title: Binary-copolymer system base on low-density lipoprotein-coupled N-succinyl chitosan lipoic acid micelles for co-delivery MDR1 siRNA and paclitaxel, enhances antitumor effects via reducing drug.
abstract: The development of effective and stable carriers of small interfering RNA (siRNA) is important for treating cancer with multidrug resistance (MDR). We developed a new gene and drug co-delivery system and checked its characteristics. Low-density lipoprotein (LDL) was coupled with N-succinyl chitosan (NSC) Lipoic acid (LA) micelles and co-delivered MDR1 siRNA and paclitaxel (PTX-siRNA/LDL-NSC-LA) to enhance antitumor effects by silencing the MDR gene of tumors (Li et al., Adv Mater 2014;26:8217-8224). In our study, we developed a new type of containing paclitaxel-loaded micelles and siRNA-loaded LDL nanoparticle. This "binary polymer" is pH and reduction dual-sensitive core-crosslinked micelles. PTX-siRNA/LDL-NSC-LA had an average particle size of (171.6 ± 6.42) nm, entrapment efficiency of (93.92 ± 1.06) %, and drug-loading amount of (12.35% ± 0.87) %. In vitro, MCF-7 cells, high expressed LDL receptor, were more sensitive to this delivery system than to taxol®and cell activity was inhibited significantly. Fluorescence microscopy showed that PTX-siRNA/LDL-NSC-LA was uptaken very conveniently and played a key role in antitumor activity. PTX-siRNA/LDL-NSC-LA protected the siRNA from degradation by macrophage phagocytosis and evidently down-regulated the level of mdr1 mRNA as well as the expression of P-gp. We tested the target ability of PTX-siRNA/LDL-NSC-LA in vivo in tumor-bearing nude mice. Results showed that this system could directly deliver siRNA and PTX to cancer cells. Thus, new co-delivering siRNA and antitumor drugs should be explored for solving MDR in cancer. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1114-1125, 2017.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, 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, 215123, 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, 215123, People's Republic of China.|Nanjing Gulou Hospital, Nanjing, 210029, People's Republic of China.
authors.forename: Qiao-Ling
authors.initials: QL
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory for Translational Research and Therapy for Neuropsycho-disoders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China.
authors.forename: Zhao-Xiang
authors.initials: ZX
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, 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, 215123, People's Republic of China.
authors.forename: Ji-Zhao
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Radiological Medicine and Protection, Soochow University, Suzhou, 215123, People's Republic of China.|Changshu Hospital of Traditional Chinese Medicine, Changshu, 215500, 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, 215000, 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, 215123, 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 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D017239:Paclitaxel / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D008063:Thioctic Acid / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D008077:Lipoproteins, LDL; D008823:Micelles; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D008063:Thioctic Acid; D048271:Chitosan; D017239:Paclitaxel
keywords: co-delivery; low-density lipoprotein; micelles; multidrug resistance; pH-sensitive; reduction-sensitive; siRNA; tumor-targeting therapy