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Current Transport Systems and Clinical Applications for Small Interfering RNA (siRNA) Drugs

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Abstract

Small interfering RNAs (siRNAs) are an attractive new agent with potential as a therapeutic tool because of its ability to inhibit specific genes for many conditions, including viral infections and cancers. However, despite this potential, many challenges remain, including off-target effects, difficulties with delivery, immune responses, and toxicity. Traditional genetic vectors do not guarantee that siRNAs will silence genes in vivo. Rational design strategies, such as chemical modification, viral vectors, and non-viral vectors, including cationic liposomes, polymers, nanocarriers, and bioconjugated siRNAs, provide important opportunities to overcome these challenges. We summarize the results of research into vector delivery of siRNAs as a therapeutic agent from their design to clinical trials in ophthalmic diseases, cancers, respiratory diseases, and liver virus infections. Finally, we discuss the current state of siRNA delivery methods and the need for greater understanding of the requirements.

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References

  1. Sontheimer RWC, Erik J. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136:642.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet. 2006;15(1):R17–29.

    Article  PubMed  CAS  Google Scholar 

  3. Monaghan M, Pandit A. RNA interference therapy via functionalized scaffolds. Adv Drug Deliv Rev. 2011;63:197–208.

    Article  PubMed  CAS  Google Scholar 

  4. Daka A, Dan P. RNAi-based nanomedicines for targeted personalized therapy. Adv Drug Deliv Rev. 2012;64:1508–21.

    Article  PubMed  CAS  Google Scholar 

  5. Agrawal N, Dasaradhi PVN, Mohmmed A, Malhotra P, Bhatnagar RK, Mukherjee SK. RNA interference: biology, mechanism, and applications. Microbiol Mol Biol Rev Membr. 2003;67:657.

    Article  CAS  Google Scholar 

  6. Vance V, Vaucheret H. RNA silencing in plants-defense and counterdefense. Science. 2001;292:2277–80.

    Article  PubMed  CAS  Google Scholar 

  7. Liu J, Carmell MA, Rivas FV, et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science. 2004;305:1437–41.

    Article  PubMed  CAS  Google Scholar 

  8. Li H, Li WX, Ding SW. Induction and suppression of RNA silencing by an animal virus. Science. 2002;296:1319.

    Article  PubMed  CAS  Google Scholar 

  9. Sijen T, Fleenor J, Simmer F, et al. On the role of RNA amplification in dsRNA-triggered gene silencing. Cell. 2001;107:465–76.

    Article  PubMed  CAS  Google Scholar 

  10. Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001;409:363–6.

    Article  PubMed  CAS  Google Scholar 

  11. Lam JKW, Chow MYT, Yu Z, Leung SWS. siRNA versus miRNA as therapeutics for gene silencing. Mol Ther Nucleic Acids. 2015;4:e252.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Gantier MP, Williams BR. The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev. 2007;18:363.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Barik S. Silence of the transcripts: RNA interference in medicine. J Mol Med. 2005;83:764.

    Article  PubMed  CAS  Google Scholar 

  14. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–8.

    Article  PubMed  CAS  Google Scholar 

  15. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol. 2003;5:834–9.

    Article  PubMed  CAS  Google Scholar 

  16. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet. 2003;34:263–4.

    Article  PubMed  CAS  Google Scholar 

  17. Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009;8:129–38.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Röhl T, Kurreck J. RNA interference in pain research. J Neurochem. 2006;99:371–80.

    Article  PubMed  CAS  Google Scholar 

  19. Devi GR. siRNA-based approaches in cancer therapy. Cancer Gene Ther. 2006;13:819–29.

    Article  PubMed  CAS  Google Scholar 

  20. Jeong EH, Kim H, Jang B, et al. Technological development of structural DNA/RNA-based RNAi systems and their applications. Adv Drug Deliv Rev. 2016;104:29–43.

    Article  PubMed  CAS  Google Scholar 

  21. Jr SO, Holen T. Many commonly used siRNAs risk off-target activity. Biochem Biophys Res Commun. 2004;319:256–63.

    Article  CAS  Google Scholar 

  22. Doench JG, Petersen CP, Sharp PA. siRNAs can function as miRNAs. Genes Dev. 2003;17:438–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M, Lim L, Linsley PS. Wide-spread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA. 2006;12:1179–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Essex S, Navarro G, Sabhachandani P, et al. Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors. Gene Ther. 2015;22:41–50.

    Article  CAS  Google Scholar 

  25. Jensen DK, Jensen LB, Koocheki S, et al. Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA. J Control Release. 2012;157:141–8.

    Article  PubMed  CAS  Google Scholar 

  26. Judge AD, Sood V, Shaw JR, Fang D, Mcclintock K, Maclachlan I. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol. 2005;23:457–62.

    Article  PubMed  Google Scholar 

  27. Hornung V, Guenthnerbiller M, Bourquin C, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med. 2005;11:263.

    Article  PubMed  CAS  Google Scholar 

  28. Sioud M. Does the understanding of immune activation by RNA predict the design of safe siRNAs? Front Biosci. 2008;13:4379–92.

    Article  PubMed  CAS  Google Scholar 

  29. Hefner E, Clark K, Whitman C, et al. Increased potency and longevity of gene silencing using validated dicer substrates. J Biomol Tech JBT. 2008;19:231–7.

    PubMed  CAS  Google Scholar 

  30. Gao K, Huang L. Nonviral methods for siRNA delivery. Mol Pharm. 2009;6:651–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Tatiparti K, Sau S, Kashaw SK, Iyer AK. siRNA delivery strategies: a comprehensive review of recent developments. Nanomaterials. 2017;7:77.

    Article  PubMed Central  CAS  Google Scholar 

  32. Chaudhary A. Development of a software tool and criteria evaluation for efficient design of small interfering RNA. Biochem Biophys Res Commun. 2011;404:313.

    Article  PubMed  CAS  Google Scholar 

  33. Zhong R, Kim J, Kim HS, et al. Computational detection and suppression of sequence-specific off-target phenotypes from whole genome RNAi screens. Nucleic Acids Res. 2014;42:8214–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Meister G. Argonaute proteins: functional insights and emerging roles. Nat Rev Genet. 2013;14:447.

    Article  PubMed  CAS  Google Scholar 

  35. Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol. 2005;23:1002–7.

    Article  PubMed  CAS  Google Scholar 

  36. Braasch DA, Paroo Z, Constantinescu A, et al. Biodistribution of phosphodiester and phosphorothioate siRNA. Bioorg Med Chem Lett. 2004;14:1139.

    Article  PubMed  CAS  Google Scholar 

  37. Lee SJ, Huh MS, Lee SY, et al. Berichtigung: tumor-homing poly-siRNA/Glycol chitosan self-cross-linked nanoparticles for systemic siRNA delivery in cancer treatment. Angew Chem Int Ed Engl. 2012;51:7203–7.

    Article  PubMed  CAS  Google Scholar 

  38. Khvorova A, Reynolds A, Jayasena SD. Functional siRNAs and miRNAs exhibit strand bias. Cell. 2003;115:209.

    Article  PubMed  CAS  Google Scholar 

  39. Schwarz DS, Tomari Y, Zamore PD. The RNA-induced silencing complex is a Mg 2 + -dependent endonuclease. Curr Biol Cb. 2004;14:787–91.

    Article  PubMed  CAS  Google Scholar 

  40. Angart P, Vocelle D, Chan C, Walton SP. Design of siRNA therapeutics from the molecular scale. Pharmaceuticals. 2013;6:440.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Czauderna F, Fechtner M, Dames S, Aygün H, Klippel A, Pronk GJ, et al. Structural variations and stabilising modifications of synthetic sirnas in mammalian cells. Nucleic Acids Res. 2003;31:2705.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Choung S, Kim YJ, Kim S, Park HO, Choi YC. Chemical modification of siRNAs to improve serum stability without loss of efficacy. Biochem Biophys Res Commun. 2006;342:919.

    Article  PubMed  CAS  Google Scholar 

  43. Richardson FC, Tennant BC, Meyer DJ, et al. An evaluation of the toxicities of 2′-fluorouridine and 2′-fluorocytidine-HCl in F344 rats and woodchucks (Marmota monax). Toxicol Pathol. 1999;27:607–17.

    Article  PubMed  CAS  Google Scholar 

  44. Richardson FC, Zhang C, Lehrman SR, et al. Quantification of 2′-fluoro-2′-deoxyuridine and 2′-fluoro-2′-deoxycytidine in DNA and RNA isolated from rats and woodchucks using LC/MS/MS. Chem Res Toxicol. 2002;15:922–6.

    Article  PubMed  CAS  Google Scholar 

  45. Wu SY, Yang X, Gharpure KM, et al. 2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nat Commun. 2014;5:3459.

    Article  PubMed  CAS  Google Scholar 

  46. Fluiter K, Asbroek ALMAT, Wissel MBD, et al. In vivo tumor growth inhibition and biodistribution studies of locked nucleic acid (LNA) antisense oligonucleotides. Nucleic Acids Res. 2003;31:953.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Swayze EE, Siwkowski AM, Wancewicz EV, et al. Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res. 2007;35:687.

    Article  PubMed  CAS  Google Scholar 

  48. Zou Y, Tiller P, Chen IW, Beverly M, Hochman J. Metabolite identification of small interfering RNA duplex by high-resolution accurate mass spectrometry. Rapid Commun Mass Spectrom. 2008;22:1871–81.

    Article  PubMed  CAS  Google Scholar 

  49. Hogrefe RI, Lebedev AV, Zon G, et al. Chemically modified short interfering hybrids (siHYBRIDS): nanoimmunoliposome delivery in vitro and in vivo for RNAi of HER-2. Nucleosides Nucleotides Nucleic Acids. 2006;25:889–907.

    Article  PubMed  CAS  Google Scholar 

  50. Barton GM, Medzhitov R. Retroviral delivery of small interfering RNA into primary cells. Proc Natl Acad Sci USA. 2002;99:14943–5.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Ji YY, Lee SJ, Lee S, et al. Tumor-targeting transferrin nanoparticles for systemic polymerized siRNA delivery in tumor-bearing mice. Bioconjug Chem. 2013;24:1850.

    Article  CAS  Google Scholar 

  52. Park J, Park J, Pei Y, Xu J, Yeo Y. Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines. Adv Drug Deliv Rev. 2016;104:93–109.

    Article  PubMed  CAS  Google Scholar 

  53. Yang X, Sierant M, Janicka M, et al. Gene silencing activity of siRNA molecules containing phosphorodithioate substitutions. ACS Chem Biol. 2012;7:1214–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Prakash TP, Allerson CR, Dande P, et al. Positional effect of chemical modifications on short interference RNA activity in mammalian cells. J Med Chem. 2005;48:4247–53.

    Article  PubMed  CAS  Google Scholar 

  55. Odadzic D, Bramsen JB, Smicius R, Bus C, Kjems J, Engels JW. Synthesis of 2′-O-modified adenosine building blocks and application for RNA interference. Bioorg Med Chem. 2008;16:518–29.

    Article  PubMed  CAS  Google Scholar 

  56. Watts JK, Deleavey GF, Damha MJ. Chemically modified siRNA: tools and applications. J Int Pharm Res. 2008;13:842.

    CAS  Google Scholar 

  57. Behlke MA. Chemical modification of siRNAs for in vivo use. Oligonucleotides. 2008;18:305.

    Article  PubMed  CAS  Google Scholar 

  58. Kim HR, Kim IK, Bae KH, Lee SH, Lee Y, Park TG. Cationic solid lipid nanoparticles reconstituted from low density lipoprotein components for delivery of siRNA. Mol Pharm. 2008;5:622.

    Article  PubMed  CAS  Google Scholar 

  59. Lee SJ, Yhee JY, Kim SH, Kwon IC, Kim K. Biocompatible gelatin nanoparticles for tumor-targeted delivery of polymerized siRNA in tumor-bearing mice. J Control Release Off J Control Release Soc. 2013;172:358.

    Article  CAS  Google Scholar 

  60. Lee SY, Huh MS, Lee S, et al. Stability and cellular uptake of polymerized siRNA (poly-siRNA)/polyethylenimine (PEI) complexes for efficient gene silencing. J Control Release. 2010;141:339–46.

    Article  PubMed  CAS  Google Scholar 

  61. Morris KV, Rossi JJ. Lentiviral-mediated delivery of siRNAs for antiviral therapy. Gene Ther. 2006;13:553.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Shen C, Buck AK, Liu X, Winkler M, Reske SN. Gene silencing by adenovirus-delivered siRNA. FEBS Lett. 2003;539:111.

    Article  PubMed  CAS  Google Scholar 

  63. Son S, Song S, Lee SJ, et al. Self-crosslinked human serum albumin nanocarriers for systemic delivery of polymerized siRNA to tumors. Biomaterials. 2013;34:9475–85.

    Article  PubMed  CAS  Google Scholar 

  64. Stewart SA, Dykxhoorn DM, Palliser D, et al. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA. 2016;9:493–501.

    Article  CAS  Google Scholar 

  65. Tiscornia G, Singer O, Ikawa M, Verma IM. A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA. 2003;100:1844–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Yoon HY, Kim HR, Saravanakumar G, et al. Bioreducible hyaluronic acid conjugates as siRNA carrier for tumor targeting. J Control Release Off J Control Release Soc. 2013;172:653.

    Article  CAS  Google Scholar 

  67. Zimmermann TS, Lee AC, Akinc A, et al. RNAi-mediated gene silencing in non-human primates. Nature. 2006;441:111.

    Article  PubMed  CAS  Google Scholar 

  68. Couto LB, High KA. Viral vector-mediated RNA interference. Curr Opin Pharmacol. 2010;10:534–42.

    Article  PubMed  CAS  Google Scholar 

  69. Felgner JH, Kumar R, Sridhar CN, et al. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J Biol Chem. 1994;269:2550–61.

    PubMed  CAS  Google Scholar 

  70. Gao X, Huang L. Cationic liposome-mediated gene transfer. Gene Ther. 1995;2:710–22.

    PubMed  CAS  Google Scholar 

  71. Gary DJ, Puri N, Won YY. Polymer-based siRNA delivery: perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery. J Control Release. 2007;121:64.

    Article  PubMed  CAS  Google Scholar 

  72. Hatakeyama H, Akita H, Harashima H. A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma. Adv Drug Deliv Rev. 2011;63:152–60.

    Article  PubMed  CAS  Google Scholar 

  73. Hui SW, Langner M, Zhao YL, Ross P, Hurley E, Chan K. The role of helper lipids in cationic liposome-mediated gene transfer. Biophys J. 1996;71:590–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Kim ST, Chompoosor A, Yeh YC, Agasti SS, Solfiell DJ, Rotello VM. Dendronized gold nanoparticles for siRNA delivery. Small. 2012;8:3253–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Li L, Wei Y, Gong C. Polymeric nanocarriers for non-viral gene delivery. J Biomed Nanotechnol. 2015;11:739.

    Article  PubMed  CAS  Google Scholar 

  76. Liu F, Huang L. Development of non-viral vectors for systemic gene delivery. J Control Release Off J Control Release Soc. 2002;78:259.

    Article  CAS  Google Scholar 

  77. Ma Z, Li J, He F, Wilson A, Pitt B, Li S. Cationic lipids enhance siRNA-mediated interferon response in mice. Biochem Biophys Res Commun. 2005;330:755–9.

    Article  PubMed  CAS  Google Scholar 

  78. Paukku T, Lauraeus S, Huhtaniemi I, Kinnunen PKJ. Novel cationic liposomes for DNA-transfection with high efficiency and low toxicity. Chem Phys Lipid. 1997;87:23–9.

    Article  CAS  Google Scholar 

  79. Severino P, Szymanski M, Favaro M, et al. Development and characterization of a cationic lipid nanocarrier as non-viral vector for gene therapy. Eur J Pharm Sci. 2015;66:78–82.

    Article  PubMed  CAS  Google Scholar 

  80. Shapira A, Livney YD, Broxterman HJ, Assaraf YG. Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist Updates Rev Comment Antimicrob Anticancer Chemother. 2011;14:150–63.

    CAS  Google Scholar 

  81. Shim MS, Kwon YJ. Efficient and targeted delivery of siRNA in vivo. FEBS J. 2010;277:4814.

    Article  PubMed  CAS  Google Scholar 

  82. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4:346.

    Article  PubMed  CAS  Google Scholar 

  83. Varkouhi AK, Scholte M, Storm G, Haisma HJ. Endosomal escape pathways for delivery of biologicals. J Control Release Off J Control Release Soc. 2011;151:220–8.

    Article  CAS  Google Scholar 

  84. Waehler R, Russell SJ, Curiel DT. Engineering targeted viral vectors for gene therapy. Nat Rev Genet. 2007;8:573–87.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Xu Y Jr, Szoka SF. Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochemistry. 1996;35:5616–23.

    Article  PubMed  CAS  Google Scholar 

  86. Zheng D, Giljohann DA, Chen DL, et al. Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation. Proc Natl Acad Sci USA. 2012;109:11975–80.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Akinc A, Thomas M, Klibanov AM, Langer R. Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J Gene Med. 2005;7:657–63.

    Article  PubMed  CAS  Google Scholar 

  88. De MH, Vauthier C, Malvy C, Couvreur P. Polymer nanocarriers for the delivery of small fragments of nucleic acids: oligonucleotides and siRNA. Eur J Pharm Biopharm. 2009;71:490–504.

    Article  CAS  Google Scholar 

  89. Yuan Y, Gong F, Cao Y, Chen W, Cheng D, Shuai X. Biodegradable multiamine polymeric vector for siRNA delivery. J Biomed Nanotechnol. 2015;11:668.

    Article  PubMed  CAS  Google Scholar 

  90. Kwon YJ. Before and after endosomal escape: roles of stimuli-converting siRNA/polymer interactions in determining gene silencing efficiency. Acc Chem Res. 2012;45:1077–88.

    Article  PubMed  CAS  Google Scholar 

  91. Mintzer MA, Simanek EE. Nonviral vectors for gene delivery. Chem Rev. 2009;109:259–302.

    Article  PubMed  CAS  Google Scholar 

  92. Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J Clin Investig. 2007;117:3623–32.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  93. Bishop CJ, Tzeng SY, Green JJ. Degradable polymer-coated gold nanoparticles for co-delivery of DNA and siRNA. Acta Biomater. 2015;11:393–403.

    Article  PubMed  CAS  Google Scholar 

  94. Borchard G. Chitosans for gene delivery. Adv Drug Deliv Rev. 2001;52:145.

    Article  PubMed  CAS  Google Scholar 

  95. Davis ME. The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol Pharm. 2009;6:659.

    Article  PubMed  CAS  Google Scholar 

  96. Davis ME, Pun SH, Bellocq NC, et al. Self-assembling nucleic acid delivery vehicles via linear, water-soluble, cyclodextrin-containing polymers. Curr Med Chem. 2004;11:179–97.

    Article  PubMed  CAS  Google Scholar 

  97. Farrell LL, Pepin J, Kucharski C, Lin X, Xu Z, Uludag H. A comparison of the effectiveness of cationic polymers poly-l-lysine (PLL) and polyethylenimine (PEI) for non-viral delivery of plasmid DNA to bone marrow stromal cells (BMSC). Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E. 2007;65:388–97.

    CAS  Google Scholar 

  98. Howard KA, Rahbek UX, Damgaard CK, et al. RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. Mol Ther J Am Soc Gene Ther. 2006;14:476–84.

    Article  CAS  Google Scholar 

  99. Lee DW, Yun KS, Ban HS, Choe W, Lee SK, Lee KY. Preparation and characterization of chitosan/polyguluronate nanoparticles for siRNA delivery. J Control Release Off J Control Release Soc. 2009;139:146.

    Article  CAS  Google Scholar 

  100. Liu X, Liu C, Zhou J, et al. Promoting siRNA delivery via enhanced cellular uptake using an arginine-decorated amphiphilic dendrimer. Nanoscale. 2015;7:3867–75.

    Article  PubMed  CAS  Google Scholar 

  101. Liu X, Rocchi P, Peng L. Dendrimers as non-viral vectors for siRNA delivery. New J Chem. 2012;36:256–63.

    Article  CAS  Google Scholar 

  102. Meng H, Liong M, Xia T, et al. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and Pgp siRNA to overcome drug resistance in a cancer cell line. ACS Nano. 2010;4:4539.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Oishi M, Nakaogami J, Ishii T, Nagasaki Y. Smart PEGylated gold nanoparticles for the cytoplasmic delivery of siRNA to induce enhanced gene silencing. Chem Lett. 2006;35:1046–7.

    Article  CAS  Google Scholar 

  104. Press AT, Traeger A, Pietsch C, et al. Cell type-specific delivery of short interfering RNAs by dye-functionalised theranostic nanoparticles. Nat Commun. 2014;5:1–13.

    Article  CAS  Google Scholar 

  105. Scholz C, Wagner E. Therapeutic plasmid DNA versus siRNA delivery: common and different tasks for synthetic carriers. J Control Release Off J Control Release Soc. 2012;161:554.

    Article  CAS  Google Scholar 

  106. Sun TM, Du JZ, Yan LF, Mao HQ, Wang J. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery. Biomaterials. 2008;29:4348.

    Article  PubMed  CAS  Google Scholar 

  107. Jiang Y, Tang R, Duncan B, et al. Direct cytosolic delivery of siRNA using nanoparticle-stabilized nanocapsules. Angew Chem Int Ed Engl. 2015;54:506–10.

    PubMed  CAS  Google Scholar 

  108. Lee SJ, Kim MJ, Kwon IC, Roberts TM. Delivery strategies and potential targets for siRNA in major cancer types. Adv Drug Deliv Rev. 2016;104:2–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Lee SH, Kang YY, Jang HE, Mok H. Current preclinical small interfering RNA (siRNA)-based conjugate systems for RNA therapeutics. Adv Drug Deliv Rev. 2016;104:78–92.

    Article  PubMed  CAS  Google Scholar 

  110. Stoltenburg R, Reinemann C, Strehlitz B. SELEX—A (r)evolutionary method to generate high-affinity nucleic acid ligands. Biomol Eng. 2007;24:381–403.

    Article  PubMed  CAS  Google Scholar 

  111. Delač M, Motaln H, Ulrich H, Lah TT. Aptamer for imaging and therapeutic targeting of brain tumor glioblastoma. Cytometry Part A. 2015;87:806–16.

    Article  CAS  Google Scholar 

  112. Song KM, Lee S, Ban C. Aptamers and their biological applications. Sensors. 2012;12:612–31.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Ma DL, Wang W, Mao Z, et al. Utilization of G-quadruplex-forming aptamers for the construction of luminescence sensing platforms. Chempluschem. 2017;82:8.

    Article  CAS  PubMed  Google Scholar 

  114. de Almeida CE, Alves LN, Paulino ET, Cabralneto JB, Missailidis S. Aptamer delivery of siRNA, radiopharmaceutics and chemotherapy agents in cancer. Int J Pharm. 2017;525:334.

    Article  PubMed  CAS  Google Scholar 

  115. Liu J, Wei T, Zhao J, et al. Multifunctional aptamer-based nanoparticles for targeted drug delivery to circumvent cancer resistance. Biomaterials. 2016;91:44.

    Article  PubMed  CAS  Google Scholar 

  116. Chu TC, Twu KY, Ellington AD, Levy M. Aptamer mediated siRNA delivery. Nucleic Acids Res. 2006;34:e73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Chen CHB, Dellamaggiore KR, Ouellette CP, et al. Aptamer-based endocytosis of a lysosomal enzyme. Proc Natl Acad Sci USA. 2008;105:15908.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Grijalvo S, Alagia A, Jorge AF, Eritja R. Covalent strategies for targeting messenger and non-coding RNAs: an updated review on siRNA, miRNA and antimiR conjugates. Genes. 2018;9:74.

    Article  PubMed Central  CAS  Google Scholar 

  119. Hussain AF, Tur MK, Barth S. An aptamer-siRNA chimera silences the eukaryotic elongation factor 2 gene and induces apoptosis in cancers expressing αvβ3 integrin. Nucleic Acid Ther. 2013;23:203–12.

    Article  PubMed  CAS  Google Scholar 

  120. Zhou J, Rossi JJ. Cell-type-specific, aptamer-functionalized agents for targeted disease therapy. Mol Ther Nucleic Acids. 2014;3:e169.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Stewart KM, Horton KL, Kelley SO. Cell-penetrating peptides as delivery vehicles for biology and medicine. Cheminform. 2008;6:2242–55.

    CAS  Google Scholar 

  122. Fonseca SB, Pereira MP, Kelley SO. Recent advances in the use of cell-penetrating peptides for medical and biological applications. Adv Drug Deliv Rev. 2009;61:953–64.

    Article  PubMed  CAS  Google Scholar 

  123. Wender PA, Cooley CB, Geihe EI. Beyond cell penetrating peptides: designed molecular transporters. Drug Discov Today Technol. 2012;9:e49–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Arukuusk P, Pärnaste L, Hällbrink M, Langel Ü. PepFects and NickFects for the intracellular delivery of nucleic acids. Methods Mol Biol. 2015;1324:303.

    Article  PubMed  Google Scholar 

  125. Pärnaste L, Arukuusk P, Langel K, Tenson T, Langel Ü. The formation of nanoparticles between small interfering RNA and amphipathic cell-penetrating peptides. Mol Ther Nucleic Acids. 2017;7:1–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Lee SH, Castagner B, Leroux JC. Is there a future for cell-penetrating peptides in oligonucleotide delivery? Eur J Pharm Biopharm. 2013;85:5–11.

    Article  PubMed  CAS  Google Scholar 

  127. Ye J, Liu E, Gong J, et al. High-yield synthesis of monomeric LMWP(CPP)-siRNA covalent conjugate for effective cytosolic delivery of siRNA. Theranostics. 2017;7:2495–508.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Shen B, Wu N, Yang JM, Gould SJ. Protein targeting to exosomes/microvesicles by plasma membrane anchors. J Biol Chem. 2011;286:14383–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Ohno S, Takanashi M, Sudo K, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther J Am Soc Gene Ther. 2013;21:185.

    Article  CAS  Google Scholar 

  130. Maguire CA, Balaj L, Sivaraman S, et al. Microvesicle-associated AAV vector as a novel gene delivery system. Mol Ther J Am Soc Gene Ther. 2012;20:960–71.

    Article  CAS  Google Scholar 

  131. Sun D, Zhuang X, Xiang X, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther J Am Soc Gene Ther. 2010;18:1606–14.

    Article  CAS  Google Scholar 

  132. Tian Y, Li S, Song J, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35:2383.

    Article  PubMed  CAS  Google Scholar 

  133. Bolukbasi MF, Mizrak A, Ozdener GB, et al. miR-1289 and “Zipcode”-like sequence enrich mRNAs in microvesicles. Mol Ther Nucleic Acids. 2012;1:e10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Dominska M, Dykxhoorn DM. Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci. 2010;123:1183–9.

    Article  PubMed  CAS  Google Scholar 

  135. Simões S, Moreira JN, Fonseca C, Düzgüneş N, de Lima MC. On the formulation of pH-sensitive liposomes with long circulation times. Adv Drug Deliv Rev. 2004;56:947–65.

    Article  PubMed  CAS  Google Scholar 

  136. Tseng YC, Mozumdar S, Huang L. Lipid-based systemic delivery of siRNA. Adv Drug Deliv Rev. 2009;61:721.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Schäfer J, Höbel S, Bakowsky U, Aigner A. Liposome–polyethylenimine complexes for enhanced DNA and siRNA delivery. Biomaterials. 2010;31:6892–900.

    Article  PubMed  CAS  Google Scholar 

  138. Lanzov VA. Gene targeting for gene therapy: prospects. Mol Genet Metab. 1999;68:276–82.

    Article  PubMed  CAS  Google Scholar 

  139. Schaffer DV, Fidelman NA, Dan N, Lauffenburger DA. Vector unpacking as a potential barrier for receptor-mediated polyplex gene delivery. Biotechnol Bioeng. 2015;67:598–606.

    Article  Google Scholar 

  140. Oliveira S, Rooy IV, Kranenburg O, Storm G, Schiffelers RM. Fusogenic peptides enhance endosomal escape improving siRNA-induced silencing of oncogenes. Int J Pharm. 2007;331:211.

    Article  PubMed  CAS  Google Scholar 

  141. Vasir JK, Labhasetwar V. Biodegradable nanoparticles for cytosolic delivery of therapeutics. Adv Drug Deliv Rev. 2007;59:718.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Xiong XB, Lavasanifar A. Traceable multifunctional micellar nanocarriers for cancer-targeted co-delivery of MDR-1 siRNA and doxorubicin. ACS Nano. 2011;5:5202–13.

    Article  PubMed  CAS  Google Scholar 

  143. Ozcan G, Ozpolat B, Coleman RL, Sood AK, Lopez-Berestein G. Preclinical and clinical development of siRNA-based therapeutics. Adv Drug Deliv Rev. 2015;87:108–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Deng L, Zhang Y, Ma L, et al. Comparison of anti-EGFR-Fab’ conjugated immunoliposomes modified with two different conjugation linkers for siRNa delivery in SMMC-7721 cells. Int J Nanomed. 2013;8:3271–83.

    Article  CAS  Google Scholar 

  145. Puri A, Loomis K, Smith B, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev Ther Drug Carrier Syst. 2009;26:523–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Anselmo AC, Mitragotri S. Nanoparticles in the clinic. Bioeng Transl Med. 2016;1:10.

    PubMed  PubMed Central  Google Scholar 

  147. Silverman JA, Deitcher SR. Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol. 2013;71:555–64.

    Article  PubMed  CAS  Google Scholar 

  148. Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17:181.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369:819.

    Article  PubMed  CAS  Google Scholar 

  150. Urbanklein B, Werth S, Abuharbeid S, Czubayko F, Aigner A. RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther. 2005;12:461–6.

    Article  CAS  Google Scholar 

  151. Wang Y, Yang C, Hu R, et al. Assembling Mn:ZnSe quantum dots-siRNA nanoplexes for gene silencing in tumor cells. Biomater Sci. 2015;3:192.

    Article  PubMed  CAS  Google Scholar 

  152. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Zhang S, Zhao B, Jiang H, Wang B, Ma B. Cationic lipids and polymers mediated vectors for delivery of siRNA. J Control Release Off J Control Release Soc. 2007;123:1.

    Article  CAS  Google Scholar 

  154. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445–50.

    Article  PubMed  CAS  Google Scholar 

  155. Aqeilan RI, Calin GA, Croce CM. miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ. 2010;17:215.

    Article  PubMed  CAS  Google Scholar 

  156. Bader AG. miR-34—a microRNA replacement therapy is headed to the clinic. Front Genet. 2012;3:120.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Bouchie A. First microRNA mimic enters clinic. Nat Biotechnol. 2013;31:577.

    Article  PubMed  CAS  Google Scholar 

  158. Esquelakerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.

    Article  CAS  Google Scholar 

  159. Farooqi AA, Rehman ZU, Muntane J. Antisense therapeutics in oncology: current status. Oncotargets Ther. 2014;7:2035–42.

    Article  CAS  Google Scholar 

  160. Frank RN. Diabetic retinopathy—NEJM. N Engl J Med. 2004;366:1227–39.

    Google Scholar 

  161. Garba AO, Mousa SA. Bevasiranib for the treatment of wet, age-related macular degeneration. Ophthalmol Eye Dis. 2010;2:75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Guzman-Aranguez A, Loma P, Pintor J. Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy. Br J Pharmacol. 2013;170:730–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Ahmadzada T, Reid G, Mckenzie DR. Fundamentals of siRNA and miRNA therapeutics and a review of targeted nanoparticle delivery systems in breast cancer. Biophys Rev. 2018;10:1–18.

    Article  CAS  Google Scholar 

  164. Kaiser PK, Symons RC, Shah SM, et al. RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am J Ophthalmol. 2010;150:33.

    Article  PubMed  CAS  Google Scholar 

  165. Kim HJ, Takemoto H, Yi Y, et al. Precise engineering of siRNA delivery vehicles to tumors using polyion complexes and gold nanoparticles. ACS Nano. 2014;8:8979–91.

    Article  PubMed  CAS  Google Scholar 

  166. Martínez T, González MV, Roehl I, Wright N, Pañeda C, Jiménez AI. In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for treatment of glaucoma. Mol Ther J Am Soc Gene Ther. 2014;22:81–91.

    Article  CAS  Google Scholar 

  167. Mcleod HL. Cancer pharmacogenomics: early promise, but concerted effort needed. Science. 2013;339:1563.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Mook OR, Baas F, de Wissel MB, Fluiter K. Evaluation of locked nucleic acid-modified small interfering RNA in vitro and in vivo. Mol Cancer Ther. 2007;6:833.

    Article  PubMed  CAS  Google Scholar 

  169. Nakamura H, Siddiqui SS, Shen X, et al. RNA interference targeting transforming growth factor-beta type II receptor suppresses ocular inflammation and fibrosis. Mol Vis. 2004;10:703.

    PubMed  CAS  Google Scholar 

  170. Suvà ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 2013;339:1567–70.

    Article  PubMed  CAS  Google Scholar 

  171. Thakur A, Fitzpatrick S, Zaman A, et al. Strategies for ocular siRNA delivery: Potential and limitations of non-viral nanocarriers. J Biol Eng. 2012;6:7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Ye H, Qian Y, Lin M, et al. Cationic nano-copolymers mediated IKKβ targeting siRNA to modulate wound healing in a monkey model of glaucoma filtration surgery. Mol Vis. 2010;16:2502.

    PubMed  PubMed Central  CAS  Google Scholar 

  173. Anthony H, Mitch D. Endocrinology and hormone therapy in breast cancer: aromatase inhibitors versus antioestrogens. Breast Cancer Res Bcr. 2004;6:1–6.

    Article  Google Scholar 

  174. Bitko V, Musiyenko A, Shulyayeva O, Barik S. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med. 2005;11:50.

    Article  PubMed  Google Scholar 

  175. Bouclier C, Moine L, Hillaireau H, et al. Physicochemical characteristics and preliminary in vivo biological evaluation of nanocapsules loaded with siRNA targeting estrogen receptor alpha. Biomacromolecules. 2008;9:2881.

    Article  PubMed  CAS  Google Scholar 

  176. Clark KL, Hughes SA, Bulsara P, et al. Pharmacological characterization of a novel ENaCα siRNA (GSK2225745) with potential for the treatment of cystic fibrosis. Mol Ther Nucleic Acids. 2013;2:e65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Grzelinski M, Pinkenburg O, Büch T, et al. Critical role of G(alpha)12 and G(alpha)13 for human small cell lung cancer cell proliferation in vitro and tumor growth in vivo. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16:1402.

    Article  CAS  Google Scholar 

  178. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420:25.

    Article  PubMed  CAS  Google Scholar 

  179. Jin Y, Qu S, Tesikova M, et al. Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. Proc Natl Acad Sci USA. 2013;110:E2572.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Lai J, Lehman ML, Dinger ME, Hendy SC, et al. A variant of the KLK4 gene is expressed as a cis sense-antisense chimeric transcript in prostate cancer cells. Rna Publ Rna Soc. 2010;16:1156.

    Article  CAS  Google Scholar 

  181. Lee YH, Seo D, Choi KJ, et al. Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2. Can Res. 2014;74:4752.

    Article  CAS  Google Scholar 

  182. Zhou Z, Liu S, Zhang Y, et al. Reductive nanocomplex encapsulation of cRGD-siRNA conjugates for enhanced targeting to cancer cells. Int J Nanomed. 2017;12:7255–72.

    Article  Google Scholar 

  183. Yang ZZ, Li JQ, Wang ZZ, Dong DW, Qi XR. Tumor-targeting dual peptides-modified cationic liposomes for delivery of siRNA and docetaxel to gliomas. Biomaterials. 2014;35:5226–39.

    Article  PubMed  CAS  Google Scholar 

  184. Yin T, Wang P, Li J, et al. Tumor-penetrating codelivery of siRNA and paclitaxel with ultrasound-responsive nanobubbles hetero-assembled from polymeric micelles and liposomes. Biomaterials. 2014;35:5932–43.

    Article  PubMed  CAS  Google Scholar 

  185. Beh CW, Wei YS, Wang Y, et al. Efficient delivery of Bcl-2-targeted siRNA using cationic polymer nanoparticles: downregulating mRNA expression level and sensitizing cancer cells to anticancer drug. Biomacromolecules. 2009;10:41–8.

    Article  PubMed  CAS  Google Scholar 

  186. Chen AM, Zhang M, Wei D, et al. Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small. 2009;5:2673–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Zheng C, Zheng M, Gong P, et al. Polypeptide cationic micelles mediated co-delivery of docetaxel and siRNA for synergistic tumor therapy. Biomaterials. 2013;34:3431–8.

    Article  PubMed  CAS  Google Scholar 

  188. Xiao B, Ma L, Merlin D. Nanoparticle-mediated co-delivery of chemotherapeutic agent and siRNA for combination cancer therapy. Exp Opin Drug Deliv. 2016;14:65.

    Article  CAS  Google Scholar 

  189. Merkel OM, Rubinstein I, Kissel T. siRNA delivery to the lung: what’s new? Adv Drug Deliv Rev. 2014;75:112.

    Article  PubMed  CAS  Google Scholar 

  190. Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 2010;277:301.

    Article  PubMed  CAS  Google Scholar 

  191. Park CC, Zhang H, Pallavicini M, et al. β1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Can Res. 2006;66:1526–35.

    Article  CAS  Google Scholar 

  192. Ren Y, Cheung HW, Maltzhan GV, et al. Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer target ID4. Sci Transl Med. 2012;4:147ra112.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol. 2007;1:19–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Stauffer JK, Scarzello AJ, Andersen JB, et al. Co-activation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors. Can Res. 2011;71:2718.

    Article  CAS  Google Scholar 

  195. Takahashi M, Chiyo T, Okada T, Hohjoh H. Specific inhibition of tumor cells by oncogenic EGFR specific silencing by RNA interference. PLoS One. 2013;8:e73214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Tward AD, Jones KD, Yant S, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci USA. 2007;104:14771–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  197. Xi Z, Klokk TK, Kurys P, et al. Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Can Res. 2004;64:2365.

    Article  CAS  Google Scholar 

  198. Xia W, Wang P, Lin C, et al. Bioreducible polyethylenimine-delivered siRNA targeting human telomerase reverse transcriptase inhibits HepG2 cell growth in vitro and in vivo. J Control Release Off J Control Release Soc. 2012;157:427–36.

    Article  CAS  Google Scholar 

  199. Xue W, Dahlman JE, Tammela T, et al. Small RNA combination therapy for lung cancer. Proc Natl Acad Sci USA. 2014;111:3553–61.

    Article  CAS  Google Scholar 

  200. Bolcato-Bellemin AL, Bonnet ME, Creusat G, Erbacher P, Behr JP. Sticky overhangs enhance siRNA-mediated gene silencing. Proc Natl Acad Sci USA. 2007;104:16050.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Bonnet ME, Gossart JB, Benoit E, et al. Systemic delivery of sticky siRNAs targeting the cell cycle for lung tumor metastasis inhibition. J Control Release. 2013;170:183.

    Article  PubMed  CAS  Google Scholar 

  202. Carmona S, Jorgensen MR, Kolli S, et al. Controlling HBV replication in vivo by intravenous administration of triggered PEGylated siRNA-nanoparticles. Mol Pharm. 2009;6:706–17.

    Article  PubMed  CAS  Google Scholar 

  203. Chandra PK, Kundu AK, Hazari S, et al. Inhibition of hepatitis C virus replication by intracellular delivery of multiple siRNAs by nanosomes. Mol Ther J Am Soc Gene Ther. 2012;20:1724.

    Article  CAS  Google Scholar 

  204. Fehring V, Schaeper U, Ahrens K, et al. Delivery of therapeutic siRNA to the lung endothelium via novel lipoplex formulation DACC. Mol Ther J Am Soc Gene Ther. 2014;22:811.

    Article  CAS  Google Scholar 

  205. Garbuzenko O, Saad MS, Zhang M, et al. Intratracheal versus intravenous liposomal delivery of siRNA, antisense oligonucleotides and anticancer drug. Pharm Res. 2009;26:382–94.

    Article  PubMed  CAS  Google Scholar 

  206. Günther M, Lipka J, Malek A, Gutsch D, Kreyling W, Aigner A. Polyethylenimines for RNAi-mediated gene targeting in vivo and siRNA delivery to the lung. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E. 2011;77:438.

    Google Scholar 

  207. Kim S, Shin D, Lee H, Ahn B, Yoon Y, Kim M. Targeted delivery of siRNA against hepatitis C virus by apolipoprotein A-I-bound cationic liposomes. J Hepatol. 2009;50:479.

    Article  PubMed  CAS  Google Scholar 

  208. Kim SI, Shin D, Choi TH, et al. Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I. Mol Ther J Am Soc Gene Ther. 2007;15:1145.

    Article  CAS  Google Scholar 

  209. Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med. 2013;369:679.

    Article  PubMed  Google Scholar 

  210. Lively T, Kossen K, Balhorn A, Koya T, et al. Effect of chemically modified IL-13 short interfering RNA on development of airway hyperresponsiveness in mice. J Aller Clin Immunol. 2008;121:88–94.

    Article  CAS  Google Scholar 

  211. Mccaskill J, Singhania R, Burgess M, et al. Efficient biodistribution and gene silencing in the lung epithelium via intravenous liposomal delivery of siRNA. Mol Ther Nucleic Acids. 2013;2:e96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Merkel OM, Beyerle A, Librizzi D, et al. Nonviral siRNA delivery to the lung: investigation of PEG − PEI polyplexes and their in vivo performance. Mol Pharm. 2009;6:1246–60.

    Article  PubMed  CAS  Google Scholar 

  213. Polach KJ, Matar M, Rice J, et al. Delivery of siRNA to the mouse lung via a functionalized lipopolyamine. Mol Ther J Am Soc Gene Ther. 2012;20:91–100.

    Article  CAS  Google Scholar 

  214. Seong JH, Lee KM, Kim ST, Jin SE, Kim CK. Polyethylenimine-based antisense oligodeoxynucleotides of IL-4 suppress the production of IL-4 in a murine model of airway inflammation. J Gene Med. 2006;8:314–23.

    Article  PubMed  CAS  Google Scholar 

  215. Watanabe T, Umehara T, Yasui F, et al. Liver target delivery of small interfering RNA to the HCV gene by lactosylated cationic liposome. J Hepatol. 2007;47:744–50.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

FL thanks the teacher and students in her lab for their help.

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Authors and Affiliations

  1. Shanxi Medical University, No. 56 Xinjian South Road, Yingze District, Taiyuan, China

    Fang Liu, Chunfang Wang, Xiao Li, Feng Tian, Yongtao Zhang, Mingyang Fu, Pengfei Li, Yali Wang & Fei Wang

  2. Queen Mary School, Nanchang University, Nanchang, China

    Yuantao Gao

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  1. Fang Liu
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Correspondence to Chunfang Wang.

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FL, CW, YG, XL, FT, YZ, MF, PL, YW, FW have no conflicts of interest.

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This work was supported by Grants from the National Natural Science Foundation of China (NSFC, 81371384).

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Liu, F., Wang, C., Gao, Y. et al. Current Transport Systems and Clinical Applications for Small Interfering RNA (siRNA) Drugs. Mol Diagn Ther 22, 551–569 (2018). https://doi.org/10.1007/s40291-018-0338-8

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