Abstract
The promise of RNA interference (RNAi) technology in cancer therapeutics aims to deliver small interfering RNA (siRNA) for silencing of gene expression in cell type-specific pathway. However, the challenge for the delivery of stable siRNA is hindered by an immune-hostile tumor microenvironment and physiological barriers of the circulatory system. Therefore, the development and validation of safe, stable, and efficient nanoengineered delivery systems are highly essential for effective delivery of siRNA into cancer cells. This review focuses on gene-silencing mechanisms, challenges to siRNA delivery, design and delivery of nanocarrier systems, ongoing clinical trials, and translational prospects for siRNA-mediated cancer therapeutics.
Similar content being viewed by others
References
Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Caner J Clin. 2016;66:7–30.
Bhargava A, Bunkar N, Khare NK, et al. Nanoengineered strategies to optimize dendritic cells for gastrointestinal tumor immunotherapy: from biology to translational medicine. Nanomedicine (Lond). 2014;9:2187–202.
Neith C, Lage H. Induction of the ABC-transporters Mdr1/P-gp (Abcb1), mrpl (Abcc1), and bcrp (Abcg2) during establishment of multidrug resistance following exposure to mitoxantrone. J Chemother. 2005;17:215–23.
Szakacs G, Paterson JK, Ludwig JA, et al. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–34.
Gillet JP, Gottesman MM. Mechanisms of multidrug resistance in cancer. Methods Mol Biol. 2010;596:47–76.
Harris AL, Hochhauser D. Mechanisms of multidrug resistance in cancer treatment. Acta Oncol. 1992;31:205–13.
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP dependent transporters. Nat Rev Cancer. 2002;2:48–58.
Bhargava A, Mishra D, Banerjee S, et al. Dendritic cell engineering for tumor immunotherapy: from biology to clinical translation. Immunotherapy. 2012;4:703–18.
Huang A, Zhang X, Zhou SL, et al. Detecting circulating tumor DNA in hepatocellular carcinoma patients using droplet digital PCR is feasible and reflects intratumoral heterogeneity. J Cancer. 2016;13:1907–14.
Gavrilov K, Saltzman WM. Therapeutic siRNA: principles, challenges, and strategies. Yale J Biol Med. 2012;85:187–200.
Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009;8:129–38.
Fire A, SQ X, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–11.
CF X, Wang J. Delivery systems for siRNA drug development in cancer therapy. Asian. J Pharm Sci. 2015;10:1–12.
Lares MR, Rossi JJ, Ouellet DL. RNAi and small interfering RNAs in human disease therapeutic applications. Trends Biotechnol. 2010;28:570–9.
Burnett JC, Rossi JJ. RNA-based therapeutics: current progress and future prospects. Chem Biol. 2012;19:60–71.
Hannon GJ. RNA interference. Nature. 2002;418:244–51.
Wilda M, Fuchs U, Wossmann W, et al. Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene. 2002;21:5716–24.
Marnoor SA, Shelke SS. Targeted delivery and development of thereapeutic siRNA: a review. Int J Res Pharm Biomed Sci. 2013;4:1313–7.
Lee JM, Yoon TJ, Cho YS. Recent developments in nanoparticles based siRNA delivery for cancer therapy. Biomed Res Int. 2013:782041.
Dominska M, Dykxhoorn DM. Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci. 2010;123:1183–9.
Williford JM, Wu J, Ren Y, et al. Recent advances in nanoparticle-mediated siRNA delivery. Annu Rev Biomed Eng. 2014;16:347–70.
Tang G. siRNA and miRNA: an insight into RISCs. Trends Biochem Sci. 2005;30:106–14.
Grimm D. Small silencing RNAs: state of the art. Adv Drug Deliv Rev. 2009;61:672–703.
McManus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs. Nat Rev Genet. 2002;3:737–47.
Wang J, Lu Z, Wientjes MG, JLS A. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 2010;12:492–503.
Fattal E, Bochot A. Ocular delivery of nucleic acids: antisense oligonucleotides, aptamers and siRNA. Adv Drug Deliv Rev. 2006;58:1203–23.
Thomas M, JJ L, Chen J, Klibanov AM. Non-viral siRNA delivery to the lung. Adv Drug Deliv Rev. 2007;59:124–33.
Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.
Perez-Martinez FC, Guerra J, Posadas I, Cena V. Barriers to non-viral vector-mediated gene delivery in the nervous system. Pharm Res. 2011;28:1843–58.
Jang SH, Wientjes MG, Lu D, Au JL. Drug delivery and transport to solid tumors. Pharm Res. 2003;20:1337–50.
Au JLS, Jang SH, Zheng J, Chen CT, Song S, Hu L, et al. Determinants of drug delivery and transport to solid tumors. J Control Rel. 2007;74:31–46.
Greish K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target. 2007;15:457–64.
Danquah MK, Zhang XA, Mahato RI. Extravasation of polymeric nanomedicines across tumor vasculature. Adv Drug Deliv Rev. 2011;63:623–39.
Mukherjee S, Ghosh RN, Maxfield FR. Endocytosis. Physiol Rev. 1997;77:759–803.
Goula D, Becker N, Lemkine GF, Normandie P, Rodrigues J, Mantero S, et al. Rapid crossing of the pulmonary endothelial barrier by polyethylenimine/DNA complexes. Gene Ther. 2000;7:499–504.
Schroeder A, Levins CG, Cortez C, Langer R, Anderson DG. Lipid-based nanotherapeutics for siRNA delivery. J Intern Med. 2010;267:9–21.
Endoh T, Ohtsuki T. Cellular siRNA delivery using cell penetrating peptides modified for endosomal escape. Adv Drug Deliv Rev. 2009;61:704–9.
Cho YW, Kim JD, Park K. Polycation gene delivery systems: escape from endosomes to cytosol. J Pharm Pharmacol. 2003;55:721–34.
Varkouhi AK, Scholte M, Storm G, Haisma HJ. Endosomal escape pathways for delivery of biologicals. J Control Rel. 2011;151:220–8.
Kariko K, Bhuyan P, Capodici J, et al. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol. 2004;172:6545–9.
Marques JT, Williams BR. Activation of the mammalian immune system by siRNAs. Nat Biotechnol. 2005;23:1399–405.
Judge AD, Sood V, Shaw JR, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005;23:457–62.
Miele E, Spinelli GP, Miele E, et al. Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy. Int J Nanomedicine. 2012;7:3637–57.
Cun D, Jensen LB, Nielsen HM, et al. Polymeric nanocarriers for siRNA delivery: challenges and future prospects. J Biomed Nanotech. 2008;4:258–75.
Harborth J, Elbashir SM, Vandenburgh K, Manninga H, Scaringe SA, Weber K, et al. Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucleic Acid Drug Dev. 2003;13:83–105.
Takasaki S, Kotani S, Konagaya A. Selecting effective siRNA target sequences for mammalian genes. RNA Biol. 2005;2:21–7.
Taxman DJ, Livingstone LR, Zhang J, Conti BJ, Iocca HA, Williams KL, et al. Criteria for effective design, construction, and gene knockdown by shRNA vectors. BMC Biotechnol. 2006;6:7.
Fakhr E, Zare F, Teimoori-Toolabi L. Precise and efficient siRNA design: a key point in competent gene silencing. Cancer Gene Ther. 2016;23:73–82.
Elbashir SM, Harborth J, Weber K, Tuschl T. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods. 2002;26:199–213.
Tafer H, Ameres SL, Obernosterer G, Gebeshuber CA, Schroeder R, Martinez J, et al. The impact of target site accessibility on the design of effective siRNAs. Nat Biotechnol. 2008;26:578–83.
Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002;296:550–3.
Miyagishi M, Taira K. U6 promoter–driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat Biotechnol. 2002;20:497–500.
Song E, Lee S-K, Wang J, Ince N, Ouyang N, Min J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med. 2003;9:347–51.
Kim YJ. Computational siRNA design considering alternative splicing. Methods Mol Biol. 2010;623:81–92.
Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A. Rational siRNA design for RNA interference. Nat Biotechnol. 2004;22:326–30.
Ui-Tei K, Naito Y, Takahashi F, Haraguchi T, Ohki-Hamazaki H, Juni A, et al. Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference. Nucleic Acids Res. 2004;32:936–48.
Amarzguioui M, Prydz H. An algorithm for selection of functional siRNA sequences. Biochem Biophys Res Commun. 2004;316:1050–8.
Dubey P, Gopinath P. Nanocarriers for AKT siRNA based gene therapy. Austin J. Biotechnol Bioeng. 2016;3:1061–3.
YK O, Park TG. siRNA delivery systems for cancer treatment. Adv Drug Deliv Rev. 2009;61:850–62.
Juliano R, Alam MR, Dixit V, et al. Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res. 2008;36:4158–71.
Romberg B, Hennink WE, Storm G. Sheddable coatings for long-circulating nanoparticles. Pharm Res. 2008;25:55–71.
Kanasty R, Dorkin JR, Vegas A, et al. Delivery materials for siRNA therapeutics. Nat Mater. 2013;12:967–77.
Mishra P, Nayak B, Dey RK. PEGylation in anti-cancer therapy: an overview. Asian. J Pharm Sci. 2016;11:337–48.
Li J, Wang Y, Xue S, et al. Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different anticancer drugs. Int J Nanomedicine. 2016;11:4609–24.
Uchida E, Mizuguchi H, Ishii-Watabe A, Hayakawa T. Comparison of the efficiency and safety of non-viral vector-mediated gene transfer into a wide range of human cells. Biol Pharm Bull. 2002;25:891–7.
Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4:145–60.
Gomes-da-Silva LC, Fonseca NA, Moura V, et al. Lipid-based nanoparticles for siRNA delivery in cancer therapy: paradigms and challenges. Acc Chem Res. 2012;45:1163–71.
Adler-Moore J, Proffitt RT. AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. J Antimicrob Chemother. 2002;49:21–30.
Elouahabi A, Ruysschaert JM. Formation and intracellular trafficking of lipoplexes and polyplexes. Molecular Ther. 2005;11:336–47.
Fenske DB, Cullis PR. Liposomal nanomedicines. Exp Opin Drug Del. 2008;5:25–44.
SY W, McMillan NAJ. Lipidic systems for in vivo siRNA delivery. AAPS J. 2009;11:639–52.
Tseng YC, Mozumdar S, Huang L. Lipid-based systemic delivery of siRNA. Adv Drug Deliv Rev. 2009;61:721–31.
Jeong JH, Park TG, Kim SH. Self-assembled and nanostructured siRNA delivery systems. Pharm Res. 2011;28:2072–85.
Balazs DA, Godbey W. Liposomes for use in gene delivery. J Drug Deliv. 2011;326497
Santel A, Aleku M, Keil O, et al. RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy. GeneTher. 2006a;13:1360–70.
Santel A, Aleku M, Keil O, et al. A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium. GeneTher. 2006b;13:1222–34.
Uner M, Yener G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int J Nanomedicine. 2007;2:289–300.
Morrissey DV, Lockridge JA, Shaw L, et al. Potent andpersistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol. 2005;23:1002–7.
Jin J, Bae KH, Yang H, et al. In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticles. Bioconjug Chem. 2011;22:2568–72.
Shen H, Sun T, Ferrari M. Nanovector delivery of siRNA for cancer therapy. Cancer Gene Ther. 2012;19:367–73.
Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discov Today. 2003;8:1112–20.
Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nature Rev Drug Discovery. 2004;3:1023–35.
Davis ME. Design and development of IT-101, a cyclodextrin-containing polymer conjugate of camptothecin. Adv Drug Deliv Rev. 2009;61:1189–92.
Kang JH, Tachibana Y, Kamata W, et al. Liver targeted siRNA delivery by polyethylenimine (PEI)-pullulan carrier. Bioorg Med Chem. 2010;18:3946–50.
Hobel S, Koburger I, John M, et al. Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab. J Gene Med. 2010;12:287–300.
Yuan X, Naguib SWZ. Recent advances of siRNA delivery by nanoparticles. Expert Opin Drug Del. 2011;8:521–36.
Howard KA, Rahbek UL, Liu X, et al. RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticles system. MolecularTher. 2006;14:476–84.
Liu X, Howard KA, Dong M, et al. The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing. Biomaterials. 2007;28:1280–8.
Jean M, Smaoui F, Lavertu M, et al. Chitosan-plasmid nanoparticle formulations for IM and SC delivery of recombinant FGF-2 and PDGF-BB or generation of antibodies. Gene Ther. 2009;16:1097–110.
Singh M, Briones M, Ott G, et al. Cationic microparticles: a potent delivery system for DNA vaccines. Proc Natl Acad Sci. 2000;97:811–6.
Luu YK, Kim K, Hsiao BS, et al. Development of a nanostructured DNA delivery scaffold via electrospinning of PLGA and PLAePEG block copolymers. J Control Rel. 2003;89:341–53.
Sun TM, JZ D, Yan LF, et al. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery. Biomaterials. 2008;29:4348–55.
Mao CQ, JZ D, Sun TM, et al. A biodegradable amphiphilic and cationic triblock copolymer for the delivery of siRNA targeting the acid ceramidase gene for cancer therapy. Biomaterials. 2011;32:3124–33.
Cheng YY, ZH X, Ma ML, Xu TW. Dendrimers as drug carriers: applications in different routes of drug administration. J Pharm Sci. 2008;97:123–43.
Esfand R, Tomalia DA. Poly (amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. Drug Discov Today. 2001;6:427–36.
Pantarotto D, Singh R, McCarthy D, et al. Functionalized carbon nanotubes for plasmid DNA gene delivery. Angew Chem. 2004;43:5242–6.
Cai D, Mataraza JM, Qin ZH, et al. Highly efficient molecular delivery into mammalian cells using carbon nanotube spearing. Nat Methods. 2005;2:449–54.
Peng XH, Qian X, Mao H, et al. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy. Int J Nanomedicine. 2008;3:311–21.
Yu Y, Sun D. Superparamagnetic iron oxide nanoparticles theranostics for multimodality tumor imaging, gene delivery, targeted drug and prodrug delivery. Expert Rev Clin Pharmacol. 2010;3:117–30.
Derfus AM, Chen AA, Min DH, Ruoslahti E, Bhatia SN. Targeted quantum dot conjugates for siRNA delivery. Bioconjug Chem. 2007;18:1391–6.
Tan WB, Jiang S, Zhang Y. Quantum-dot based nanoparticles for targeted silencing of HER2/neu gene via RNA interference. Biomaterials. 2007;28:1565–71.
Yezhelyev MV, Qi L, O’Regan RM, Nie S, Gao X. Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging. J Am Chem Soc. 2008;130:9006–12.
Smith AM, Duan H, Mohs AM, Nie S. Bioconjugated quantum dots for in vivo molecular and cellular imaging. Adv Drug Del Rev. 2008;60:1226–40.
Rosi NL, Giljohann DA, Thaxton CS, et al. Oligonucleotide-modified gold nanoparticles for infracellular gene regulation. Science. 2006;312:1027–30.
Ghosh P, Han G, De M, Kim CK, Rotello VM. Gold nanoparticles in delivery applications. Adv Drug Del Rev. 2008;60:1307–15.
Kong WH, Bae KH, Jo SD, Kim JS, Park TG. Cationic lipid-coated gold nanoparticles as efficient and noncytotoxic intracellular siRNA delivery vehicles. Pharm Res. 2012;29:362–74.
Jeong JH, Mok H, YK O, et al. siRNA conjugate delivery systems. Bioconjug Chem. 2008;20:5–14.
Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 2004;432:173–8.
Chiu YL, Ali A, Chu C, et al. Visualizing a correlation between siRNA localization, cellular uptake, and RNAi in living cells. Chem Biol. 2004;11:1165–75.
Moschos SA, Jones SW, Perry MM, et al. Lung delivery studies using siRNA conjugated to TAT (48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug Chem. 2007;18:1450–9.
Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.
Simpson RJ, Lim JWE, Moritz RL, et al. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009;6:267–83.
Bhargava A, Mishra D, Banerjee S, et al. Engineered dendritic cells for gastrointestinal tumor immunotherapy: opportunities in translational research. J Drug Target. 2013;21:126–36.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Mishra, D.K., Balekar, N. & Mishra, P.K. Nanoengineered strategies for siRNA delivery: from target assessment to cancer therapeutic efficacy. Drug Deliv. and Transl. Res. 7, 346–358 (2017). https://doi.org/10.1007/s13346-016-0352-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13346-016-0352-5