title: Distinctive polymer micelle designed for siRNA delivery and reversal of MDR1 gene-dependent multidrug resistance.
abstract: P-glycoprotein (P-gp) plays an importantrole in multidrug resistance (MDR), proved to be one of the major obstacles in cancer chemotherapy. Cationic polymers could specifically deliver siRNA to tumor cells and thus reverse MDR by the downregulation of P-gp. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl-chitosan-poly-l-lysine-palmitic acid (NSC-PLL-PA) to deliver siRNA-P-gp (siRNA-micelle) or doxorubicin (Dox-micelle). The resulting micelle exhibited an efficient binding ability for siRNA and high encapsulation efficiency for Dox, with an average particle size of ∼170 nm. siRNA-micelle and Dox-micellewere instable at low pH, thereby enhancing tumor accumulation and intracellular release of the encapsulated siRNA and Dox. siRNA-micelle micelles could enhance the knockdown efficacy of siRNA by improving the transfection efficiency, downregulating P-gp expression, and passing the drug efflux transporters, thereby improving the therapeutic effects of Dox-micelle. However, P-gp could transfer from HepG2/ADM to HepG2 cells independent of the expression of mdr1, and the acquired resistance could permit tumor cells to survive and develop intrinsic P-gp-mediated resistance, thereby limiting the desired efficiency of chemotherapeutics. This study demonstrated the effectiveness of siRNA-micelle for tumor-targeted delivery, MDR reversal, and provided an effective strategy for the treatment of cancers that develop MDR. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2093-2106, 2017.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.|The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
authors.forename: Chun-Ge
authors.initials: CG
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Shu-di
authors.initials: SD
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Ben-Gang
authors.initials: BG
authors.lastname: You
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Ji-Zhao
authors.initials: JZ
authors.lastname: Li
authors.affiliation: College of Radiological Medicine and Protection, Soochow University, Suzhou, People's Republic of China.|Changshu Hospital of Traditional Chinese Medicine, Changshu, People's Republic of China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: The Hospital of Suzhou People's Hospital Affiliated to Nanjing Medical University, Suzhou, People's Republic of China.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People's Republic of China.
authors.forename: Xue-Nong
authors.initials: XN
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods*; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D008823:Micelles; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D008823:Micelles; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D004317:Doxorubicin
keywords: cationic triblock copolymer; micelle; multidrug resistance; siRNA