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Tumor-Targeting Multifunctional Nanoparticles for siRNA Delivery: Recent Advances in Cancer Therapy Sook Hee Ku, Kwangmeyung Kim, Kuiwon Choi, Sun Hwa Kim,* and Ick Chan Kwon*

worldwide and is characterized by genetic or epigenetic alterations, leading to uncontrolled cell proliferation. Thus, downregulation of specific genes, which are associated to cancer progress, has been considered as a loss-of-function strategy for cancer therapy.[5] Among various RNAi-based therapeutics, for example, siRNA, small hairpin RNA (shRNA), and micro RNA (miRNA), siRNA is the most commonly used form. This small double-stranded RNA, consisting of 21–23 base pairs, acts regardless to the location of target proteins compared with antibody or tyrosine kinase inhibitors, which react with surface antigens or tyrosine kinase protein. Further, siRNA does not lead to genome modification, thereby considering as safer therapeutics. However, the clinical applications of siRNA have been still limited. Naked siRNA exhibits potentials for the stimulation of the innate immune responses and the susceptibility to enzymatic degradation. To solve these problems, various chemical modification strategies of siRNA have been developed: 1) replacement of backbone phosphate group to phosphothioate or boranophosphate linkage, 2) modification of 2′-hydroxyl group of the pentose sugar, and 3) 4′-thio-RNA modification.[6,7] Despite these efforts, gene therapy using siRNA is still hampered by the lack of targeting ability to be delivered into the desired region and the low intracellular translocation efficiency due to anionic charge and high molecular weight (−15 kDa) of siRNA.[8] To overcome these drawbacks, the development of efficient siRNA delivery systems is critically required. Recently, nanoparticles have received a great attention as a gene delivery vector due to the highly tunable features.[9,10] Nanocarrier should be designed to protect siRNA from serum nucleases, to deliver the therapeutic siRNA to desired tissue, and to translocate into cytoplasmic region of target cells. Here, we focus to the development of nanoscaled siRNA delivery system for cancer therapy (Figure 1). First, the principles of tumor-targeting strategies using nanoparticles are overviewed. Second, we summarize a variety of siRNA delivery nanoplatforms, including polymer nanocomplexes, lipid-based nanomaterials, gold nanoparticles, magnetic nanoparticles, mesoporous silica nanoparticles, and carbon nanomaterials. Finally, the recent advances on multifunctional nanocarriers for theranostics and combinatorial therapy are highlighted.

RNA interference (RNAi) is a naturally occurring regulatory process that controls posttranscriptional gene expression. Small interfering RNA (siRNA), a common form of RNAi-based therapeutics, offers new opportunities for cancer therapy via silencing specific genes, which are associated to cancer progress. However, clinical applications of RNAi-based therapy are still limited due to the easy degradation of siRNA during body circulation and the difficulty in the delivery of siRNA to desired tissues and cells. Thus, there have been many efforts to develop efficient siRNA delivery systems, which protect siRNA from serum nucleases and deliver siRNA to the intracellular region of target cells. Here, the recent advances in siRNA nanocarriers, which possess tumor-targeting ability are reviewed; various nanoparticle systems and their antitumor effects are summarized. The development of multifunctional nanocarriers for theranostics or combinatorial therapy is also discussed.

1. Introduction RNA interference (RNAi) is a highly effective regulatory pathway, which controls posttranscriptional gene expression.[1] The endogenous small double-stranded RNA is responsible for RNAi mechanism by interaction to target mRNA with sequence homology. RNAi process can be activated exogenously by introducing synthetic small interfering RNA (siRNA).[2] In cytoplasm, siRNA is incorporated into RNA-induced silencing complex (RISC) and removes sense strand.[3] The activated RISC recognizes target mRNA in a sequence-specific manner and degrades the mRNA.[4] Since RNAi phenomenon was first discovered in 1998,[1] therapeutic potentials of RNAi have been extensively investigated for genetic disorders, viral infections, autoimmune disease, and cancer. Among various diseases, cancer has been received a great attention in RNAi-based therapeutic applications because it is a leading cause of death

Dr. S. H. Ku, Dr. K. Kim, Dr. K. Choi, Dr. S. H. Kim, Dr. I. C. Kwon Center for Theragnosis, Biomedical Research Institute Korea Institute of Science and Technology (KIST) Seoul 136–791, Republic of Korea E-mail: [email protected]; [email protected] Dr. I. C. Kwon KU-KIST Graduate School of Converging Science and Technology Korea University Seoul 136–701, Republic of Korea

DOI: 10.1002/adhm.201300607

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Dr. Sun Hwa Kim is a senior research scientist at the center for theragnosis in KIST. She received her Ph.D. in 2007 from the Department of Biological Science at KAIST under supervision of Prof. Tae Gwan Park. Her main research interests include biomaterialsbased drug delivery, siRNA therapy, and stem cell delivery.

Figure 1. Schematic illustration of multifunctional nanoparticles for cancer therapy.

2. Tumor-Targeting Strategies 2.1. Passive Targeting Tumor-targeting strategies are categorized to passive and active targeting (Figure 2A). Passive targeting exploits the defective vascular architecture of tumor tissue. Due to rapid and defective angiogenesis, tumor has fenestrated blood vessels resulting in the extravasation of nanoparticles into tumor interstitium (Figure 2A).[11] Moreover, inefficient lymphatic drainage of tumor enhances the retention of nanoparticles in interstitial space. This provokes “enhanced permeability and retention (EPR) effects,” discovered by Maeda et al.[12] It is generally accepted that nanoparticles in the size range of 10–500 nm are highly permeable to endothelial pores in tumor vessels.[13] Body circulation time of nanoparticles is a significant factor, which influences the nanoparticle accumulation in tumor.[14] For longer circulation, physicochemical properties of nanomaterials are significantly concerned. The ideal size of nanoparticles is considered in the range of 20–200 nm, because nanoparticles smaller than 20 nm are eliminated by renal clearance and large nanoparticles (>200 nm) are detected by immune system. Positively charged nanoparticles are also recognized and eliminated by immune system; thus, neutral or negative surface charge is required for longer circulation. The surface of nanoparticles should be modified to avoid the capture by reticulo-endothelial system (RES). PEGylation is one of the widely used methods to provide the stealth properties to nanocarriers. Nevertheless, passive targeting strategies still have some limitations. The extravasation of nanoparticles relays on the degree of tumor vascularization and the pore size.[15] Thus, the reach of nanoparticles to tumor site varies with tumor types and heterogeneity. High interstitial fluid pressure (IFP) is other barrier for the tumor-targeted delivery. IFP is higher at the center of tumor tissue than the periphery, leading to mass flow movement of fluid away from the central region of tumor.[16] Whereas small

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Dr. Sook Hee Ku is a postdoctoral fellow at the center for theragnosis in Korea Institute of Science and Technology (KIST). She received her Ph.D. in 2013 from the Department of Materials Science and Engineering at Korea Advanced Institute of Science and Technology (KAIST). Her research interests include nanocarriers for gene delivery and cell-nanomaterial interactions.

Dr. Ick Chan Kwon is a principal research scientist of the center for theragnosis in KIST. He is also a professor of KU-KIST Graduate School in Korea University. He received his Ph.D. in pharmaceutics and pharmaceutical chemistry from the University of Utah in 1993. His research interests include targeted drug delivery with polymeric nanoparticles and the development of smart nanoplatforms for theragnosis.

molecules are easily diffused, large nanoparticles less affected this enhanced IFP.

2.2. Active Targeting Active targeting strategy generally means the specific ligandreceptor-mediated interactions between nanoparticles and target cells (Figure 2A). For tumor targeting, cancer cells or tumoral endothelial cells are considered as target cells.[17] When the ligands interact to the receptors on the tumor cell surface, the active targeting strategies enhance the cellular uptake of

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Figure 2. A) Schematic illustration of tumor-targeting strategies (passive and active targeting). B) Common targeting agents such as antibody, protein, peptide, vitamin, and aptamer.

nanoparticles, rather than accumulation in the tumor site. In contrast, targeting tumoral endothelium inhibits the growth of tumor blood vessel, thereby suppressing tumor growth indirectly. To effectively deliver nanoparticles to specific tumor site, the ligand-receptor pairs should be chosen as follows: 1) target receptors should be overexpressed on cancer cells or tumor vasculature, rather than normal cells; 2) receptors should be homogenously expressed on all target cells. The targeting ligands are categorized to antibodies and non-antibody ligands (Figure 2B). Antibodies can be used as their native form or as fragments. The advantages of whole antibodies come from two binding sites within a single molecule and their stability during long-term storage. However, Fc domain of antibody can bind to the Fc receptors on normal cells, leading to immunogenicity. Thus, antibody fragments, such as antigen-binding fragments (Fab) and single-chain fragment variables (scFv), have been considered safer, attributing to the reduced nonspecific binding.[18] The widely used antibodies include anti-epidermal growth factor receptor (EGFR) on cancer cells and anti-vascular endothelial growth factor (VEGF) and anti-VEGF receptor (VEGFR) in tumoral endothelium. Non-antibody ligands include proteins, peptides, vitamins, and aptamers. The famous ligand-receptor pairs for tumor targeting are as follows: transferrin–transferrin receptor, folic acid–folate receptor, RGD (Arg-Gly-Asp)-αvβ3 integrin, and A10 aptamer-prostate-specific membrane antigen (PSMA). The receptor for transferrin, which is a vital protein involved in iron homeostasis, is significantly overexpressed in malignant cells compared with normal cells.[19] The expression of folate receptor-α or -β is upregulated on 40% of human cancers or malignant cells of hematopoietic origin, respectively.[20] Thus, targeting these receptors using their ligands or antibodies enhances the intracellular translocation of nanocarriers. The level αvβ3 integrin is elevated in both tumor cells and neovascular endothelial cells.[21] For targeting αvβ3 integrin, cyclic or linear derivatives of RGD peptides are widely used. More recently, aptamers have been intensively investigated as promising ligands for tumor targeting. Aptamers are single-stranded DNA or RNA oligonucleotides and bind to a wide variety of

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targets, including intracellular proteins, transmembrane proteins, soluble proteins, carbohydrates, and small molecules.[22] As representative aptamer-ligands pairs for cancer cell targeting, both A10 against PSMA[23] and AS-1411 against nucleolin[24] have been suggested.

3. Tumor-Targeting Nanoparticles for siRNA Delivery 3.1. Polymer-Based Nanoparticles Polymer-based nanomaterials have been extensively studied as siRNA delivery systems. In general, polymer-based siRNA delivery system involves cationic moieties, which can easily form a complex with negatively charged siRNA via electrostatic interactions. The properties of polymer/siRNA complexes, such as size, surface charge, and structure, can be modulated by regulating the ratio of positive charge in polymer to negative charge in siRNA. Among various cationic polymers, synthetic polymers, including polyethylenimine (PEI), poly-L-lysine (PLL), cyclodextrin-based polycations, and natural polymers, such as chitosan and atelocollagen, have been used as siRNA delivery carriers. PEI has been considered as a gold standard of gene delivery carrier due to its high transfection efficacy. PEI forms polyelectrolyte complex with siRNA through charge–charge interactions, resulting in the protection of siRNA from serum nucleases. Attributing to many protonable amine groups, PEI exhibits “proton sponge effect,” to allow the endosomal escape of polyplex. However, it shows severe cytotoxicity, which is dependent on molecular weight and the number of branches.[25,26] To avoid toxicity issues, low-molecular-weight PEI has been used. Urban-Klein reported that commercial low-molecular-weight PEI (JetPEI)/siRNA complexes were selectively delivered to tumor sites after intraperitoneal injection. The silence of HER2 gene by JetPEI/siRNA complexes significantly inhibited tumor growth.[27] Introduction of poly(ethylene glycol) (PEG) into PEI/ siRNA complexes is an alternative method for reducing the cytotoxicity of PEI. Kim et al. developed PEI/PEG-conjugated siRNA

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REVIEW Figure 3. Polymer-based siRNA delivery system. Schematic illustration, tumor accumulation, and antitumor effects on tumor growth of A) PEI/PEGconjugated siRNA complexes, B) cyclodextrin-based polymer nanoparticles, and C) thiolated glycol chitosan/polymeric siRNA nanocomplexes. Reproduced with permission: A)[28] Copyright 2008, Elservier; B)[33] Copyright 2010, Nature Publishing Group; C)[35] Copyright 2012, Wiley-VCH.

polyelectrolyte complexes (Figure 3A). The PEGylated polyplexes containing VEGF siRNA were accumulated in tumor regions, and knockdown of VEGF suppressed microvessel formation, thereby inhibiting tumor growth.[28] These tumor-homing effects may attribute to EPR effects. To increase targeting ability, active targeting moieties have been conjugated to PEI. RGDconjugated PEG–PEI successfully incorporated siRNA, resulting in nanoscaled complexes. RGD peptide enhanced the nanocomplex accumulation in tumor site after intravenous administration. The delivered siRNA against VEGFR inhibited the tumor neovascularization.[29] Cyclodextrin is one of cyclic oligosaccharides, which composed of five or more α-D-glucopyranoside units. Due to the lack of immune stimulation and the low toxicity, cyclodextrin has been used in pharmaceutical applications.[30] Davis et al. developed cyclodextrin-based polymers, which were assembled into nanoparticles via interactions with nucleic acids. Cyclodextrin within the polymer chain was displayed on the surface of the nanoparticles, and interaction between cyclodextrin and adamantine was used to functionalize the nanoparticle with stabilizing agent (PEG) and targeting moiety (transferrin) (Figure 3B). The developed nanoparticles were successfully delivered to tumor tissue by EPR effects, and transferrin enhanced the cellular uptake of nanocarriers.[31] In vivo antitumor effects of cyclodextrin-based siRNA delivery system was demonstrated by bioluminescence imaging of metastatic Ewing's sarcoma model.[32] Furthermore, cyclodextrin-based polymer nanocomplexes were applied to human melanoma patients, and the intracellular localization of nanoparticles were observed.[33] The nanoparticles exhibited increased genesilencing efficacy, indicated at mRNA and protein levels. Chitosan also has been widely used for siRNA delivery due to their biocompatibility and biodegradability. Huh et al.[34] showed that the polyplexes, composed of 5β-cholanic acid-modified

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glycol chitosan, 5β-cholanic acid-modified PEI, and siRNA, were specifically delivered to tumor sites and silenced the target gene expression after systemic administration. Self-assembled nanoparticles were developed through hydrophobic interactions of 5β-cholanic acid and charge–charge interactions between polycations and siRNA. Recently, thiolated glycol chitosan were reported as a tumor-homing carrier for polymerized siRNA (Figure 3C).[35] Thiol modification of glycol chitosan resulted in the formation of stable nanoparticles via electrostatic interaction and chemical cross-linking. Furthermore, the nanocomplexes liberated the intact siRNA under cytoplasmic reduction environment. To improve tumor-targeting ability, chitosan nanoparticles were modified with active targeting moieties such as antibody and peptide. For example, mPEG-chitosan nanoparticles, covalently bonded with anti-HER2, exhibited higher cellular uptake of siRNA with negligible cytotoxicity.[36] RGD peptide was also used for targeted delivery to αvβ3 integrin-positive tumor endothelial cells. RGD-labeled chitosan nanoparticles were delivered into endothelial cells in the tumor vasculature, whereas unmodified nanoparticles were not localized in tumor endothelium.[37] Delivery of therapeutic siRNA against PLXDC1 resulted in the increased apoptotic cell death of endothelial cells in the tumor vasculature, thereby inhibition of tumor growth inhibition.

3.2. Lipid-Based Nanoparticles Lipid-based nanostructures have been broadly used for in vivo siRNA delivery. Up to now, various lipid-based systems have been reported including liposomes, micelles, emulsions, and solid lipid nanoparticles. The physicochemical properties of lipid-based nanoparticles, such as structure, size, surface charge, may be optimized by lipid composition, drug-to-lipid

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ratio, and manufacturing process. Generally, cationic lipids have been used as siRNA delivery carriers because they easily associate with negatively charged nucleic acids. Here, we review the development of liposomes and solid lipid nanoparticles for tumor-targeted siRNA delivery. Liposomes, composed of cationic lipids DOTAP (1,2-dioleoyl-3-trimethylammoniumpropane) and DOPE (1,2-dioleoyl3-phosphatidylethanolamine) and ScFv against transferrin receptor, were constructed for siRNA delivery to tumor site. The developed liposomes were specifically accumulated in both primary and metastatic tumors after systemic administration.[38] Incorporation of pH-sensitive histidine–lysine peptide further improved cellular uptake and cytoplasmic delivery. The immunoliposome containing therapeutic siRNA, such as antiHER-2 siRNA, induced cancer cell death and inhibited tumor growth in pancreatic cancer model.[39] Huang groups developed DOTAP/cholesterol/DSPE-PEG liposomes for siRNA delivery (Figure 4A). Anisamide, a ligand for sigma receptor, improved the accumulation of the liposomes in both xenograft and metastatic tumor.[40,41] Tumor-targeting GC4 scFv also enhanced the cancer cell uptake in vitro and in vivo.[42] The liposomes containing multiple genes, c-Myc, VEGF, and MDM2, exhibited significant antitumor effects.[41,42] Recently, solid lipid nanoparticles (SLN) have been utilized for siRNA delivery due to their superior stability in body. Kim et al. showed that SLN, prepared by self-assembly of lipid portions of low-density lipoprotein, DOPE, and DC-cholesterol, loaded siRNA via electrostatic interactions between positively

charged SLN surface and siRNA. The complexes exhibited high gene-silencing efficacy.[43] The siRNA release profile from SLN can be modified by varying the amount of oil phase into the solid-lipid matrix; thus, tailoring of intracellular siRNA kinetics is achievable.[44] Solid lipid-PEI hybrid nanocarrier exhibited the sustained intracellular release of siRNA, and folate labeling allowed the reduction in nonspecific uptake (Figure 4B). After systemic delivery of survivin siRNA using solid lipid-PEI hybrid nanocarriers, expression of survivin gene was significantly suppressed, thereby reducing tumor volume.[45]

3.3. Gold Nanoparticles

Gold nanoparticles (AuNPs) have received great interests in biomedical applications such as biosensing, drug/gene delivery, and hydrothermal cancer therapy, due to their biocompatibility, simple synthesis, and easy conjugation of bioactive molecules. For siRNA loading, AuNP can be directly conjugated siRNA via gold-thiol chemistry. Conde et al.[46] functionalized AuNPs with siRNA as a therapeutic agent and RGD peptide for cancer targeting. The developed AuNPs were delivered to lung cancer by intratracheal instillation, and silencing c-myc gene led to the inhibition of tumor cell proliferation and tumor size reduction. Furthermore, scFv targeting EGFR, transferrin, and PSMA targeting aptamer have been used to provide the cancer cell targeting ability to AuNPs;[47–49] the addition of targeting agents resulted in the enhanced tumor accumulation of AuNPs or the intracellular translocation efficacy. Modification of AuNPs with polycations also allows siRNA loading via electrostatic interactions. For example, PEI-capped AuNPs successfully bound to siRNA and enhanced the transfection efficiency compared with PEI/siRNA complexes.[50] AuNPmediated delivery of siRNA against Plk-1 caused apoptosis of cancer cells. Cationic dendrimer-modified AuNPs incorporated siRNA through charge–charge interactions, and the generation of dendrimer influenced on the siRNA binding.[51] Layer-by-layer method has been also applied to incorporate siRNA to AuNPs through alternating deposition of polycations, e.g., PEI, PLL, and siRNA molecules on the surface of AuNPs.[52,53] The developed AuNP systems enabled the gradual release of siRNA and higher gene-silencing efficacy. Moreover, the unique property of AuNPs due to the strong surface plasmon resonance absorption can be utilized for the selective siRNA release. Lu et al.[54] demonstrated that siRNA-conjugated AuNPs liberated siRNA when they were exposure to near infrared (NIR) laser, and this property was termed as “photothermal transfection” (Figure 5A). Figure 4. Lipid-based siRNA delivery system. Schematic illustration, biodistribution/cellular uptake, and tumor growth inhibition of A) liposomes and B) solid lipid-PEI hybrid nano- The siRNA release upon NIR exposure may particles. Reproduced with permission: A)[40] Copyright 2007, Nature Publishing Group; B)[45] attribute to the local temperature elevation after absorption of NIR light by AuNPs. Copyright 2011, American Chemical Society.

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Magnetic nanoparticles can be used to enhance the cellular uptake efficacy via magnetic guidance. Considering that magnetic nanoclusters showed the enhanced magnetic properties compared with single magnetic nanoparticles, the formation of nanocluster using polymers has been investigated. Park et al.[59] developed the cross-linked magnetic nanocluster using chemically modified PEI, which easily incorporated siRNA through charge–charge interactions. The developed magnetic nanoclusters exhibited high transfection efficiency under external magnetic field, followed by the improved gene silencing (Figure 5B). The magnetic nanoclusters containing siRNA exhibited the potentials as both gene-silencing agents and MR imaging agents with high T2 relaxivity.[60] Development of polymeric shell on the surface of magnetic nanoparticles allowed binding active targeting moieties. Manganese oxide nanoparticles, which modified with PEI, incorporated siRNA via electrostatic Figure 5. siRNA delivery system using gold nanoparticles and magnetic nanoparticles. A) Sche- interactions, and bound to monoclonal antimatic illustration of photothermal release of siRNA from gold nanoparticles. B) Schematic body (Herceptin) through covalent bonding. illustration of magnetofection using magnetic nanocluster under external magnetic field. The cellular uptake and target gene silencing were observed only in HER2-positive cell lines.[61] Lee et al.[62] modified manganese-doped iron oxide Further modification of AuNPs with folate facilitated the tumortargeted delivery of AuNPs after systemic delivery, and NIR nanoparticles with serum albumin, and further decorated irradiation increased the antitumor effects of NF-κB p65 knockthe nanoparticles with siRNA and RGD peptide via cleavable disulfide bonds. The developed nanoparticles were translocated down. More recently, it was reported that pH-responsive charge into the αvβ3-expressing cancer cell lines. Chlorotoxin, which reversible polymers facilitated endosomal escape of the AuNPs and released free siRNA in cytoplasmic region.[55,56] targets the MMP-II receptor on the cancer cell membrane, has also been applied as active targeting molecules. Veiseh et al.[63,64] reported that chlorotoxin-bound magnetic nanovector increased the efficacy of both cellular uptake and gene 3.4. Magnetic Nanoparticles silencing. The blood–brain barrier (BBB) crossing ability of the developed nanomaterials enabled the applications to simultaMagnetic nanoparticles, including iron oxide nanoparticles neous imaging and therapy of brain tumor.[65] and manganese oxide nanoparticles, have been widely used as magnetic resonance (MR) imaging agents due to their superparamagnetic properties and biocompatibility; thus, the incorporation of siRNA into magnetic nanoparticles allows 3.5. Mesoporous Silica Nanoparticles the development of multifunctional nanoplatforms, which enable simultaneous molecular imaging and gene therapy. Mesoporous silica nanoparticles (MSNs) have been extensively Magnetic nanoparticles for siRNA delivery were prepared by studied as anti-cancer nanomedicine due to their unique polymeric decoration, followed by attachment of siRNA via properties, such as uniform mesoporosity, high surface area covalent bonds. For example, polyarginine-coated iron oxide and large pore volume, facile surface functionalization, bionanoparticles exhibited highly efficient gene silencing with compatibility, and biodegradability.[66] To enhance the siRNA less cytotoxicity to several cancel cell lines.[57] Medarova et al.[58] loading efficiency and the cellular uptake efficacy of MSNs, the surface or inner pore of MSN was coated with cationic constructed multifunctional magnetic nanoparticles, consisting polymer. PEI-coated MSN showed highly improved intracelof iron oxide nanoparticles for MR imaging, Cy5.5 dye for NIR lular translocation and gene-silencing effects.[67] Similarly, fluorescence imaging, myristoylated polyarginine peptides as a membrane translocation module, and survivin siRNA as a poly(2-dimethylaminoethyl methacrylate)-coated MSN suctherapeutic gene. According to the MR imaging and NIR fluocessfully delivered the siRNA in tumor site after intravenous rescence imaging, the selective accumulation of the nanopartiinjection. Downregulation of the Plk-1 expression inhibited cles in tumor tissue was demonstrated. Knocking down of the tumor growth.[68] Li et al. loaded siRNA in the inner pore of expression of survivin, a member of the inhibitor of apoptosis MSNs and then coated the surface of nanoparticles with catiprotein (IAP) family, led to the increase in tumor-associated onic polymer PEI and fusogenic peptide KALA. Delivery of levels of apoptosis. siRNA against VEGF inhibited the expression of VEGF pro-

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to incorporate negatively charged siRNA. PEI is one of the most widely used polymers for surface functionalization of CNTs. Covalent bonding of PEI to CNTs allowed easy binding of siRNA to CNTs through electrostatic interactions and enabled to deliver siRNA to tumor cells.[72–74] PEI-modified CNTs exhibited higher gene-silencing effects with lower cytotoxicity compared with PEI. Amino-functionalized CNTs were also associated with siRNA, and delivery of therapeutic siRNA showed antitumor effects in vivo.[75,76] Delivery of siRNA targeting telomerase reverse transcriptase or Plk-1 using aminofunctionalized CNTs silenced the expression of target gene, and suppressed tumor growth after intratumoral injection (Figure 6B). Similar to CNTs, graphene and its derivatives have also been considered as gene delivery vectors. Chemically functionalized graphene oxide with PEI and PEG incorporated siRNA, and delivery of siRNA against Stat3 to tumor site via intratumoral injection resulted in the suppressed malignant melanoma growth.[77] Active targeting moiety can be conjugated to graphene oxide via covaFigure 6. siRNA delivery system using mesoporous silica nanoparticle and carbon nanotube. lent linkage. Yang et al.[78] showed that folic Schematic illustration and antitumor effects of A) siRNA (siVEGF)-loaded mesoporous silica acid conjugation enhanced both the cellular nanoparticles and B) siRNA (siTOX)-loaded, amine-functionalized carbon nanotubes. Reprouptake and gene-silencing efficiency of graduced with permission: A)[70] Copyright 2012, Wiley-VCH; B)[76] Copyright 2009, Wiley-VCH. phene oxide/siRNA nanocarriers. Graphene derivatives possess the unique photothermal effects, which enable the controlled gene delivery. Kim group[79] tein and tumor angiogenesis, thereby leading to the suppression of tumor growth.[69] reported that PEG-BPEI-rGO/plasmid DNA nanocomplexes deliver the pDNA to intracellular regions via photothermally MSNs containing ultra-large pores allowed the enhanced triggered endosomal escape. adsorption of siRNA in the inner pores. Na et al.[70] developed According to the biodistribution studies, carbon-based nanoMSNs with large pores, whose sizes are approximately 23 nm. materials were accumulated tumor tissue via EPR effects. The highly enhanced siRNA loading capacity was observed in PEGylated CNTs exhibited long blood circulation times and the MSNs with large pores compared with conventional MSNs low uptake by RES. RGD peptide conjugation allowed the effiwith small pores (2–3 nm). Intratumoral injection of MSNs cient targeting of αvβ3 integrin positive tumor in mice.[80] EGF containing siRNA targeting VEGF resulted in the downregulation of VEGF mRNA level, and the inhibition of blood vessel labeling for EGFR targeting also enhanced the accumulation growth and tumor growth (Figure 6A). Recently, the developof CNTs in tumor region.[81] Yang et al.[82] reported that nanog[ 71 ] ment of MSN-supported lipid bilayers was reported. siRNAraphene oxide was delivered to tumor tissue after intravenous administration. Taken together, carbon nanomaterials may be loaded MSNs were further modified with lipid bilayer, targeting accumulated in tumor site via EPR effects, and conjugation of peptide (SP94), which binds to hepatocellular carcinomas, and active targeting agents can further enhance the tumor-targeting endosomolytic peptide (H5WYG), which promotes endosomal/ effects. lysosomal escape. siRNAs against cyclin superfamily, which involved in the regulation of both cell cycle traverse and cell viability, silenced the target gene expression, resulting in the induced apoptosis of hepatocellular carcinomas, Hep3B. 4. Tumor-Targeting Multifunctional Nanoparticles 3.6. Carbon-Based Nanomaterials

4.1. Dual-Modal Nanoparticles for Simultaneous Molecular Imaging and siRNA Delivery

Carbon-based nanomaterials include 0D fullerenes, 1D carbon nanotubes (CNTs), and 2D graphene sheets. Among various derivatives of carbon-based nanomaterials, functionalized CNTs and graphene oxides have been used as gene delivery vectors. CNTs were modified with cationic polymers or small molecules

Association of molecular imaging with siRNA delivery allows real-time assessment of the therapeutic process. Thus, noninvasive imaging of biodistribution and pharmacokinetics of delivery vectors provide information for designing safe and efficient delivery systems. Several noninvasive imaging methods,

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PET/CT also allowed noninvasive monitoring of nanocarriers, and 64Cu has been used as a PET/CT imaging agent. In the previous report, 64Cu was attached to cyclodextrin-containing polycation/siRNA nanocomplexes, and the biodistribution of the nanoparticles was investigated.[31] According to PET imaging, the modification of nanoparticles with targeting agent, transferrin, did not affect to intratumoral localization, but improved cellular uptake. In contrast, Lu et al.[54] showed that folic acid-modified gold nanoparticles containing siRNA were more effectively accumulated in tumor tissue via PET/CT imaging (after modification with 64Cu). 124I-labeling also enabled in vivo biodistribution analysis of micelleplexes via PET/ CT imaging.[85] Recently, NIR fluorescence has been broadly used for molecular imaging, because light at NIR wavelength exhibits deep penetration in tissue, in contrast to visible light. Various NIR fluorescence dyes including Cy5.5, FPR-675, and Vivo-Tag 750, have been used to enable tracking siRNA delivery system due to its easy conjugation to polymers. Li et al.[84] monitored temporal location of polymeric nanoparticles containing siRNA and prodrug-activating enzyme. Similarly, Cy5.5-conjugated siRNA in glycol chitosan/PEI polyplexes and FPR-675-labeled poly(siRNA)/thiolated glycol chitosan nanocomplexes were monitored via real-time NIRF imaging.[34,35]

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such as MR imaging, PET/CT, or NIR fluorescence imaging, can be applied to monitoring of nanomaterials. Iron oxide nanoparticle-based siRNA carriers enable to monitor their location in body via MR imaging due to their superparamagnetism. Medarova et al.[58] developed multifunctional nanoparticles containing iron oxide nanoparticles, Cy5.5, siRNA, and membrane translocation moiety (Figure 7A). This multifunctional nanoparticle allowed dual-modal imaging, both MR imaging and NIR fluorescence imaging; thus, the accumulation of nanoparticles in tumor site after systemic delivery was demonstrated by both methods. Survivin siRNA on the nanoparticle surface finally participated in RNAi mechanism, thereby increasing apoptosis and necrosis of tumor cells. Tumor-specific targeting agent facilitated the specific delivery of iron oxide nanoparticles to tumor tissue.[65,83] Chlorotoxinlabeled nanoparticles and folic acid-conjugated nanoparticles were developed, and the accumulation of nanoparticles in tumor sites was observed by MR imaging. An alternative method for providing MRI capability to gene nanovectors is the assessment of Gd3+, one of FDA-approved T1-weighted MR contrast agents. Intratumoral delivery of Gd3+-labeled PEI/siRNA/ prodrug-activating enzyme complexes was visualized via MRI, and combinational treatment of siRNA against chk and prodrug enzyme resulted in the delay of tumor growth (Figure 7B).[84]

Figure 7. Multifunctional nanoparticles for simultaneous molecular imaging and siRNA delivery. A) Schematic illustration of magnetic nanoparticles, containing NIR dye, siRNA, and membrane translocation peptide; tumoral accumulation demonstrated by MR imaging and NIR fluorescence imaging; and therapeutic effects of siRNA against survivin. B) Schematic illustration of polymeric nanoparticles, containing Gd3+, NIR dye, siRNA, and prodrugactivating enzyme; biodistribution investigated by NIR fluorescence imaging; and antitumor effects of the nanoparticles. Reproduced with permission: A)[58] Copyright 2007, Nature Publishing Group; B)[84] Copyright 2010, American Chemical Society.

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4.2. Combinatorial Cancer Therapy 4.2.1. Concomitant Treatment of Gene and Chemotherapeutics In the past several years, synergic effects of siRNA and traditional anticancer drug have been investigated. One of the most extensively studied combinations is siRNA against P-glycoprotein (Pgp) drug exporter and doxorubicin (Dox). Although chemotherapy is the most effective cancer treatment, cancer cells exhibited the resistance to several structurally unrelated drugs, termed as multidrug resistance (MDR). To overcome MDR, downregulation of drug exporter expression has been investigated. For example, Meng et al.[86,87] developed mesoporous silica nanoparticles, which incorporated both Dox in the inner pores of nanoparticles and siRNA on the positively functionalized surface (Figure 8A). The resultant nanoparticle system effectively downregulated the expression of Pgp and increased intranuclear Dox concentration in drug-resistant cancer cell line. Therefore, the co-delivery of siRNA and Dox led to the significantly reduced tumor growth after intravenously injection to xenograft model.[87] Liposomes, PEI/PLGA polymeric nanoparticles, and cyclodextrin-modified quantum dots were also used as vectors for co-delivery of siPgp and Dox.[88–90]

Bcl-2 family proteins such as Bcl-2, Bcl-xL, and Mcl-1 play a critical role in the regulation of apoptosis, and these anti-apoptotic proteins are overexpressed in cancer. Furthermore, previous studies reported that high-level expression of Bcl-2 and Bcl-xL is associated with drug resistance. Thus, concomitant treatments of siRNA against Bcl-2 family and anticancer drugs have been tried to improve anticancer effects. Zheng et al.[91] showed that PEG-PLL-PLLeu triblock copolymer entrapped docetaxel (DTX) in the hydrophobic core and siRNA in cationic backbone. Co-treatment of siBcl-2 and DTX significantly inhibited the tumor growth and improved the survival rate. Codelivery of siBcl-2 and Dox was also widely investigated using mesoporous silica nanoparticles, PEG-PGA polymers, PEGPCL copolymers,[92–94] and targeting moiety such as folic acid increased cellular uptake and gene-silencing efficacy of nanoparticle systems.[93] Polo-like kinase 1 (Plk-1) is associated mitosis, and inhibition of Plk-1 may lead to “mitotic catastrophe” and apoptosis. Combination of siRNA targeting Plk-1 and chemical drugs might prolong G2/M phase arrest, thereby undergoing apoptosis rather than mitotic slippage. Polymeric micelles containing both siPlk-1 and paclitaxel successfully accumulated in tumor sites via EPR effects, and they exhibited better

Figure 8. Combinatorial cancer therapy. A) Co-delivery of siRNA and anti-cancer drug (doxorubicin). B) Co-delivery of multiple siRNA using multimeric siRNA system. Reproduced with permission: A)[87] Copyright 2013, American Chemical Society; B)[99] Copyright 2011, Elservier.

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4.2.2. Co-Delivery of Multiple Gene Therapeutics Recently, combinatorial effects of multiple siRNA on cancer therapy have been investigated to improve antitumor effects by attacking multiple oncogene pathways. Song et al.[97] demonstrated that the combination of siRNAs targeting MDM2, c-myc, and VEGF, which are associated with p53 inactivation, cell proliferation, and angiogenesis/metastasis, respectively, resulted in the greatest anti-proliferation effects in gp160-B16 cells. Delivery of three siRNA by using cationic liposomes exhibited successful gene-silencing and inhibitory effects on lung metastasis model.[41,42] Mok et al.[98] developed multimeric siRNA containing cleavable disulfide bonds. This multimeric siRNA can be utilized as a new platform for co-delivery of various siRNAs (Figure 8B). siRNAs against survivin and Bcl-2 were selected because upregulated Blc-2 and survivin genes in cancer cells block the apoptotic pathways. Dual gene-targeted multimeric siRNA systems led to more HeLa cell death compared with single gene-targeted multimeric siRNA against survivin or Blc-2 each, or their mixture.[99] Co-delivery of Mcl-1 and Ribosomal protein S6 kinase (RPS6KA5) siRNA significantly inhibited tumor growth in both drug-sensitive and -resistant breast cancer model.[100]

4.2.3. Simultaneous Photothermal and Gene Therapy As depicted above, several nanoplatforms such as gold nanomaterials or carbon-based nanomaterials possess their unique photothermal properties, and this effect allows controllable gene release upon NIR irradiation. Recently, PEI-grafted graphene/ gold composites were proposed to play a role as both siRNA delivery vector and photothermal agent.[101] siRNA against Bcl-2 was loaded to the graphene/gold nanocomposites and downregulated the target gene expression. Under NIR laser irradiation, the temperature of the tumor tissue containing nanocomposite solution was elevated, and the viability of tumor cells incubated with the nanocomposites under NIR was decreased. Synergic effects of RNAi and photothermal cancer therapy in vivo also reported.[102] CNTs were conjugated with cationic PEI for siRNA incorporation and NGR peptide for tumor targeting. According to the report, siRNA delivery or photothermal therapy alone somewhat suppressed the tumor growth. However, combination of siRNA treatment and NIR irradiation exhibited the best anticancer effects. These studies showed that combinatorial treatment of gene and photothermal treatment has a potential for cancer therapy.

5. Conclusion and Perspectives Nanoparticles have been successfully demonstrated as efficient siRNA delivery carriers for cancer therapy. Nanomaterials tend to be accumulated in tumor tissue by extravasation through

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leaky tumor vasculature. The addition of active targeting molecules, such as antibodies and non-antibody ligands (protein, peptide, vitamin, aptamer), enhanced the tumor-targeting efficacy or the transfection efficiency to tumor cells. However, tumor-targeting delivery of siRNA using nanoparticles still has many limitations. Current strategies rely on EPR effects; but the degree of vascularization varies on tumor types. Moreover, understanding the spatial and temporal heterogeneity of tumor and diffusional barriers in solid tumor such as high IFP is critically required. The selection of ligands is also important; the target receptor should be overexpressed on the surface of cancer cells, not on the surface of normal cells. Recently, multifunctional nanoparticles have been investigated for simultaneous molecular imaging and gene therapy or for co-delivery of multiple therapeutic agents. These approaches may improve the efficacy of RNAi-based cancer therapy. Before the clinical applications of multifunctional nanoparticles, the toxicity issue should be addressed. Optimization of physicochemical properties of nanoparticles, such as size, structure, and surface properties, is required to minimize toxic effects. Although unresolved issues and challenges are remained, nanomedicine will be promising candidates for molecular diagnostics, gene therapy, and personalized medicine.

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therapeutic effects compared with single treatment of siPlk-1 or paclitaxel.[95] Vitamin E TPGS was also proposed to co-deliver siPlk-1 and docetaxel with targeting molecule, Herceptin.[96]

Acknowledgements This work was supported by Global Research Laboratory Project (NRF2013K1A1A2032346) and GiRC Project (2012K1A1A2A01055811) of MSIP, Korea Health Technology R&D Project of Ministry of Health & Welfare (A110879), and Intramural Research Program (Global RNAi Carrier Initiative) of KIST.

Received: November 4, 2013 Revised: January 20, 2014 Published online: February 28, 2014

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Tumor-targeting multifunctional nanoparticles for siRNA delivery: recent advances in cancer therapy.

RNA interference (RNAi) is a naturally occurring regulatory process that controls posttranscriptional gene expression. Small interfering RNA (siRNA), ...
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