2018 ; Vol.28-3: 367~374
|Author||Young Woong Lee, Young Eun Hwang, Ju Young Lee, Jung-Hoon Sohn, Bong Hyun Sung, Sun Chang Kim|
|Place of duty||Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea|
|Title||VEGF siRNA Delivery by a Cancer-Specific Cell-Penetrating Peptide|
J. Microbiol. Biotechnol.2018 ;
|Abstract||RNA interference provides an effective tool for developing antitumor therapies. Cellpenetrating
peptides (CPPs) are delivery vectors widely used to efficiently transport smallinterfering
RNA (siRNA) to intracellular targets. In this study, we investigated the efficacy of
the cancer-specific CPP carrier BR2 to specifically transport siRNA to cancer-target cells. Our
results showed that BR2 formed a complex with anti-vascular endothelial growth factor
siRNA (siVEGF) that exhibited the appropriate size and surface charge for in vivo treatment.
Additionally, the BR2-VEGF siRNA complex exhibited significant serum stability and high
levels of gene-silencing effects in vitro. Moreover, the transfection efficiency of the complex
into a cancer cell line was higher than that observed in non-cancer cell lines, resulting in
downregulated intracellular VEGF levels in HeLa cells and comprehensively improved
antitumor efficacy in the absence of significant toxicity. These results indicated that BR2 has
significant potential for the safe, efficient, and specific delivery of siRNA for diverse
|Key_word||RNA interference, small-interfering RNA, cell-penetrating peptide, cancer-specific peptide|
Hannon GJ. 2002. RNA interference. Nature 418: 244-251.
Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. 1998. Potent and specific genetic interference by doublestranded RNA in Caenorhabditis elegans. Nature 391: 806-811.
Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. 2001. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411: 494-498.
Morris KV, Chan SW, Jacobsen SE, Looney DJ. 2004. Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305: 1289-1292.
Aagaard L, Rossi JJ. 2007. RNAi therapeutics: principles, prospects and challenges. Adv. Drug Deliv. Rev. 59: 75-86.
Castanotto D, Rossi JJ. 2009. The promises and pitfalls of RNA-interference-based therapeutics. Nature 457: 426-433.
de Fougerolles A, Vornlocher HP, Maraganore J, Lieberman J. 2007. Interfering with disease: a progress report on siRNAbased therapeutics. Nat. Rev. Drug Discov. 6: 443-453.
Stevenson M, Ramos-Perez V, Singh S, Soliman M, Preece JA, Briggs SS, et al. 2008. Delivery of siRNA mediated by histidine-containing reducible polycations. J. Control. Release 130: 46-56.
Meade BR, Dowdy SF. 2007. Exogenous siRNA delivery using peptide transduction domains/cell penetrating peptides. Adv. Drug Deliv. Rev. 59: 134-140.
Tomar RS, Matta H, Chaudhary PM. 2003. Use of adenoassociated viral vector for delivery of small interfering RNA. Oncogene 22: 5712-5715.
Barquinero J, Eixarch H, Perez-Melgosa M. 2004. Retroviral vectors: new applications for an old tool. Gene Ther. 11 Suppl 1: S3-S9.
Devroe E, Silver PA. 2002. Retrovirus-delivered siRNA. BMC Biotechnol. 2: 15.
Golzio M, Mazzolini L, Ledoux A, Paganin A, Izard M, Hellaudais L, et al. 2007. In vivo gene silencing in solid tumors by targeted electrically mediated siRNA delivery. Gene Ther. 14: 752-759.
Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. 2006. RNAi-mediated gene silencing in non-human primates. Nature 441: 111-114.
de Martimprey H, Bertrand JR, Fusco A, Santoro M, Couvreur P, Vauthier C, et al. 2008. siRNA nanoformulation against the Ret/PTC1 junction oncogene is efficient in an in vivo model of papillary thyroid carcinoma. Nucleic Acids Res. 36: e2.
Choi YS, Lee JY, Suh JS, Kwon YM, Lee SJ, Chung JK, et al. 2010. The systemic delivery of siRNAs by a cell penetrating peptide, low molecular weight protamine. Biomaterials 31:1429-1443.
Pan R, Xu W, Ding Y, Lu S, Chen P. 2016. Uptake mechanism and direct translocation of a new CPP for siRNA delivery. Mol. Pharm. 13: 1366-1374.
Wang F, Wang Y, Zhang X, Zhang W, Guo S, Jin F. 2014. Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery. J. Control. Release 174: 126-136.
Cleal K, He L, Watson PD, Jones AT. 2013. Endocytosis, intracellular traffic and fate of cell penetrating peptide based conjugates and nanoparticles. Curr. Pharm. Des. 19: 2878-2894.
Nakase I, Niwa M, Takeuchi T, Sonomura K, Kawabata N, Koike Y, et al. 2004. Cellular uptake of arginine-rich peptides:roles for macropinocytosis and actin rearrangement. Mol. Ther. 10: 1011-1022.
Richard JP, Melikov K, Vives E, Ramos C, Verbeure B, Gait MJ, et al. 2003. Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J. Biol. Chem. 278: 585-590.
Milletti F. 2012. Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov. Today 17: 850-860.
Nakase I, Tanaka G, Futaki S. 2013. Cell-penetrating peptides (CPPs) as a vector for the delivery of siRNAs into cells. Mol. Biosyst. 9: 855-861.
Vives E, Schmidt J, Pelegrin A. 2008. Cell-penetrating and cell-targeting peptides in drug delivery. Biochim. Biophys. Acta 1786: 126-138.
Chung JY, Ul Ain Q, Lee HL, Kim SM, Kim YH. 2017. Enhanced systemic anti-angiogenic siVEGF delivery using PEGylated oligo-D-arginine. Mol. Pharm. 14: 3059-3068.
Kanazawa T, Sugawara K, Tanaka K, Horiuchi S, Takashima Y, Okada H. 2012. Suppression of tumor growth by systemic delivery of anti-VEGF siRNA with cell-penetrating peptidemodified MPEG-PCL nanomicelles. Eur. J. Pharm. Biopharm. 81: 470-477.
Egorova A, Shubina A, Sokolov D, Selkov S, Baranov V, Kiselev A. 2016. CXCR4-targeted modular peptide carriers for efficient anti-VEGF siRNA delivery. Int. J. Pharm. 515:431-440.
Raucher D, Ryu JS. 2015. Cell-penetrating peptides: strategies for anticancer treatment. Trends Mol. Med. 21: 560-570.
Lim KJ, Sung BH, Shin JR, Lee YW, Kim DJ, Yang KS, et al. 2013. A cancer specific cell-penetrating peptide, BR2, for the efficient delivery of an scFv into cancer cells. PLoS One 8: e66084.
Wallbrecher R, Ackels T, Olea RA, Klein MJ, Caillon L, Schiller J, et al. 2017. Membrane permeation of arginine-rich cell-penetrating peptides independent of transmembrane potential as a function of lipid composition and membrane fluidity. J. Control. Release 256: 68-78.
Yoo J, Lee D, Gujrati V, Rejinold NS, Lekshmi KM, Uthaman S, et al. 2017. Bioreducible branched poly(modified nona-arginine) cell-penetrating peptide as a novel gene delivery platform. J. Control. Release 246: 142-154.
Chomoucka J, Drbohlavova J, Huska D, Adam V, Kizek R, Hubalek J. 2010. Magnetic nanoparticles and targeted drug delivering. Pharmacol. Res. 62: 144-149.
Crombez L, Aldrian-Herrada G, Konate K, Nguyen QN, McMaster GK, Brasseur R, et al. 2009. A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol. Ther. 17: 95-103.
Garzon R, Marcucci G, Croce CM. 2010. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat. Rev. Drug Discov. 9: 775-789.
Rejman J, Oberle V, Zuhorn IS, Hoekstra D. 2004. Sizedependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem. J. 377:159-169.
Zhang S, Li J, Lykotrafitis G, Bao G, Suresh S. 2009. Sizedependent endocytosis of nanoparticles. Adv. Mater. 21: 419-424.
Maeda H. 2010. Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjug. Chem. 21: 797-802.
Lee M, Rentz J, Han SO, Bull DA, Kim SW. 2003. Watersoluble lipopolymer as an efficient carrier for gene delivery to myocardium. Gene Ther. 10: 585-593.
Moghimi SM, Symonds P, Murray JC, Hunter AC, Debska G, Szewczyk A. 2005. A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy. Mol. Ther. 11: 990-995.
Svensen N, Walton JG, Bradley M. 2012. Peptides for cellselective drug delivery. Trends Pharmacol. Sci. 33: 186-192.