process that rst has a targeting ligand localized within
a tumor by virtue of its anti-tumor binding site, followed by treatment
with nanoparticles that recognize the targeting ligand conjugate on
the cell surface. Using a cell targeting recombinant fusion protein (FP)
composed of a single-chain antibody (scFv) and streptavidin (SA) to
specically pre-label the targeted cells, followed by application of a biotinylated nanoparticle that binds to the SA of the FP on the target cells,
the nanoparticle system with two FPs, anti-CD20 and anti-TAG-72
CC49, could specically target two model cancer cell lines, i.e., Ramos
and Jurkat, respectively (Gunn et al., 2011). Besides using the
Fig. 2. Schematic illustration of active targeting strategies that have been used for design intelligent drug delivery systems for cancer therapy. The active targeting strategy involves the
attachment of the targeting ligands such as folic acid, antibodies, aptamers, or proteins to the nanoparticles for specically targeting to tumor tissue, tumor vasculature, specic cancer
cells, or even cellular organelles (nucleus, cytoplasm, mitochondria). Pre-targeting is a multi-step process that rst has a targeting ligand localize within a tumor by virtue of its antitumor binding site, followed by treatment with nanoparticles that recognize the targeting ligand conjugate on the cell surface. Dual-targeting strategy and sequential-targeting strategy
have been applied to develop nanoparticles that can both penetrate the BBB and target the glioma cells.
interaction between biotin and avidin or streptavidin, bioorthogonal

chemistry such as tetrazine/trans-cyclooctene cycloaddition reaction
has also been employed to nanoparticles recognition of pre-labeled
cells (Devaraj et al., 2009; Haun et al., 2010; Rossin et al., 2010).
Dual-targeting strategy has been applied to develop nanoparticles for
treatment of brain tumor. The treatment of brain tumor entails efcient
delivery of therapeutic agents to specic regions of the brain after penetrating the bloodbrain barrier (BBB). The BBB is a physiological barrier
that selectively allows the entry of certain molecules. Many strategies
have been employed to across the BBB such as the disruption BBB integrity by osmotic means or by ultrasound means, the use of endogenous
carrier-mediated transporters, receptor-mediated transcytosis, and
blocking of active efux transporters. Nanotechnology is considered to
be one of the most promising methods to deliver drugs across the BBB
by attaching BBB-penetrating ligands to the surface of nanoparticles
(Yang, 2010). To targeting inltrated glioma cells or the glioblastoma
multiform after crossing the BBB, nanoparticles were modied with
dual ligands such as angiopep, transferrin, wheat germ agglutinin,
which recognize the receptors over-expressed on both BBB and glioma
cells for transporting the drug across the BBB and then targeting brain
glioma (Du et al., 2009; He et al., 2011; Xin et al., 2011; Y. Li et al.,
2012; Ying et al., 2010). Recently, a sequential-targeting strategy
has been applied to develop nanoparticles that can come across the
BBB and recognize the glioma cells subsequently. The exterior of the
micelle was conjugated with transferrin to enhance the cellular uptake
and BBB-penetrating through receptor mediated endocytosis. Then
the loaded drug cyclo-[ArgGlyAspdPheLys] (c[RGDfK])-PTX conjugate (RP) was released from micelle subsequently to target integrin
over-expressed glioma cells (Zhang et al., 2012). This sequentialtargeting nanoparticulate system could not only protect the ligands
from degradation during transportation across the BBB (Knisely et al.,
2008), but also overcome the non-specic recognition of the receptors
that are highly expressed throughout the brain (Bu et al., 1994).
Many research groups have studied the mechanism of active
targeting in solid tumors with ligand-modied nanoparticles. The improvement of cellular uptake of ligand-modied nanoparticles could
be achieved through receptor-mediated endocytosis by tumor cells
over-expressing corresponding receptors on the surface. However,
whether ligand-modied nanoparticles could increase drug accumulation at the tumor site is largely dependent on the ligands. In a subcutaneous KB-3-1 xenograft model, the administration of the nanoparticles
formed by ternary conjugate heparin-folic acid-PTX and additional PTX
(HFT-T) enhanced the specic delivery of PTX into tumor tissues (Wang
et al., 2009). Using transferrin-containing gold nanoparticles as study
model, Choi et al. found that the content of targeting ligands signicantly inuences the number of nanoparticles localized within the cancer
cells (Choi et al., 2010). Some contrary results were also found in
some nanoparticulate systems such as antibody targeting of longcirculating lipidic nanoparticles and chlorotoxin labeled magnetic
nanovectors that the targeting ligand only enhanced cellular uptake of
nanoparticles, but did not affect the accumulation of nanoparticles at
the tumor site (Kievit et al., 2010; Kirpotin et al., 2006).
Besides the cancer cells, tumor vasculature is also a potential target
for drug delivery (Jain and Stylianopoulos, 2010). In vivo phase display
is a very useful tool to identify numerous peptides targeting the tumor
vasculature (Li and Cho, 2012; Trepel et al., 2008). Several peptides
such as arginineglycineaspartic acid (RGD), asparagineglycine

arginine (NGR) (Arap et al., 1998), TCP-1 (Li et al., 2010), iRGD
(Sugahara et al., 2009; Sugahara et al., 2010), F3 (Porkka et al., 2002),
and LyP-1 (Laakkonen et al., 2002) have been identied to specically
target tumor blood vessels or simultaneously recognize the tumor vasculature and cancer cells. Nanoparticles modied with peptides that
targeting the tumor vasculature could enhance efcacy of the chemotherapeutic agents against human cancer xenografts (Chang et al.,
2009), suppress tumor growth (Hood et al., 2002), and metastasis in
mice (Murphy et al., 2008).
Active targeting not only can direct the nanoparticles to specic cells
of the tumor, but also been applied to deliver cargos to specic cellular
organelles. As oncogenes and tumor suppressor genes play a crucial role
in the processes of cancer development, gene therapy provides a tool to
cure the disease at its source. The DNA-based medicines require carriers
efciently and safely carry the plasmid DNA into the nucleus of the desired cells. The cationic non-viral vectors which could interact with
negatively charged DNA through electrostatic interactions to form
polyplexes or lipoplexes, have been considered to be the most promising gene delivery systems compared to naked DNA or viral vectors
(Al-Dosari and Gao, 2009). To successfully deliver genes into the nucleus, the cationic nanoparticles should circumvent a series of barriers including survival in the bloodstream, extravasation into the tissue,
binding and internalization into the target cells, escaping from endosome, subcellular trafcking, and nally entry into nucleus (Khalil
et al., 2006; Wiethoff and Middaugh, 2003). Numerous efforts have
been made to develop effective and safe gene delivery systems and a
large amount of strategies has been employed to improve systemic delivery and intracellular trafcking of cationic nanoparticles including attachment of ligand for cell-specic targeting and receptor-mediated
endocytosis, use of protein transduction domain (PTD) such as TAT
peptides to mediate cellular transduction, incorporation of pH-sensitive
endosomolytic peptides, fusogenic peptides or membrane-destabilizing
compounds to facilitate endosomal escape, employment of nuclear localization sequence to improve the uptake of plasmid DNA into the nucleus (Morille et al., 2008). Some multifunctional nanoparticles that
could circumvent several biological barriers have been designed. For example, a multifunctional nano device consisting of poly(folate-poly(ethylene glycol)cyanoacrylate-co-hexadecylcyanoacrylate), dioleoyl
phosphatidylethanolamine (DOPE), and DNA condensed by protamine
sulfate (PS) was developed for nucleus delivery of DNA. The folic acid
on the surface of the nano device could increase its active targeting ability to cancer cells. The PEG chain within the polymer could decrease its
macrophages recognition and extend its half-life in blood circulation.
DOPE could facilitate endosomal escape and PS could be served for nuclear transfer (Gao et al., 2007). Unlike the pDNA delivery to the cell nucleus, siRNA delivery involves fewer barriers because the target of
delivery of siRNA is in the cytoplasm (Nguyen and Szoka, 2012). It is
worthy to mention that a complex nanoparticle formulation CALAA01 (Calando Pharmaceuticals, Inc.), which consists of cyclodextrinbased polymer, transferrin targeting ligand, a hydrophilic PEG chain,
and siRNA targeting ribonucleotide reductase M2, a critical biomolecule
in DNA synthesis, has been recently shown to effectively deliver siRNA
to humans (Davis et al., 2010).
Mitochondria are playing an important role in regulating cell metabolism and cell death, and are involved in diverse physiological activities
in the course of cancer development and progression. As an alternative
subcellular target, some novel mitochondrial TDDSs have been developed (Yamada and Harashima, 2008). Torchilin's group developed
mitochondrial-targeted liposomal drug-delivery system by incorporation a mitochondriotropic dye rhodamine-123 (Rh123)-PEG-DOPE
into the liposomal lipid bilayer (Biswas et al., 2011) or by modication
of a mitochondria-targeting triphenylphosphonium cation to liposome
surfaces (Boddapati et al., 2008). The mitochondria-targeting liposomes
could efciently deliver the model drug to mitochondria to enhance its
activity.
3.2. Combination drug delivery approaches

To achieve better treatment efcacy, multimodality treatment or
combination treatment is commonly used to treat cancer. Compared
with single-modality treatment, multimodality treatment can do an excellent job with additive or even synergistic efcacy. On the one hand,
using drugs acting through different molecular targets could delay or
block the cancer adaptation processes from different aspects. On the
other hand, the drugs with the same molecular target could function
synergistically for higher therapeutic efcacy. The combination of chemotherapy, biologic therapy, endocrine therapy and/or thermotherapy
has been investigated for their synergistic effects recently (Goodwin
et al., 2012; Mehta et al., 2012).
Although combination therapy has synergistic efcacy, it could also
lead to increased toxicity in some cases. Some anticancer agents are
mixed together for administration but they are eliminated independently, which could cause the additive adverse effects. The combination
of taxanes with anthracyclines in rst-line chemotherapy for metastatic
breast carcinoma produces a signicant benet in activity, but with a
signicant cost in hematologic toxicity (Bria et al., 2005). In phase III
trial, combination of PTX and bevacizumab signicantly prolonged
progression-free survival as compared with PTX alone, however, grade
3 or 4 hypertension, proteinuria, headache, and cerebrovascular ischemia were more frequent in patients receiving PTX plus bevacizumab
(Miller et al., 2007). In addition, combination of anticancer agents
which have different routes of administration would decrease patient
satisfaction and compliance. For example, when employing the combination therapy of lapatinib and trastuzumab to treat ErbB2-positive
breast cancer, patients needed to receive doses of lapatinib administered once daily (continuous) in combination with trastuzumab weekly
(Storniolo et al., 2008).
Nanomedicine can provide a fantastic platform for multimodality
treatment. Nanoparticulate DDSs demonstrate many advantages over
conventional formulations by physically blending multiple drugs together including: (1) improved solubility and bioavailability, (2) escape
of elimination by macrophages and prolonged drug circulation half-life,
(3) increased tumor site accumulation by passive or active targeting, (4)
efcient internalization with the mechanism of endocytosis, (5) controlled pharmacokinetics of each drug, resulting in enhanced drug efcacy and reduced side effects. Many nanoparticulate platforms have
been developed as co-delivery systems that can deliver a combination
of small molecule drugs or a combination of small molecule drugs and
macromolecular therapeutics.
Liposomes are commonly used as co-delivery carriers with the ability to load both hydrophilic and hydrophobic drugs. In a study by Wong
et al., co-encapsulation of vincristine and quercetin into a liposome formulation exhibited signicant antitumor activity than free vincristine/
quercetin combinations (Wong and Chiu, 2011). Stealth liposomes
(Ong et al., 2011) and targeted liposomes (Wu et al., 2007) were also
developed as co-delivery carriers for cancer therapy. Some combination
DDSs based on liposomes are currently in clinical trial. Liposomes encapsulated with irinotecan and oxuridine (CPX-1) (Batist et al.,
2009) and liposomes containing cytarabine and daunorubicin (CPX351) (Feldman et al., 2011) have been entered into phase I trials. To ensure the product quality of complex liposome formulations, Zucker et al.
showed the methods to characterize the critical features of LipoViTo
where vincristine (VCR) and topotecan (TPT) were encapsulated in
the same nanoliposome. The characterization methods are useful for a
rational clinical development of liposomal formulations alike (Zucker
et al., 2012).
Cationic lipoplexes were initially proposed to co-delivery of anticancer drug and gene. The lipoplexes developed by L. Huang's team could
co-deliver DNA and inammatory suppressors into one immune cell
(Liu et al., 2004). Co-delivery of antitumor agent docetaxel and DNA
which suppress surviving protein, was achieved by a folate-modied
multifunctional lipoplexes as a therapeutic approach for human
hepatocellular carcinoma (Xu et al., 2010). Cationic liposomes were also

applied to co-deliver siRNA and an anticancer drug (Saad et al., 2008;
Shim et al., 2011). In the preparation of lipoplexes, a condenser is always
needed to condense pDNA to form the core of the cationic liposomes.
But the cationic liposome:siRNA complexes are always formed by
mixing siRNA and cationic liposomes together.
Polymer-based nanoparticles have been extensively studied as codelivery carriers as the drug can be entrapped inside or covalently linked
to the polymer matrix. Polyalkylcyanoacrylate nanoparticles were used to
entrapped DOX and chemo-sensitizing compound cyclosporin A to
achieve the synergistic effect in multidrug resistance (MDR) cancer cells
(Soma et al., 2000) Amphiphilic block copolymers such as PEG-PLGA
and PEG-PLA could self-assemble into micelles to co-deliver two
chemotherapeutic agents (H. Wang et al., 2011; Shin et al., 2009). Micelles
formed by cationic copolymers such as amphiphilic copolymer poly{(Nmethyldietheneamine sebacate)-co-[(cholesteryl oxocarbonylamido
ethyl) methyl bis(ethylene) ammonium bromide] sebacate} (P(MDSco-CES)) (Wang et al., 2006) and triblock copolymers poly(N,Ndimethylamino-2-ethylmethacrylate)-polycaprolactone-poly(N,Ndimethylamino-2-ethyl methacrylate) (PDMAEMA-PCL-PDMAEMA)
(Zhu et al., 2010) have been used to co-deliver genes and drugs to the
same cells, in which hydrophobic anticancer drug PTX was entrapped in
the core of the micelles, and genes were complexed onto their surface.
PEI-graft-poly(-caprolactone) copolymer was also reported to codeliver DOX and a reporter gene (Qiu and Bae, 2007). A core-shell nanoparticle formed from folate coated PEGlated lipid shell and PLGA core
was also developed for targeted co-delivery of drug and gene (Wang
et al., 2010). Recently, a nanoparticle system formed by blend of
poly(lactide)-D--tocopheryl polyethylene glycol succinate and carboxyl group-terminated TPGS (TPGS-COOH) copolymer was developed
for triple modality treatment of cancer. The nanoparticles were formulated with docetaxel, herceptin and iron oxides for the chemo, bio, and
thermo therapies (Mi et al., 2012). Besides entrapped inside the
polymer-based nanoparticle systems, two or more drugs could be conjugated to one kind of polymer carrier for combination delivery. The
aromatase inhibitor aminoglutethimide and DOX were simultaneously
conjugated to HPMA copolymer. The results showed that the conjugate
carrying two drugs was more potent than the combination of two polymer conjugates carrying only one drug (Vicent et al., 2005). The HPMAbased polymer was also used to simultaneously deliver DOX and antiinammatory drug dexamethasone (DEX) (Krakovicova et al., 2009).
In another study, DOX and gemcitabine were co-conjugated to the
same HPMA polymer, which increased the efcacy of the combination
of gemcitabine and DOX without increasing its toxicity (Lammers
et al., 2009). Dendrimers have also been used for successfully synchronous delivery of two therapeutic agents by either complexation of two
drugs or by conjugation of two drugs in the same polymer, as well as
by complexation of one drug and simultaneous conjugation of another
drug (Clementi et al., 2011; Kaneshiro and Lu, 2009; Kim et al., 2011;
Lee et al., 2011). Also, nanoparticles formed by blending of selfassembled amphilic copolymer in the presence of a chemotherapeutic
agent and polymer-prodrug conjugate could be used to achieve combination drug delivery (Kolishetti et al., 2010).
Some inorganic nanoparticulate systems have been successfully
employed for co-delivery. Successfully synchronous delivery of chemotherapeutic drug and siRNA was achieved by mesoporous silica nanoparticles coating with the cationic polymer. MSNs modied with
PAMAM dendrimers were utilized to simultaneously deliver DOX
and a Bcl-2 siRNA into MDR cancer cells (A. M. Chen et al., 2009). PEI
functionalized MSNs were also used to synchronously deliver DOX
and P-gp siRNA to reverse drug resistance in MDR cancer cells (Meng
et al., 2010). The in vivo efcacy of the use of this dual drug/siRNA
nanocarrier was also tested in a xenograft to overcome DOX resistance
(Meng et al., 2013). Positively charged ammonium-functionalized
MSNs could also immobilize negatively charged single strand DNA
(ssDNA) for drug/ssDNA co-delivery (X. Ma et al., 2012). In a recent
work, hydrophilic-hydrophobic anticancer drug pairs, such as doxorubicinpaclitaxel and doxorubicinrapamycin, could be loaded into magnetic mesoporous silica nanoparticles for simultaneous delivery of
hydrophilic and hydrophobic drugs for combination treatment (Q. Liu
et al., 2012). Magnetic nanoparticles embedded in polylactide-coglycolide matrixes were also designed as drug delivery and imaging
vector for loading both hydrophilic and hydrophobic drugs (A. Singh
et al., 2011). Layer-by-layer assembled charge-reversal functional gold
nanoparticles were employed to co-deliver siRNA and plasmid DNA
into cancer cells (Guo et al., 2010).
Some hybrid systems such as lipid-polymer hybrid systems, lipidinorganic silica hybrid systems were developed for combination drug
delivery. A polymer-caged nanobin (PCN) formed by liposomal core encapsulated with DOX and a polymer shell conjugated with cisplatin
prodrug was designed to co-deliver of DOX and cisplatin. The PCN
could exert synergistic cytotoxic effects of each drug against cancer
cells at reduced doses (Lee et al., 2010). In another study, the protocells
were designed with nanoporous silica cores enveloped by a lipid bilayer,
which was further functionalized with poly(ethylene glycol),targeting
peptides, and pH-responsive peptides, to deliver combinations of diverse drug cargos such as quantum dots, small molecules and oligonucleotides (Ashley et al., 2011).
3.3. Environment-response controlled release strategies
Development of stimuli-responsive nanoparticles is a particularly
appealing approach for the goal of increasing the specicity of drug delivery in vivo. Environmentally-responsive nanoparticles have the ability to produce physicochemical changes that regulate drug release at the
target site when exposed to external stimuli. The differences between
tumor environment and normal tissue such as pH value, protease expression, and the change of external conditions such as the local application of heat, ultrasound, light, magnetic eld, or electric eld could
be served as stimuli (Fig. 3). The environmentally-responsive nanoparticles could improve tumor accumulation, tumor penetration of cancer
therapeutics, and increase the intracellular localization of anticancer
therapeutics, and thus further enhance the efcacy of antitumor therapeutics (MacEwan et al., 2010).
Among these environmentally-responsive nanoparticles, pHresponsive nanoparticulate DDSs have been widely studied in the eld
of cancer therapy. A change in pH can be used in two ways to trigger
drug release. First, the extracellular pH values of most human tumors
(pHe) are found to be at an average value of ~ 7.0, which is a
distinguishing phenotype of solid tumor to normal tissue (Vaupel,
2004). A second is used after cellular uptake when nanoparticles
reached the endosomal and lysosomal compartments with low pH of
about 56 (Murphy et al., 1984).
Nanoparticles could be formulated with pH-responsive polymers that
could change their physical and chemical properties in response to different pH values for pH-dependent drug release. One strategy is to take
advantage of the changes in polymer protonation states to make pHdependent hydrophobic-to-hydrophilic transitions to affect polymer
swelling or solubility, which will then acquire pH-responsive drug release.
Expansile nanoparticles formulated by acrylate-based hydrophobic polymers modied with pH-labile protecting groups were stable at neutral
pH, but in a mildly acidic pH, the protecting group was cleaved to reveal
hydroxyls, which corresponded to a hydrophobic-to-hydrophilic transformation, resulting in swelling of the polymeric structure to create a hydrogel and subsequent drug release. The expanded nanoparticles can act
as an intracellular or intratumoral depot for the chemotherapeutic agent
PTX, affording higher intracellular drug concentrations (Zubris et al.,
2012). PTX loaded expanded nanoparticles showed superior in vivo
efcacy in murine tumor models including non-small cell lung cancer
(Griset et al., 2009) and mesothelioma (Colson et al., 2011). PEGpoly(-amino ester) polymers have also been used to design for
pH-responsive nanoparticles targeting the low pH present in the
Fig. 3. Schematic illustration of environmental response drug delivery systems for cancer therapy. The low extracellular pH or up-regulated protease expression at the tumor environment,
and the local application of heat, electric eld, magnetic eld, ultrasound or light could be utilized to trigger drug release from nanoparticulate drug delivery systems.
extratumoral and cellular microenvironment. The polymers are designed to incorporate some amines that are unprotonated at pH 7.4
to make the polymer insoluble in water, but are protonated at
pH 6.46.8 to increase polymer solubility and induce a sharp micellizationdemicellization transition for drug release (Shenoy et al., 2005;
X.L. Wu et al., 2010). The micellizationdemicellization transition was
also found in DDSs formulated by combination of poly(L-histidine)-bPEG and PLLA-b-PEG (Lee et al., 2003). The low pH tumor microenvironment could also serve as stimulus to trigger a change in surface
charge of nanoparticle which could facilitate uptake of nanoparticles
by tumor cells. Poon et al. designed the trilayer nanoparticles which
consist of iminobiotin modied PLL, the linker protein neutravidin,
and biotin end-functionalized PEG layer. The PEG layer in the nanoparticles could selectively deshield when localized in low pH tumor microenvironment to expose positive charged nanoparticles for improving
cellular uptake by tumor cells and decreasing non-specic cellular uptake by normal cells (Poon et al., 2011). Another work based on a
charge-reversal nanogel triggered by the pHe was reported by Du
et al. At physiological pH values, the nanogel was negatively charged
with high positively charged drug loading capacity and was relatively
inert to tumor cells. When exposed to the tumor microenvironment,
the nanogel was turned to be positively charged to strengthen
nanogel-cell interaction and enhance cellular uptake by cancer cells
(Du et al., 2010).
An alternate pH-triggered strategy involves the use of acid-labile
linkers upon cleavage at a specic pH. Commonly used acid-labile
crosslinkers include ester, hydrazone, carboxy dimethylmaleic anhydride,
orthoester, imine, vinylether, phosphoramidate, and so on (Gao et al.,

2010). The prodrug strategy often conjugates drug molecules to macromolecular chains via pH-labile linkers. In response to the acidic extracellular or intracellular environment, these macromolecular carriers are
able to release the drug to exert its efcacy (Ulbrich and Subr, 2004). In
an example of this approach, cisplatin was conjugated to poly(ethylene
glycol)-b-poly(L-lactide) using hydrazone cross-linkers to allow release
of the drug after the nanoparticles were endocytosed by the target cells
(Aryal et al., 2010). Likewise, a hydrazone linker was used to link the
doxorubicinyl group and the PEG chain to the surface of the gold nanoparticles, which released DOX in acidic organelles after endocytosis (F. Wang
et al., 2011). Acid-labile linkers were also used to synthesize acid-labile
polymers for pH triggered rapid degradation to release the entrapped
drugs. One example is the use of nanoparticles composed of a copolymer
(poly--aminoester ketal-2) for efcient gene delivery. The nanoparticles
can respond to endosomal pH and undergo a hydrophobic-hydrophilic
switch and a rapid degradation in series, resulting in increased cytoplasmic delivery (Morachis et al., 2012). As many chemotherapeutics and
some macromolecules such as DNA, exert their action in the nucleus,
the pH-labile linkers have been used to develop charge-reversal polymers
for the nuclear-targeted drug delivery. Modication of the positive
amines in the cationic polymers such as PLL (Zhou et al., 2009) and
PAMAM dendrimers (Shen et al., 2010) with negatively charged groups
with acid-labile amides so that the polymer was negatively charged at
physiological condition, but was hydrolyzed at low pH to restore its positive charge, can obtain efcient nuclear-targeted gene delivery. For favoring gene expression, pH labile linker was also employed to construct a
10
smart nanoassembly which has the ability for self-dePEGylation. The

nanoassembly containing lipid envelope based on PEG-vinyl etherDOPE can self-remove PEG and recover the fusogenic ability of DOPE at
low pH, resulting a higher transfection efciency and much lower cytotoxicity than that of commercial Lipofectamine 2000 in several cancer
cell lines (Xu et al., 2008).
Over-expressed cancer-associated enzymes are also utilized to trigger drug release. Many kinds of nanomaterials such as liposomes,
polymer-based nanoparticles, mesoporous silica nanoparticles and
gold nanoparticles have been designed with high specicity for the enzyme stimulus (Andresen et al., 2010; Ghadiali and Stevens, 2008; Ulijn,
2006). The general strategy to design enzyme-responsive nanoparticle
systems is to employ biological motifs that can be degraded by enzymes. By this approach, the self-assembled polymers could be synthesized with enzyme-responsive motifs to the encapsulated drug or
the conjugated drug using enzyme-responsive linkers. When these
nanomaterials encounter the enzyme, they could degrade to release
the encapsulated drug or conjugated drug. In other cases, the nanoparticles can be designed to generate a change in the physical properties
upon enzymatic stimulation, which could facilitate cellular uptake or intracellular delivery of nanoparticles. Matrix metalloproteinases (MMPs)
especially MMP-2 and MMP-9, have been regarded to be up-regulated
in the tumor microenvironment (Roy et al., 2009). Banerjee et al. had
integrated an MMP-cleavable lipopeptide into the liposome formulation to prepare MMP-sensitive liposomes which can rapidly release
their contents by MMP-9 (Banerjee et al., 2009). In another work,
PEG-mesoporous silica nanoparticles (MSNPs) to respond to MMP for
controlled drug delivery were engineered. The proteases present at
the tumor site could trigger DOX release from the MSNPs, resulting in
signicant cellular apoptosis (N. Singh et al., 2011). Basel et al. incorporated peptides with a sequence that can be recognized by cancerassociated proteases into a polymer-stabilized liposome formulation.
The liposomes were much stable and resistant to osmotic swelling,
but released their payloads quickly in response to the protease presented at the tumor site (Basel et al., 2011). As abnormally high concentrations of phospholipase A2 (PLA2) have been found in the evading zone
of tumors (Yamashita et al., 1993), several liposome systems consisting
prodrugs of antitumor ether lipids (proAELs) were investigated for
PLA2-triggered degradation, resulting in the release of antitumor
ether lipids (AELs). As the AELs possess the ability to enhance transmembrane drug diffusion, encapsulation of the conventional chemotherapeutic drugs in liposomes containing proAELs can enhance the
intracellular distribution of drug in cancer cells (Andresen et al.,
2004). Sugar-based nanocarrier has also been designed to release
anti-cancer drugs selectively to tumors. Bernardos et al. used saccharide
derivatives which could respond to the lyzosomal amylase to modify
the pore of the MSNPs for specic release of drugs by enzymatic stimulus. After the internalization of the nanoparticle, the saccharide molecular gate opened in the presence of the lyzosomal amylase, and the
cytotoxic agent consequently released to attain a decreased cell viability
(Bernardos et al., 2010).
Differences in the reducing potential between the extra- and intracellular environment provide another stimulus for drug delivery. The disulde linkage has been extensively employed to design redox sensitive
nanocarriers for drug delivery due to their stability in the typically oxidizing extracellular environment and their lability in the elevated reducing intracellular environment (high glutathione concentration) to
efciently release entrapped cargos (Saito et al., 2003). Gao et al. synthesized a linear cationic click polymer containing disulde bonds via
the click chemistry. The polymer could facilitate efcient gene delivery through releasing DNA efciently by the cleavage of disulde
bonds under the reduction condition (Gao et al., 2011). The disulde
bond was also used to link poly(epsiloncaprolactone) and poly(ethyl
ethylene phosphate) to synthesize diblock copolymer. The micelles
formed by the diblock copolymer could load drug in its inner core
in aqueous solution, while release drug rapidly under glutathione
stimulus, leading to enhanced drug toxicity to tumor cells (Tang et al.,

2009). The disulde linkage was also applied to design micelles with
the capability to self-remove PEG chain under the intracellular reducing
environment. The successful detachment of PEG in endosome is benecial for endosomal escape of micelles and enhanced gene transfection
efciency (Takae et al., 2008).
An extrinsic stimuli can also be utilized to enhance drug distribution at
the tumor site or improve intracellular drug accumulation by selectively
release of its payload at the tumor tissue or cancer cells. Thermosensitive
polymers that exhibit a volume phase transition in response to temperature have been developed for triggering drug release and local accumulation by application of heat. Ultrasound and electromagnetic (EM) elds
have been employed as external stimuli to produce heat (O'Neill and
Rapoport, 2011). Polymers based on N-isopropylacrylamide (NIPAm), N,
N-diethylacrylamide and N-vinylcaprolactam monomers have a lower
critical solution temperature (LCST) and polymers based on a combination of acrylamide and acrylic acid monomers showed a upper critical solution temperature (UCST) (Schmaljohann, 2006). Thermoresponsive
chitosan-g-poly (N-vinylcaprolactam) polymers loaded with curcumin
can specically kill cancer cells at above their LCST (Rejinold et al.,
2011). Hoare et al. produced thermosensitive nanoparticles by wrapping superparamagnetic iron oxide nanoparticles with a lm formed
by PNIPAm-based nanogels and ethyl cellulose. The entrapped drug
molecules could transport across the lm through heating the
superparamagnetic nanoparticles to dissolve of the PNIPAm (Hoare
et al., 2011). Inducing a local hyperthermia effect by the magnetic
eld at the level of the polymersome membrane could achieve triggered drug release from polymersomes encapsulate DOX together
with superparamagnetic iron oxide nanoparticles (USPIO; -Fe2O3)
(Oliveira et al., 2013). Similarly, ultrasound can be employed to trigger
the release of DOX and other hydrophobic drugs from polymeric micelles at denite time and space (Husseini and Pitt, 2008, 2009).
Some smart nanoparticles are designed to respond to a mixture of
two or more stimuli. A nanoparticle system composed of a conducting
polymer (polypyrrole) and a temperature-sensitive hydrogel matrix
(PLGA-PEG-PLGA) were developed with response to temperature and
electric eld dual-stimulus for programmed drug delivery (Ge et al.,
2012). Superparamagnetic maghemite (-Fe2O3) nanoparticles modied with poly (2-(dimethylamino)ethyl methacrylate) (pDMAEMA)
which exhibit a pH- and temperature-dependent reversible agglomeration showed remarkable gene delivery efciency in CHO-K1 cells
(Majewski et al., 2012). A novel PEG and cRGD peptide modied
poly(2-(pyridin-2-yldisulfanyl)ethyl acrylate) nanoparticle loaded with
DOX (RPDSG/DOX) was designed to be both pH-responsive and redox
sensitive. The RPDSG/DOX nanoparticle is stable in physiological condition while releasing DOX fast with the trigger of acidic pH and redox potential (Bahadur et al., 2012). Micelles formed by block copolymer
which consisted of an acid-sensitive tetrahydropyran-protected 2hydroxyethyl methacrylate (HEMA) hydrophobic chain and a
temperature-sensitive poly(N-isopropylacrylamide) (PNIPAM) hydrophilic chain can respond to triple stimuli including temperature, pH
and redox potential (Klaikherd et al., 2009).
3.4. Multi-stage delivery nanovectors
Between the point of intravenous administration and the tumor
tissue, systemically administered nanoparticles should go through a
three-step process: blood delivery to the blood vessels of the tumor,
transported across the vessel wall into the interstitium, and migrated
through the interstitium to reach cancer cells in tumor (Jain, 1999). To
circumvent the multiplicity of biological barriers that the nanoparticles
encounter after administration, and maximize drug localization and
release in cancer cells, multistage nanovectors have been developed
recently. The rationale for the multistage approach is based on the
arrangement of different tasks to a single nanoparticle which could
complete the tasks at different stages.
This concept was rst applied to design a nanocell which overcomes

the barriers unique to solid tumors. The nanocell was composed of a nuclear polymer-based nanoparticle containing a chemotherapy drug and a
pegylated-lipid envelope, which entrapped an anti-angiogenesis agent.
The anti-angiogenesis agent was rst released from the outer envelope
causing a vascular shutdown, and the chemotherapy drug was then released from the inner nanoparticle, which is trapped inside the tumor.
The multistage release prole within a tumor results in improved therapeutic effects with reduced toxicity (Sengupta et al., 2005).
Based on mathematical modeling, mesoporous silicon nanoparticles
could be designed to carry the payload trafcking efciently and controlling the release rate of the burden. Recently, Ferrari's group developed a multistage silicon nanocarrier system which was composed of
mesoporous silican particles (also known as the rst stage) and the
entrapped nanoparticles (the second stage) loaded with anticancer
therapeutics (the third stage). The rst stage mesoporous silican particles could protect and ferry the inner nanoparticles until they recognize
and dock at the tumor vasculature. Then the second stage nanoparticles
released from the MSP with the biodegradation of porous multistage
particles under physiological conditions. The released nanoparticles
were able to extravasate through fenestrations of vessels and enter
the tumor parenchyma, thus concentrating diagnostic and therapeutic
agents within the target microenvironment (Tasciotti et al., 2008).
This kind of multistage nanovectors was also applied to gene delivery.
Liposomes consisted of dioleoyl phosphatidylcholine containing siRNA
targeted against the EphA2 oncoprotein (the second-stage carriers)
were loaded into mesoporous biodegradable silicon particles (the
rst-stage carriers). The mesoporous silicon particles allowed for the
loading and release of second-stage nanocarriers in a sustained manner.
Compared with the one-stage neutral nanoliposomes that require twice
weekly injections to achieve continuous gene silencing, the multistage
delivery methods could achieve sustained EphA2 gene silencing which
could last for at least 3 weeks after a single i.v. administration (Tanaka
et al., 2010). Similarly, superparamagnetic CaCO3 mesocrystals were
used to encapsulate DOX, AuDNA, and Fe3O4@silica nanoparticles for
the co-delivery of drug and gene via a multistage method for treatment
of cancer. The stage-one nanoparticles-CaCO3 system protected the encapsulated payloads from degradation and phagocytosis during navigation in the blood. After they docked to the vascular walls, the stage-one
nanoparticles degraded to gradually release the stage-two nanoparticles and drugs (Zhao et al., 2010). A multistage system with sizeshrinking property was designed for deep tumor tissue penetration.
The 100-nm multistage nanoparticles are composed of a gelatin core
with surface covered with 10-nm QDs. After they exposed to the
tumor microenvironment, the 100-nm nanoparticles shrink to 10nm nanoparticles due to the hydrolysis of gelatin by the MMPs. This
shrinkable multistage system can combine the advantage of large 100nm nanoparticles that are suitable for the EPR effect, and small 10-nm
nanoparticles that are suitable for diffusion in the collagen matrix of
the interstitial space and penetration into the tumor parenchyma
(Stylianopoulos et al., 2012; Wong et al., 2011).
3.5. Cancer nanotheranostics
Cancer nanotheranostics is the use of nanotechnology for the combined therapeutics and diagnostics for cancer (Sumer and Gao, 2008). Besides for therapeutic purposes, potential applications of nanotheranostics
range from the visualizing the blood circulation, biodistribution of drugs
in real time, noninvasively assessing drug accumulation and drug release
at the target site, facilitating triggered drug release and monitoring drug
distribution, to predicting drug responses and evaluating drug efcacy
longitudinally (Lammers et al., 2010). Integration of imaging capability
into the design of nanoparticles made it possible to evaluate the fate of
nanoparticles in real time, which will allow physicians to adjust the
type and dosing of drugs for more personalized treatment regimens
(Diou et al., 2012). The currently accessible imaging techniques include
11
MRI, single photon emission computed tomography (SPECT), positron

emission tomography (PET), computer tomography (CT), and ultrasonography (US) (Mura and Couvreur, 2012). Nanotheranostics can be obtained by either attaching different imaging moieties (i.e. NIR probes,
radionuclides) to the available nanocarriers or taking advantage of the intrinsic properties of some nanoparticle materials such as SPIOs for MRI
and QDs for uorescence imaging (Brigger et al., 2002). Till now, a variety
of nanotheranostics that combine anti-cancer therapeutics with aforementioned imaging modalities has been developed using liposomes, micelles, polymers, gold-based nanomaterials, magnetic nanomaterials,
carbon nanomaterials, and silica-based nanomaterials. From a recent
summary of selected papers published between 2009 and 2012 on
nanotheranostics, optical and MRI are the preferable modalities performed for imaging functionality, through use of NIR emission and magnetic agents, respectively (Wang et al., 2012).
Magnetic nanoparticles have been used as nanotheranostics for
both targeted drug delivery and tumor imaging due to their magnetic
property as nanostructured contrast probes for MRI. Among the magnetic nanoparticles, SPIOs are the most commonly used nanomaterials.
A number of polymers, including dextran, dendrimer, polyaniline, and
polyvinylpyrrolidone, have been utilized to coat magnetic nanoparticles. Pluronic polymer F127 and -cyclodextrin (-CD) were coated
onto the iron oxide core nanoparticles by a multi-layer approach for encapsulation of the anti-cancer drugs and for sustained drug release, respectively. The optimized water-dispersible SPIOs formulation showed
improved MRI characteristics and improved therapeutic effects
(Yallapu et al., 2011). By tuning the properties of the coating polymers,
the triggered drug release could be realized in magnetic theranostic
nanoparticles. A poly (beta-amino ester) (PBAE) copolymer was used
to entrap SPIO and DOX for sensitive detection and effective treatment
of cancer by pH sensitive controlled drug release (Fang et al., 2012).
The magnetic nanoparticle formulation loaded with other imaging moieties could allow for multimodal imaging. Foy et al. loaded near-infrared
dyes into a magnetic nanoparticle (MNP) formulation stabilized by an
amphiphilic block copolymer to provide for both tumor MRI and optical
imaging (Foy et al., 2010). To achieve targeted delivery, a variety of ligands has been attached to the outside layer of magnetic theranostic
nanoparticles such as folate (Santra et al., 2009), cRGD, (Nasongkla
et al., 2006) and antibody (Zou et al., 2010). Yang et al. designed an
FR-targeted multifunctional polymer vesicle nanocarrier system loaded
with SPIO and DOX to increase specic cellular uptake by FR positive
cancer cells (Yang et al., 2010). Similarly, a multifunctional antibodyand uorescence-labeled HuCC49CH2-SPIO nanotheranostics was
developed for combined targeted anticancer drug delivery and
multimodel imaging of cancer cells (Zou et al., 2010). Cyclo(ArgGly
AspdPheCys) (c(RGDfC)) peptides were also employed to modify
SPIO nanocarriers for targeted drug delivery and dual PET/MRI imaging
(Yang et al., 2011). Magnetic theranostic nanoparticles can also be used
for gene delivery. An MRI visible gene delivery system developed with a
core of SPIO nanocrystals and a shell of biodegradable stearic acidmodied low molecular weight PEI (Stearic-LWPEI) via self-assembly
showed synergistic advantages in the effective transfection of mcDNA
and non-invasive MRI of gene delivery (Wan et al., 2013).
Gold-based nanoparticles have been investigated as nanotheranostics
due to their unique optical characteristics known as surface plasmon resonance and photothermal characteristics, which enable them not only to
be used for imaging applications but also to induce photothermal effects
for therapeutic purposes (Dykman and Khlebtsov, 2012; Saha et al.,
2012). The optical and thermal properties of gold materials can be
tuned by changing their morphology and surface properties, as spherical
gold nanoparticles (AuNP), nanorod (AuNR), nanoshell, and nanocage
exhibit different optical and thermal properties. Different kinds of
gold-based nanoparticles such as high-photoluminescence-yield gold
nanocubes (X. Wu et al., 2010), gold nanorod-in-shell nanostructures
(Hu et al., 2009), silica-modied gold nanorods (Huang et al., 2011),
and matrix metalloproteinase sensitive gold nanorod (Yi et al., 2010)
12
have been developed for combined imaging and photothermal therapy

of cancer. Due to the well-established strategies for surface modication
(ie, goldthiol bonding) of gold-based nanoparticles, targeting ligands
and chemotherapeutic agents could be conjugated to the surface of
gold-based nanoparticles to achieve targeted drug delivery and diagnosing. Heo et al. designed a gold nanoparticle modied with PEG, biotin, PTX and rhodamine B linked -CD which could specically interact
with cancer cells by biotin and effectively release the entrapped PTX
under the intracellular glutathione condition (Heo et al., 2012). Another
gold nanoparticle modied with a PSMA RNA aptamer was developed
for simultaneous CT imaging and prostate cancer therapy. The PSMA
aptamer conjugation could signicantly improve CT intensity and
DOX efcacy of gold nanoparticles for targeted LNCaP cells than that
of non-targeted PC3 cells (D. Kim et al., 2010).
Silica-based nanoparticles especially MSNs have been qualied as a
new type of excellent theranostic nano-platform, due to their unique
features, such as high surface area, large pore volume, tunable porosity,
and facile functionalization, and many kinds of imaging and therapeutic
agents have been encapsulated into MSNs to achieve theranostic purposes (Ambrogio et al., 2011; Lee et al., 2011). By decoration with magnetite nanocrystals, carbon or Si nanocrystals, MSNs could be used for
synchronous drug delivery and imaging. He et al. encapsulated carbon
and Si nanocrystals into the framework of mesoporous silica nanoparticles (CS-MSNs) to constructed a nanoparticle system with high payload
of insoluble drugs and unique NIR-to-Vis luminescence imaging feature
(He et al., 2012). Hyeon's group developed a dye-doped mesoporous silica shell containing a single Fe3O4 nanocrystal core as drug delivery system and dual MRI/uorescence imaging agents (Kim et al., 2008). In a
study by Cheng et al., mesoporous silica nanoparticle loading both contrast agent and drug was functionalized with biomolecular ligands
cRGDyK peptides for targeted drug delivery to the over-expressed
v3 integrins of cancer cells and tumor imaging (Cheng et al., 2010).
In addition, MSNs could be combined with gold composites to achieve
multimodal imaging and multimodality treatment. Nanoparticles
consisted of AuNRs-capped magnetic core and mesoporous silica shell
designed by Ma et al could achieve synchronous chemotherapy,
photo-thermotherapy, in vivo MR-, infrared thermal and optical imaging into one single system (M. Ma et al., 2012).
In addition to the conventional nanomaterials AuNPs, SPIO, MSNs
which have the unique properties, nanotheranostics using lipid- and
polymer-based formulations have been widely studied in cancer research. They can be loaded with a variety of contrast agents such as
SPIOs and gadolinium-based compounds for MRI applications. They
can also be loaded or conjugated with radionuclide agents such
as 64Cu, 99mTc, and 111In for radionuclide imaging, or loaded with uorescent molecules or QDs for uorescence imaging (Luk et al., 2012).
Some of the lipid- and polymer-based nanotheranostics can be designed
with environment sensitivity by incorporating thermosensitive polymer chains (Kono et al., 2011) or pH-sensitive linkages within polymer
backbone (T. Liu et al., 2012).
Single walled carbon nanotube (SWNT) is one potential candidate as
a theranostic agent since it generates signicant amounts of heat upon
excitation with near-infrared light for the photothermal destruction of
tumors (Kam et al., 2005; Moon et al., 2009). In addition, due to its
strong optical absorbance, it has been used as contrast agents for photoacoustic imaging (De la Zerda et al., 2008). Mashal et al. reported that at
frequency of 3 GHz, SWNTs could be used for both microwave-induced
thermoacoustic imaging and hyperthermia treatment (Mashal et al.,
2010).
Other nanomaterials such as upper-conversion nanoparticles (UCNPs)
(Cheng et al., 2011), QDs (Mitra et al., 2012), and silver nanoparticles (W.
Wu et al., 2010) were also employed for theranostic applications. Some
nanotheranostics can be designed by mixing drug loaded nanoparticulate
systems with peruoropentane (PFP) nano/microbubbles to facilitate
ultrasound-mediated cellular uptake and ultrasonic tumor imaging
(Rapoport et al., 2007).
4. Conclusions and outlook

Since its advent in the eld of cancer, nanotechnology has shown
immense potential for cancer detection, prevention, and treatment.
Nanoparticles have revolutionalized drug delivery, allowing for therapeutic agents to selectively targeting tumor tissue and cancer cells,
while minimizing toxicity to normal cells. Liposome and protein based
nanomedicine formulation are already approved for commercial use
and many new formulations are in the phase II and phase III stages of
evaluation for cancer therapy. In addition to drug delivery, some kinds
of nanoparticles are promising materials for physical therapy methods
such as hyperthermia to provide a non-invasive approach to treat cancer. Furthermore, some delicately designed nanoparticles can combine
imaging and therapy of cancer together with the ability to monitor
treatment process in real-time. Till now, increasingly sophisticated
nanoparticles have been developed to combat cancer on the molecular
scale through careful engineering of nanomedicines.
Looking into the future, some considerations or directions require a
concerted effort for success for a pharmaceutical scientist in developing
nanoparticulate cancer therapeutics. The rst direction is the optimal
design of nanoparticles to be disease-specic. Because one tumor may
be different from another, the primary tumor is different from its metastasis, and even the same tumor can change from one day to the next, the
nanoparticles should be delicately designed on a case-by-case basis for
personalized treatment. This is indeed a formidable task to choose
specic nanocarrier or combinations which could lead to improved
therapeutic outcomes considering the highly heterogeneous and continuously evolving nature of the tumor microenvironment. The second
direction is the design of nanoparticles from the practical pharmaceutical point of view. The colloidal properties and the stability of nanoparticles, the time and cost on preparation of a formulation, whether the
materials used in the formulation could receive approval from regulatory authorities, whether the preparation methods could be transformed
into industrial processes etc. should be all taken into consideration
when beginning to design the nanoparticles. The third direction is to address toxicology concerns of nanoparticles. Although many kinds of
nanoparticles were employed as TDDS and showed great potential for
cancer treatment, the safety issue of those nanoparticles is scarcely addressed. The fourth direction is the introduction of new interdisciplinary
sciences such as computer science, analytical science, advanced instrumental techniques to develop suitable screening methodologies for determining optimal characteristics of nanocarriers, and to study the
mechanism of action and the fate of nanoparticles in vivo, thus to design
more intelligent TDDS. The last direction is to emerge new concepts
from interdisciplinary collaborations to design nanoparticles with multiple functions, more than those functions mentioned above.
Declaration of interest
The authors do not have any conicts of interest to declare.
Acknowledgment
This work was supported in part by the Fuzhou University Start-up
Fund No. 033084, Chinese National Science Foundation Grant (Nos.
81201709, 81102388 and 81273548), the National Science Foundation
for Fostering Talents in Basic Research of China (No. J1103303), and
the Science and Technology Development Foundation of Fuzhou University (2013-XQ-8 and 2013-XQ-9).
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JBA-06756; No of Pages 17

Biotechnology Advances xxx (2013) xxxxxx

Contents lists available at ScienceDirect

Research review paper

Nanotechnology-based intelligent drug design for cancer

Available online xxxx

dollars in spending have increased our understanding of the underlying

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

chemotherapy continue to be the therapeutic options for most cancers

nanoparticle platforms based on the difference in composition including

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

speaking, polymer-based nanomedicine can be categorized into three

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

Current stage of development

Approved in Europe and Canada

Approved in the USA

Refractory Kaposi's sarcoma, recurrent breast cancer,

Thomas and his co-workers used antibody-conjugated dendrimers to

single-walled carbon nanotubes (SWNTs, 0.42.0 nm in diameters,

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

characteristics of the antibodies will have great effects on the circulation

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

interaction between biotin and avidin or streptavidin, bioorthogonal

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

such as arginineglycineaspartic acid (RGD), asparagineglycine

3.2. Combination drug delivery approaches

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

hepatocellular carcinoma (Xu et al., 2010). Cationic liposomes were also

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

orthoester, imine, vinylether, phosphoramidate, and so on (Gao et al.,

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

smart nanoassembly which has the ability for self-dePEGylation. The

stimulus, leading to enhanced drug toxicity to tumor cells (Tang et al.,

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

This concept was rst applied to design a nanocell which overcomes

MRI, single photon emission computed tomography (SPECT), positron

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

have been developed for combined imaging and photothermal therapy

4. Conclusions and outlook

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

Cheng L, Yang K, Li Y, Chen J, Wang C, Shao M, et al. Facile preparation of multifunctional

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

Y. Gao et al. / Biotechnology Advances xxx (2013) xxxxxx

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