Nanotechnology-based intelligent drug design for cancer metastasis treatment.

JBA-06756; No of Pages 17 Biotechnology Advances xxx (2013) xxx–xxx

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-specific 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 specifically and safely reach tumor foci with enhanced efficacy 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 significantly 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: [email protected] (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), http://dx.doi.org/10.1016/j.biotechadv.2013.10.013

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

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-specific 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 (10−9) 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 specific 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 field of oncology, TDDS offers many potential benefits 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 profile 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 first 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 specific 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 first formulation approved for application in the clinic (Barenholz, 2012). With the aim to sitespecific delivery of cancer drugs to the cancerous tissues, the surface of liposomes can be modified with ligands or antibodies targeting those receptors overexpressed on cancer cell membranes (Gabizon et al., 2006). For tumor site-specific 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 modification 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, modified 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 efficient drug release in a controlled manner, which confirm 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 modification or surface functionalization. The last two characters are the utmost important criteria for their clinical use. Generally



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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 efficiency, fewer side effects, flexible 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 sitespecific 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 Förster, 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 modification (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 (1–15 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.


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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 floxuridine

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 specifically bound to the antigen-expressing cells in a dose-and time-dependent manner with affinity 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 beneficial 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 (4–9) and temperature (4 °C–60 °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 classified to two categories:

single-walled carbon nanotubes (SWNTs, 0.4–2.0 nm in diameters, 20–1000 nm in lengths) and multi-walled carbon nanotubes (MWNTs, 1.4–100 nm in diameters, ≥1 μm 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 efficacy 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 modification. 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 efficiency 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 μg/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 fluorescent 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 flux 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 efficiencies of magnetic nanoparticles. Among the MNPs, SPIOs with the diameter of 5–100 nm, which show high magnetization in an external magnetic field, 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 modification with functional groups through formation of stable gold-thiolate bonds (Au\S) by reacting with disulfide (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, specific 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 specifically and efficient intracellular drug release, including the conjugation of AuNPs with appropriate surface ligands (membrane-translocating peptides) or specific 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 modification with amphiphilic reagents (PEG). Though advances have been made in the research field 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 efficiency, 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 specifically 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-α (TNFα), 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 affinity and the configuration 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

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characteristics of the antibodies will have great effects on the circulation time, cellular uptake, tolerability, and efficacy 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 specificity while reducing nonspecific 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 modified 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 affinity and specificity. 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 flexibility, higher affinity and specificity, 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 efficiency, stability, and biodistribution profile (Kanwar et al., 2011). The chimeric aptamernanoparticle conjugates can bind to the target cells by the interaction of aptamer–receptor interaction, and finally enter into the target cells, resulting in release of the entrapped drugs (Estevez et al., 2010). In a study, branched PEI-PEG polyplexes modified with an anti-prostatespecific membrane antigens (PSMA) aptamer were used to co-deliver DOX and Bcl-xL-specific 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 specific 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 profile of the nanoparticles. Pre-targeting is a multi-step process that first 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 specifically 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 specifically target two model cancer cell lines, i.e., Ramos and Jurkat, respectively (Gunn et al., 2011). Besides using the


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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 specifically targeting to tumor tissue, tumor vasculature, specific cancer cells, or even cellular organelles (nucleus, cytoplasm, mitochondria). Pre-targeting is a multi-step process that first 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 efficient delivery of therapeutic agents to specific regions of the brain after penetrating the blood–brain 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 efflux 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 infiltrated glioma cells or the glioblastoma multiform after crossing the BBB, nanoparticles were modified 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-[Arg–Gly–Asp–d–Phe–Lys] (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-specific 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-modified nanoparticles. The improvement of cellular uptake of ligand-modified nanoparticles could be achieved through receptor-mediated endocytosis by tumor cells over-expressing corresponding receptors on the surface. However, whether ligand-modified 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 specific 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 significantly influences 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 arginine–glycine–aspartic acid (RGD), asparagine–glycine– 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 identified to specifically target tumor blood vessels or simultaneously recognize the tumor vasculature and cancer cells. Nanoparticles modified with peptides that targeting the tumor vasculature could enhance efficacy 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 specific cells of the tumor, but also been applied to deliver cargos to specific 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 efficiently 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 trafficking, and finally 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 trafficking of cationic nanoparticles including attachment of ligand for cell-specific 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 modification of a mitochondria-targeting triphenylphosphonium cation to liposome surfaces (Boddapati et al., 2008). The mitochondria-targeting liposomes could efficiently deliver the model drug to mitochondria to enhance its activity.

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3.2. Combination drug delivery approaches To achieve better treatment efficacy, 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 efficacy. 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 efficacy. 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 efficacy, 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 first-line chemotherapy for metastatic breast carcinoma produces a significant benefit in activity, but with a significant cost in hematologic toxicity (Bria et al., 2005). In phase III trial, combination of PTX and bevacizumab significantly 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) efficient internalization with the mechanism of endocytosis, (5) controlled pharmacokinetics of each drug, resulting in enhanced drug efficacy 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 significant 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 floxuridine (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 inflammatory 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-modified multifunctional lipoplexes as a therapeutic approach for human


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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(ε-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-α-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 antiinflammatory drug dexamethasone (DEX) (Krakovicova et al., 2009). In another study, DOX and gemcitabine were co-conjugated to the same HPMA polymer, which increased the efficacy 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 modified 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 efficacy 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 doxorubicin–paclitaxel and doxorubicin–rapamycin, 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 specificity 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 field, or electric field 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 efficacy of antitumor therapeutics (MacEwan et al., 2010). Among these environmentally-responsive nanoparticles, pHresponsive nanoparticulate DDSs have been widely studied in the field 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 5–6 (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 modified 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 efficacy in murine tumor models including non-small cell lung cancer (Griset et al., 2009) and mesothelioma (Colson et al., 2011). PEGpoly(β-amino ester) polymers have also been used to design for pH-responsive nanoparticles targeting the low pH present in the



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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 field, magnetic field, 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 6.4–6.8 to increase polymer solubility and induce a sharp micellization–demicellization transition for drug release (Shenoy et al., 2005; X.L. Wu et al., 2010). The micellization–demicellization 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 modified 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-specific 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 specific 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 efficacy (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-β-aminoester ketal-2) for efficient 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. Modification 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 efficient nuclear-targeted gene delivery. For favoring gene expression, pH labile linker was also employed to construct a


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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 efficiency 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 specificity 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 significant 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 specific 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 disulfide 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 efficiently release entrapped cargos (Saito et al., 2003). Gao et al. synthesized a linear cationic click polymer containing disulfide bonds via the “click chemistry”. The polymer could facilitate efficient gene delivery through releasing DNA efficiently by the cleavage of disulfide bonds under the reduction condition (Gao et al., 2011). The disulfide bond was also used to link poly(epsilon–caprolactone) 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 disulfide 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 beneficial for endosomal escape of micelles and enhanced gene transfection efficiency (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) fields 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 specifically 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 film formed by PNIPAm-based nanogels and ethyl cellulose. The entrapped drug molecules could transport across the film through heating the superparamagnetic nanoparticles to dissolve of the PNIPAm (Hoare et al., 2011). Inducing a local hyperthermia effect by the magnetic field at the level of the polymersome membrane could achieve triggered drug release from polymersomes encapsulate DOX together with superparamagnetic iron oxide nanoparticles (USPIO; γ-Fe2O3) (Oliveira et al., 2013). Similarly, ultrasound can be employed to trigger the release of DOX and other hydrophobic drugs from polymeric micelles at definite 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 field dual-stimulus for programmed drug delivery (Ge et al., 2012). Superparamagnetic maghemite (γ-Fe2O3) nanoparticles modified with poly (2-(dimethylamino)ethyl methacrylate) (pDMAEMA) which exhibit a pH- and temperature-dependent reversible agglomeration showed remarkable gene delivery efficiency in CHO-K1 cells (Majewski et al., 2012). A novel PEG and cRGD peptide modified 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 first 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 first 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 profile 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 trafficking efficiently 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 first stage) and the entrapped nanoparticles (the second stage) loaded with anticancer therapeutics (the third stage). The first 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 first-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, Au–DNA, 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 efficacy 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

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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 fluorescence 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 β-cyclodextrin (β-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 specific cellular uptake by FR positive cancer cells (Yang et al., 2010). Similarly, a multifunctional antibodyand fluorescence-labeled HuCC49ΔCH2-SPIO “nanotheranostics” was developed for combined targeted anticancer drug delivery and multimodel imaging of cancer cells (Zou et al., 2010). Cyclo(Arg–Gly– Asp–d–Phe–Cys) (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 acidmodified 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-modified gold nanorods (Huang et al., 2011), and matrix metalloproteinase sensitive gold nanorod (Yi et al., 2010)


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have been developed for combined imaging and photothermal therapy of cancer. Due to the well-established strategies for surface modification (ie, gold–thiol 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 modified with PEG, biotin, PTX and rhodamine B linked β-CD which could specifically interact with cancer cells by biotin and effectively release the entrapped PTX under the intracellular glutathione condition (Heo et al., 2012). Another gold nanoparticle modified with a PSMA RNA aptamer was developed for simultaneous CT imaging and prostate cancer therapy. The PSMA aptamer conjugation could significantly improve CT intensity and DOX efficacy 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 qualified 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/fluorescence 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 αvβ3 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 fluorescent molecules or QDs for fluorescence 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 significant 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 perfluoropentane (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 field 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 first direction is the optimal design of nanoparticles to be disease-specific. 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 specific 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 conflicts 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). Reference Agasti SS, Chompoosor A, You CC, Ghosh P, Kim CK, Rotello VM. Photoregulated release of caged anticancer drugs from gold nanoparticles. J Am Chem Soc 2009;131:5728–9. Al-Dosari MS, Gao X. Nonviral gene delivery: principle, limitations, and recent progress. AAPS J 2009;11:671–81.


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Intelligent system design for bionanorobots in drug delivery.

Approaches for optimal drug development and clinical trial design for breast cancer brain metastasis.

Immunogenomics: a foundation for intelligent immune design.

Structural DNA nanotechnology for intelligent drug delivery.

Intelligent design: combination therapy with oncolytic viruses.

Evolving TAVR, and the need for intelligent design.

Drug delivery system design and development for boron neutron capture therapy on cancer treatment.

Intelligent screening systems for cervical cancer.

Design characteristics for drug nebulizers.

Design, fabrication and evaluation of intelligent sulfone-selective polybenzimidazole nanofibers.

Treatment plan for breast cancer with sentinel node metastasis.

Treatment of brain metastasis from lung cancer.

Design of an intelligent sub-50 nm nuclear-targeting nanotheranostic system for imaging guided intranuclear radiosensitization.

Exosomes in development, metastasis and drug resistance of breast cancer.

Recommendations for the ethical use and design of artificial intelligent care providers.

Peptides and Peptidomimetics for Antimicrobial Drug Design.

Protein targets for structure-based drug design.

Improving data mining strategies for drug design.

TRPV1: A Target for Rational Drug Design.

Hyperbranched polymer drug delivery treatment for lung metastasis of salivary adenoid cystic carcinoma in nude mice.

Potential of targeted drug delivery system for the treatment of bone metastasis.

Drug Delivery Approaches for the Treatment of Cervical Cancer.

Mitochondria-targeted drug delivery system for cancer treatment.

Integrating Multiscale Modeling with Drug Effects for Cancer Treatment.