Nanoparticles for cancer gene therapy: Recent advances, challenges, and strategies

Siegel, 2016, Cancer statistics, 2016, CA Cancer J. Clin., 66, 7, 10.3322/caac.21332 Edwards, 2014, Annual report to the nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer, Cancer, 120, 1290, 10.1002/cncr.28509 DeSantis, 2014, Cancer treatment and survivorship statistics, 2014, CA. Cancer J. Clin., 64, 252, 10.3322/caac.21235 Dasari, 2014, Cisplatin in cancer therapy: molecular mechanisms of action, Eur. J. Pharmacol., 740, 364, 10.1016/j.ejphar.2014.07.025 Stubbe, 2013, Complementary strategies for the management of radiation therapy side effects, J. Adv. Pract. Oncol., 4, 219 Tabernero, 2013, First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement, Cancer Discov., 3, 406, 10.1158/2159-8290.CD-12-0429 Sheridan, 2011, Gene therapy finds its niche, Nat. Biotechnol., 29, 121, 10.1038/nbt.1769 Ginn, 2013, Gene therapy clinical trials worldwide to 2012-an update, J. Gene Med., 15, 65, 10.1002/jgm.2698 Heise, 1997, ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents, Nat. Med., 3, 639, 10.1038/nm0697-639 Pecot, 2011, RNA interference in the clinic: challenges and future directions, Nat. Rev. Cancer, 11, 59, 10.1038/nrc2966 Yin, 2014, Non-viral vectors for gene-based therapy, Nat. Rev. Genet., 15, 541, 10.1038/nrg3763 Wang, 2016, Iron-oxide-based nanovector for tumor targeted siRNA delivery in an orthotopic hepatocellular carcinoma xenograft mouse model, Small, 12, 477, 10.1002/smll.201501985 Wang, 2015, Nanoparticle-mediated target delivery of TRAIL as gene therapy for glioblastoma, Adv. Healthc. Mater., 4, 2719, 10.1002/adhm.201500563 Dahlman, 2014, In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight, Nat. Nano, 9, 648, 10.1038/nnano.2014.84 Leinonen, 2012, Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment, Cancer Res., 72, 6227, 10.1158/0008-5472.CAN-12-1166 Liu, 2016, Exogenous p53 and ASPP2 expression enhances rAdV-TK/GCV-induced death in hepatocellular carcinoma cells lacking functional p53, Oncotarget, 7, 18896, 10.18632/oncotarget.7749 Wang, 2011, HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector, Nanomedicine, 7, 193, 10.1016/j.nano.2010.08.003 Aboody, 2013, Neural stem cell-mediated enzyme-prodrug therapy for glioma: preclinical studies, Sci. Transl. Med., 5, 184ra159, 10.1126/scitranslmed.3005365 Mizrak, 2013, Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth, Mol. Ther., 21, 101, 10.1038/mt.2012.161 Kang, 2012, Human amniotic fluid-derived stem cells expressing cytosine deaminase and thymidine kinase inhibits the growth of breast cancer cells in cellular and xenograft mouse models, Cancer Gene Ther., 19, 412, 10.1038/cgt.2012.15 Huang, 2010, Target gene therapy of glioma: overexpression of BAX gene under the control of both tissue-specific promoter and hypoxia-inducible element, Acta Biochim. Biophys. Sin., 42, 274, 10.1093/abbs/gmq016 Li, 2001, Adenovirus-mediated bax overexpression for the induction of therapeutic apoptosis in prostate cancer, Cancer Res., 61, 186 Huh, 2001, Bax-induced apoptosis as a novel gene therapy approach for carcinoma of the cervix, Gynecol. Oncol., 83, 370, 10.1006/gyno.2001.6403 Perlstein, 2013, TRAIL conjugated to nanoparticles exhibits increased anti-tumor activities in glioma cells and glioma stem cells in vitro and in vivo, Neuro Oncol., 15, 29, 10.1093/neuonc/nos248 Miao, 2006, Adenovirus-mediated tBid overexpression results in therapeutic effects on p53-resistant hepatocellular carcinoma, Int. J. Cancer, 119, 1985, 10.1002/ijc.22040 Forner, 2012, Hepatocellular carcinoma, Lancet, 379, 1245, 10.1016/S0140-6736(11)61347-0 Freytag, 2002, Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer, Cancer Res., 62, 4968 Stribbling, 2000, Regressions of established breast carcinoma xenografts by carboxypeptidase G2 suicide gene therapy and the prodrug CMDA are due to a bystander effect, Hum. Gene Ther., 11, 285, 10.1089/10430340050016021 Wang, 2013, Treatment of glioblastoma multiforme using a combination of small interfering RNA targeting epidermal growth factor receptor and β-catenin, J. Gene Med., 15, 42, 10.1002/jgm.2693 Davis, 2010, Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles, Nature, 464, 1067, 10.1038/nature08956 Burnett, 2011, Current progress of siRNA/shRNA therapeutics in clinical trials, Biotechnol. J., 6, 1130, 10.1002/biot.201100054 Dias, 2002, Antisense oligonucleotides: basic concepts and mechanisms, Mol. Cancer Ther., 1, 347 Sharma, 2014, Antisense oligonucleotides: modifications and clinical trials, Med ChemComm, 5, 1454 Sun, 2014, Oligonucleotide aptamers: new tools for targeted cancer therapy, Mol. Ther. Nucleic Acids, 3, e182, 10.1038/mtna.2014.32 Jagat, 2015, Nucleic acid-based aptamers: applications, development and clinical trials, Curr. Med. Chem., 22, 2539, 10.2174/0929867322666150227144909 McNamara, 2006, Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras, Nat. Biotechnol., 24, 1005, 10.1038/nbt1223 Thiel, 2012, Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamers, Nucleic Acids Res., 40, 6319, 10.1093/nar/gks294 Bader, 2011, Developing therapeutic microRNAs for cancer, Gene Ther., 18, 1121, 10.1038/gt.2011.79 Price, 2014, MicroRNAs in cancer biology and therapy: current status and perspectives, Genes Dis., 1, 53, 10.1016/j.gendis.2014.06.004 Bouchie, 2013, First microRNA mimic enters clinic, Nat. Biotechnol., 31, 577, 10.1038/nbt0713-577 Rosenberg, 2015, Adoptive cell transfer as personalized immunotherapy for human cancer, Science, 348, 62, 10.1126/science.aaa4967 Stauss, 2013, Immunotherapy with gene-modified T cells: limiting side effects provides new challenges, Gene Ther., 20, 1029, 10.1038/gt.2013.34 Johnson, 2009, Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen, Blood, 114, 535, 10.1182/blood-2009-03-211714 Rapoport, 2015, NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma, Nat. Med., 21, 914, 10.1038/nm.3910 Morvan, 2016, NK cells and cancer: you can teach innate cells new tricks, Nat. Rev. Cancer, 16, 7, 10.1038/nrc.2015.5 Boissel, 2013, Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity, OncoImmunology, 2, e26527, 10.4161/onci.26527 Schirrmann, 2005, Specific targeting of CD33+ leukemia cells by a natural killer cell line modified with a chimeric receptor, Leuk. Res., 29, 301, 10.1016/j.leukres.2004.07.005 Chang, 2013, A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells, Cancer Res., 73, 1777, 10.1158/0008-5472.CAN-12-3558 Kruschinski, 2008, Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas, Proc. Natl. Acad. Sci. U. S. A., 105, 17481, 10.1073/pnas.0804788105 Nagashima, 1998, Whiteside TL: Stable transduction of the interleukin-2 gene into human natural killer cell lines and their phenotypic and functional characterization in vitro and in vivo, Blood, 91, 3850, 10.1182/blood.V91.10.3850 Somanchi, 2012, Engineering lymph node homing of ex vivo–expanded human natural killer cells via trogocytosis of the chemokine receptor CCR7, Blood, 119, 5164, 10.1182/blood-2011-11-389924 Jonuleit, 2001, A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection, Int. J. Cancer, 93, 243, 10.1002/ijc.1323 Shurin, 2010, Genetically modified dendritic cells in cancer immunotherapy: a better tomorrow, Expert Opin. Biol. Ther., 10, 1539, 10.1517/14712598.2010.526105 Kantoff, 2010, Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer, J. Clin. Oncol., 28, 1099, 10.1200/JCO.2009.25.0597 Emens, 2009, Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation, J. Clin. Oncol., 27, 5911, 10.1200/JCO.2009.23.3494 Odunsi, 2012, Efficacy of vaccination with recombinant vaccinia and fowlpox vectors expressing NY-ESO-1 antigen in ovarian cancer and melanoma patients, Proc. Natl. Acad. Sci. U. S. A., 109, 5797, 10.1073/pnas.1117208109 Klinman, 2006, Adjuvant activity of CpG oligodeoxynucleotides, Int. Rev. Immunol., 25, 135, 10.1080/08830180600743057 Rice, 2008, DNA vaccines: precision tools for activating effective immunity against cancer, Nat. Rev. Cancer, 8, 108, 10.1038/nrc2326 Elliott, 2013, Adjuvant breast cancer vaccine improves disease specific survival of breast cancer patients with depressed lymphocyte immunity, Surg. Oncol., 22, 172, 10.1016/j.suronc.2013.05.003 Nemunaitis, 2009, Phase II trial of Belagenpumatucel-L, a TGF-β2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients, Cancer Gene Ther., 16, 620, 10.1038/cgt.2009.15 Smith, 2010, K562/GM-CSF immunotherapy reduces tumor burden in chronic myeloid leukemia patients with residual disease on lmatinib mesylate, Clin. Cancer Res., 16, 338, 10.1158/1078-0432.CCR-09-2046 Lassi, 2010, Update on castrate-resistant prostate cancer: 2010, Curr. Opin. Oncol., 22, 263, 10.1097/CCO.0b013e3283380939 Iwamura, 2012, siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions, Gene Ther., 19, 959, 10.1038/gt.2011.185 Sioud, 2015, Immunosuppressive factor blockade in dendritic cells via siRNAs results in objective clinical responses, 269 Kotterman, 2015, Viral vectors for gene therapy: translational and clinical outlook, Annu. Rev. Biomed. Eng., 17, 63, 10.1146/annurev-bioeng-071813-104938 Amer, 2014, Gene therapy for cancer: present status and future perspective, Mol. Cell. Ther., 2, 27, 10.1186/2052-8426-2-27 Gabitzsch, 2011, An Ad5[E1-, E2b-]-HER2/neu vector induces immune responses and inhibits HER2/neu expressing tumor progression in Ad5 immune mice, Cancer Gene Ther., 18, 326, 10.1038/cgt.2010.82 Nayak, 2010, Progress and prospects: immune responses to viral vectors, Gene Ther., 17, 295, 10.1038/gt.2009.148 Thomas, 2003, Progress and problems with the use of viral vectors for gene therapy, Nat. Rev. Genet., 4, 346, 10.1038/nrg1066 Lamichhane, 2015, Exogenous DNA loading into extracellular vesicles via electroporation is size-dependent and enables limited gene delivery, Mol. Pharm., 12, 3650, 10.1021/acs.molpharmaceut.5b00364 Raposo, 2013, Extracellular vesicles: exosomes, microvesicles, and friends, J. Cell Biol., 200, 373, 10.1083/jcb.201211138 Ohno S-i Takanashi, 2013, Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells, Mol. Ther., 21, 185, 10.1038/mt.2012.180 Shtam, 2013, Exosomes are natural carriers of exogenous siRNA to human cells in vitro, Cell Commun. Signal., 11, 1, 10.1186/1478-811X-11-88 Kosaka, 2010, Secretory mechanisms and intercellular transfer of microRNAs in living cells, J. Biol. Chem., 285, 17442, 10.1074/jbc.M110.107821 Taylor, 2015, Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes, Methods, 87, 3, 10.1016/j.ymeth.2015.02.019 Forbes, 2010, Engineering the perfect (bacterial) cancer therapy, Nat. Rev. Cancer, 10, 785, 10.1038/nrc2934 Baban, 2010, Bacteria as vectors for gene therapy of cancer, Bioeng Bugs, 1, 385, 10.4161/bbug.1.6.13146 Ganai, 2009, Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice, Br. J. Cancer, 101, 1683, 10.1038/sj.bjc.6605403 Zhu, 2009, Therapeutic efficacy of Bifidobacterium longum-mediated human granulocyte colony-stimulating factor and/or endostatin combined with cyclophosphamide in mouse-transplanted tumors, Cancer Sci., 100, 1986, 10.1111/j.1349-7006.2009.01275.x Fest, 2009, Survivin minigene DNA vaccination is effective against neuroblastoma, Int. J. Cancer, 125, 104, 10.1002/ijc.24291 Cronin, 2010, Orally administered bifidobacteria as vehicles for delivery of agents to systemic tumors, Mol. Ther., 18, 1397, 10.1038/mt.2010.59 Reagan, 2011, Mesenchymal stem cell tumor-homing: detection methods in disease model systems, Stem Cells, 29, 920, 10.1002/stem.645 Chan, 2013, Human mesenchymal stem cells and their paracrine factors for the treatment of brain tumors, Cancer Gene Ther., 20, 539, 10.1038/cgt.2013.59 Shah, 2012, Mesenchymal stem cells engineered for cancer therapy, Adv. Drug Deliv. Rev., 64, 739, 10.1016/j.addr.2011.06.010 Wang, 2012, Neural stem cell-based dual suicide gene delivery for metastatic brain tumors, Cancer Gene Ther., 19, 796, 10.1038/cgt.2012.63 Jeong, 2011, Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy, Circ. Res., 108, 1340, 10.1161/CIRCRESAHA.110.239848 Wang, 2012, Nanoparticle delivery of cancer drugs, Annu. Rev. Med., 63, 185, 10.1146/annurev-med-040210-162544 Albanese, 2012, The effect of nanoparticle size, shape, and surface chemistry on biological systems, Annu. Rev. Biomed. Eng., 14, 1, 10.1146/annurev-bioeng-071811-150124 Akbarzadeh, 2013, Liposome: classification, preparation, and applications, Nanoscale Res. Lett., 8, 1, 10.1186/1556-276X-8-102 Schroeder, 2010, Lipid-based nanotherapeutics for siRNA delivery, J. Intern. Med., 267, 9, 10.1111/j.1365-2796.2009.02189.x Simberg, 2004, DOTAP (and other cationic lipids): chemistry, biophysics, and transfection, Crit. Rev. Ther. Drug Carrier Syst., 21, 257, 10.1615/CritRevTherDrugCarrierSyst.v21.i4.10 Zhang, 2010, DC-Chol/DOPE cationic liposomes: a comparative study of the influence factors on plasmid pDNA and siRNA gene delivery, Int. J. Pharm., 390, 198, 10.1016/j.ijpharm.2010.01.035 Kirtane, 2013, Polymer nanoparticles: weighing up gene delivery, Nat. Nano, 8, 805, 10.1038/nnano.2013.234 Wang, 2015, Convertine AJ. Polymer nanostructures synthesized by controlled living polymerization for tumor-targeted drug delivery, J. Control. Release, 219, 345, 10.1016/j.jconrel.2015.08.054 Look, 2015, Ligand-modified human serum albumin nanoparticles for enhanced gene delivery, Mol. Pharm., 12, 3202, 10.1021/acs.molpharmaceut.5b00153 Regier, 2012, Fabrication and characterization of DNA-loaded zein nanospheres, J. Nanobiotechnol., 10, 1, 10.1186/1477-3155-10-44 Koping-Hoggard, 2001, Chitosan as a nonviral gene delivery system: structure-property relationships and characteristics compared with polyethylenimine in vitro and after lung administration in vivo, Gene Ther., 8, 1108, 10.1038/sj.gt.3301492 Chen, 2012, Chitosan/siRNA nanoparticles encapsulated in PLGA nanofibers for siRNA delivery, ACS Nano, 6, 4835, 10.1021/nn300106t Nograles, 2012, Formation and characterization of pDNA-loaded alginate microspheres for oral administration in mice, J. Biosci. Bioeng., 113, 133, 10.1016/j.jbiosc.2011.10.003 Zhao, 2012, Alginate modified nanostructured calcium carbonate with enhanced delivery efficiency for gene and drug delivery, Mol. Biosyst., 8, 753, 10.1039/C1MB05337J Ganesh, 2013, Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors, Biomaterials, 34, 3489, 10.1016/j.biomaterials.2013.01.077 Patnaik, 2013, Novel polyethylenimine-derived nanoparticles for in vivo gene delivery, Expert Opin. Drug Deliv., 10, 215, 10.1517/17425247.2013.744964 Kadlecova, 2013, DNA delivery with hyperbranched polylysine: a comparative study with linear and dendritic polylysine, J. Control. Release, 169, 276, 10.1016/j.jconrel.2013.01.019 Wen, 2012, Serum tolerance and endosomal escape capacity of histidine-modified pDNA-loaded complexes based on polyamidoamine dendrimer derivatives, Biomaterials, 33, 8111, 10.1016/j.biomaterials.2012.07.032 Zhou, 2012, Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors, Biomaterials, 33, 583, 10.1016/j.biomaterials.2011.09.061 Liechty, 2010, Polymers for drug delivery systems, Annu. Rev. Chem. Biomol. Eng., 1, 149, 10.1146/annurev-chembioeng-073009-100847 Ramos-Perez, 2013, Modification of carbon nanotubes for gene delivery vectors, 261 Ding, 2014, Gold nanoparticles for nucleic acid delivery, Mol. Ther., 22, 1075, 10.1038/mt.2014.30 Olton, 2011, Intracellular trafficking pathways involved in the gene transfer of nano-structured calcium phosphate-DNA particles, Biomaterials, 32, 7662, 10.1016/j.biomaterials.2011.01.043 Probst, 2013, Quantum dots as a platform for nanoparticle drug delivery vehicle design, Adv. Drug Deliv. Rev., 65, 703, 10.1016/j.addr.2012.09.036 Du, 2013, Developing functionalized dendrimer-like silica nanoparticles with hierarchical pores as advanced delivery nanocarriers, Adv. Mater., 25, 5981, 10.1002/adma.201302189 Jain, 2012, Gold nanoparticles as novel agents for cancer therapy, Br. J. Radiol., 85, 101, 10.1259/bjr/59448833 Conde, 2012, Child H, Berry CC, Ibarra MR, Baptista PV, Tortiglione C, de la Fuente JM. Design of multifunctional gold nanoparticles for in vitro and in vivo gene silencing, ACS Nano, 6, 8316, 10.1021/nn3030223 Gupta, 2005, Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications, Biomaterials, 26, 3995, 10.1016/j.biomaterials.2004.10.012 Wang, 2015, 3D porous chitosan–alginate scaffolds as an in vitro model for evaluating nanoparticle-mediated tumor targeting and gene delivery to prostate cancer, Biomacromolecules, 16, 3362, 10.1021/acs.biomac.5b01032 Petros, 2010, Strategies in the design of nanoparticles for therapeutic applications, Nat. Rev. Drug Discov., 9, 615, 10.1038/nrd2591 Blanco, 2015, Principles of nanoparticle design for overcoming biological barriers to drug delivery, Nat. Biotechnol., 33, 941, 10.1038/nbt.3330 Chiou, 1994, Enhanced resistance to nuclease degradation of nucleic acids complexed to asialoglycoprotein-polylysine carriers, Nucleic Acids Res., 22, 5439, 10.1093/nar/22.24.5439 Kievit, 2011, Surface engineering of iron oxide nanoparticles for targeted cancer therapy, Acc. Chem. Res., 44, 853, 10.1021/ar2000277 Ladd, 2008, Zwitterionic polymers exhibiting high resistance to nonspecific protein adsorption from human serum and plasma, Biomacromolecules, 9, 1357, 10.1021/bm701301s Spill, 2016, Impact of the physical microenvironment on tumor progression and metastasis, Curr. Opin. Biotechnol., 40, 41, 10.1016/j.copbio.2016.02.007 Prabhakar, 2013, Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology, Cancer Res., 73, 2412, 10.1158/0008-5472.CAN-12-4561 Gilleron, 2013, Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape, Nat. Biotechnol., 31, 638, 10.1038/nbt.2612 Shima, 2014, The role of hydrophobicity in the disruption of erythrocyte membrane by nanoparticles composed of hydrophobically modified poly(gamma-glutamic acid), J. Biomater. Sci. Polym. Ed., 25, 203, 10.1080/09205063.2013.848328 Wittrup, 2015, Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown, Nat. Biotechnol., 33, 870, 10.1038/nbt.3298 Putnam, 2001, Polymer-based gene delivery with low cytotoxicity by a unique balance of side-chain termini, Proc. Natl. Acad. Sci. U. S. A., 98, 1200, 10.1073/pnas.98.3.1200 Copolovici, 2014, Cell-penetrating peptides: design, synthesis, and applications, ACS Nano, 8, 1972, 10.1021/nn4057269 Huang, 2013, Tumor targeting and microenvironment-responsive nanoparticles for gene delivery, Biomaterials, 34, 5294, 10.1016/j.biomaterials.2013.03.043 Cun, 2015, A novel strategy through combining iRGD peptide with tumor-microenvironment-responsive and multistage nanoparticles for deep tumor penetration, ACS Appl. Mater. Interfaces, 7, 27458, 10.1021/acsami.5b09391 Liu, 2015, Delivery of siRNA using CXCR4-targeted nanoparticles modulates tumor microenvironment and achieves a potent antitumor response in liver cancer, Mol. Ther., 23, 1772, 10.1038/mt.2015.147 Song, 2014, Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models, Clin. Cancer Res., 20, 6083, 10.1158/1078-0432.CCR-14-0493 Sasportas, 2009, Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy, Proc. Natl. Acad. Sci. U. S. A., 106, 4822, 10.1073/pnas.0806647106 Hu, 2014, Therapeutic efficacy of improved α-fetoprotein promoter-mediated tBid delivered by folate-PEI600-cyclodextrin nanopolymer vector in hepatocellular carcinoma, Exp. Cell Res., 324, 183, 10.1016/j.yexcr.2014.04.005 Huang, 2009, Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice, Cancer Res., 69, 6184, 10.1158/0008-5472.CAN-09-0061 Mak, 2014, Lost in translation: animal models and clinical trials in cancer treatment, Am. J. Transl. Res., 6, 114 Singh, 2012, Genetically engineered mouse models: closing the gap between preclinical data and trial outcomes, Cancer Res., 72, 2695, 10.1158/0008-5472.CAN-11-2786 Cekanova, 2014, Animal models and therapeutic molecular targets of cancer: utility and limitations, Drug Des. Dev. Ther., 8, 1911, 10.2147/DDDT.S49584 Yamada, 2007, Modeling tissue morphogenesis and cancer in 3D, Cell, 130, 601, 10.1016/j.cell.2007.08.006 Thoma, 2014, 3D cell culture systems modeling tumor growth determinants in cancer target discovery, Adv. Drug Deliv. Rev., 69–70, 29, 10.1016/j.addr.2014.03.001 Kelm, 2003, Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types, Biotechnol. Bioeng., 83, 173, 10.1002/bit.10655 Ong, 2010, Engineering a scaffold-free 3D tumor model for in vitro drug penetration studies, Biomaterials, 31, 1180, 10.1016/j.biomaterials.2009.10.049 Ivascu, 2006, Rapid generation of single-tumor spheroids for high-throughput cell function and toxicity analysis, J. Biomol. Screen., 11, 922, 10.1177/1087057106292763 Barrila, 2010, Organotypic 3D cell culture models: using the rotating wall vessel to study host-pathogen interactions, Nat. Rev. Microbiol., 8, 791, 10.1038/nrmicro2423 Girard, 2013, A 3D fibrous scaffold inducing tumoroids: a platform for anticancer drug development, PLoS One, 8, e75345, 10.1371/journal.pone.0075345 Härmä, 2010, A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses, PLoS One, 5, e10431, 10.1371/journal.pone.0010431 Jaganathan, 2014, Three-dimensional in vitro co-culture model of breast tumor using magnetic levitation, Sci. Rep., 4, 6468, 10.1038/srep06468 Florczyk, 2013, Porous chitosan-hyaluronic acid scaffolds as a mimic of glioblastoma microenvironment ECM, Biomaterials, 34, 10143, 10.1016/j.biomaterials.2013.09.034 Goodman, 2008, Pun SH. 3-D tissue culture systems for the evaluation and optimization of nanoparticle-based drug carriers, Bioconjugate Chem., 19, 1951, 10.1021/bc800233a Osswald, 2015, Three-dimensional tumor spheroids for in vitro analysis of bacteria as gene delivery vectors in tumor therapy, Microb. Cell Fact., 14, 1, 10.1186/s12934-015-0383-5 Sapet, 2013, 3D-fection: cell transfection within 3D scaffolds and hydrogels, Ther. Deliv., 4, 673, 10.4155/tde.13.36 Wong, 2011, Paclitaxel tumor-priming enhances siRNA delivery and transfection in 3-dimensional tumor cultures, Mol. Pharm., 8, 833, 10.1021/mp1004383 Ho, 2012, Penetration of endothelial cell coated multicellular tumor spheroids by iron oxide nanoparticles, Theranostics, 2, 66, 10.7150/thno.3568 Zhang, 2010, Gene delivery in three-dimensional cell cultures by superparamagnetic nanoparticles, ACS Nano, 4, 4733, 10.1021/nn9018812 Vauthier, 2011, Processing and scale-up of polymeric nanoparticles, 433 Pratik, 2012, Nanoparticles in the pharmaceutical industry and the use of supercritical fluid technologies for nanoparticle production, Curr. Drug Deliv., 9, 269, 10.2174/156720112800389052