title: Multifunctional Polymeric Micelles Co-loaded with Anti-Survivin siRNA and Paclitaxel Overcome Drug Resistance in an Animal Model of Ovarian Cancer.
abstract: Ovarian cancer is a dreadful disease estimated to be the second most common gynecologic malignancy worldwide. Its current therapy, based on cytoreductive surgery followed by the combination of platinum and taxanes, is frequently complicated by the onset of multidrug resistance (MDR). The discovery that survivin, a small antiapoptotic protein, is involved in chemoresistance provided a new prospect to overcome MDR in cancer, because siRNA could be used to inhibit the expression of survivin in cancer cells. With this in mind, we have developed self-assembly polymeric micelles (PM) able to efficiently co-load an anti-survivin siRNA and a chemotherapeutic agent, such as paclitaxel (PXL; survivin siRNA/PXL PM). Previously, we have successfully demonstrated that the downregulation of survivin by using siRNA-containing PM strongly sensitizes different cancer cells to paclitaxel. Here, we have evaluated the applicability of the developed multifunctional PM in vivo. Changes in survivin expression, therapeutic efficacy, and biologic effects of the nanopreparation were investigated in an animal model of paclitaxel-resistant ovarian cancer. The results obtained in mice xenografed with SKOV3-tr revealed a significant downregulation of survivin expression in tumor tissues together with a potent anticancer activity of survivin siRNA/PXL PM, while the tumors remained unaffected with the same quantity of free paclitaxel. These promising results introduce a novel type of nontoxic and easy-to-obtain nanodevice for the combined therapy of siRNA and anticancer agents in the treatment of chemoresistant tumors.
authors: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts. Department of Pharmacy, School of Pharmacy Federico II, Naples, Italy.
authors: Giuseppina
authors: G
authors: Salzano
authors: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts.
authors: Gemma
authors: G
authors: Navarro
authors: Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts.
authors: Malav S
authors: MS
authors: Trivedi
authors: Department of Pharmacy, School of Pharmacy Federico II, Naples, Italy.
authors: Giuseppe
authors: G
authors: De Rosa
authors: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. v.torchilin@neu.edu.
authors: Vladimir P
authors: VP
authors: Torchilin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008823:Micelles; D008870:Microtubules / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008823:Micelles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; D017239:Paclitaxel
references: Cancer Res. 2007 Sep 1;67(17):8014-21
references: 17804712
references: Expert Opin Ther Targets. 2008 Apr;12(4):463-76
references: 18348682
references: J Clin Oncol. 1990 Jul;8(7):1263-8
references: 1972736
references: Nat Rev Drug Discov. 2008 Sep;7(9):771-82
references: 18758474
references: Nat Rev Cancer. 2008 Jan;8(1):61-70
references: 18075512
references: Cancer Res. 1999 Aug 15;59(16):4129-35
references: 10463618
references: Curr Oncol Rep. 2012 Apr;14(2):120-8
references: 22234703
references: Med Lett Drugs Ther. 1993 May 14;35(896):39-40
references: 8097551
references: Int J Oncol. 2007 Nov;31(5):1111-7
references: 17912437
references: Cancer Res. 2005 May 1;65(9):3531-4
references: 15867343
references: Gynecol Oncol. 2014 Jan;132(1):211-20
references: 24262875
references: Cancer Lett. 2014 Feb 28;343(2):224-31
references: 24099916
references: Br J Cancer. 2005 Jan 31;92(2):271-7
references: 15655541
references: J Control Release. 2014 Nov 28;194:238-56
references: 25204288
references: J Cancer. 2014 Jan 01;5(1):25-30
references: 24396495
references: Cancer Biol Ther. 2005 Jul;4(7):716-9
references: 15970709
references: Int J Pharm. 2002 Mar 20;235(1-2):179-92
references: 11879753
references: Adv Drug Deliv Rev. 2012 Dec;64(15):1717-29
references: 22800620
references: Cell Mol Life Sci. 2002 Aug;59(8):1406-12
references: 12363043
references: J Control Release. 2014 Mar 28;178:79-85
references: 24462901
references: Biomaterials. 2012 Sep;33(27):6580-91
references: 22717365
references: Bioconjug Chem. 2010 Aug 18;21(8):1530-6
references: 20669936
references: Br J Cancer. 2005 Jan 31;92(2):212-6
references: 15611788
references: Mol Pharmacol. 2014 May;85(5):747-57
references: 24569088
references: J Cancer Res Clin Oncol. 2012 Jul;138(7):1221-9
references: 22426961
references: J Ovarian Res. 2011 Nov 10;4(1):20
references: 22075440
references: N Engl J Med. 2004 Dec 30;351(27):2817-26
references: 15591335
references: JAMA. 2001 Jan 17;285(3):324-8
references: 11176843
references: Yonago Acta Med. 2013 Jun;56(2):43-50
references: 24031151
references: Tumour Biol. 2013 Aug;34(4):2053-62
references: 23690235
references: Front Biosci (Landmark Ed). 2013;18:58-79
references: 23276909
references: J Cell Sci. 2003 Jul 15;116(Pt 14):2987-98
references: 12783991
references: Int J Gynecol Cancer. 2013 Feb;23(2):256-63
references: 23358177
references: Cancer Chemother Pharmacol. 2005 Mar;55(3):277-85
references: 15565326
references: Drug Resist Updat. 2002 Apr;5(2):65-72
references: 12135582
references: J Control Release. 2001 May 14;72(1-3):191-202
references: 11389998
references: Cancer Chemother Pharmacol. 1989;24(3):148-54
references: 2544306
references: Crit Rev Oncol Hematol. 2010 Sep;75(3):173-234
references: 20047843
references: Mol Cancer Ther. 2012 Sep;11(9):1936-47
references: 22784709
references: Nat Med. 1997 Aug;3(8):917-21
references: 9256286
references: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4349-54
references: 11917134