title: Biocompatible polymeric nanocomplexes as an intracellular stimuli-sensitive prodrug for type-2 diabetes combination therapy.
abstract: Combination therapy is usually considered as a promising strategy owing to its advantages such as reduced doses, minimized side effects and improved therapeutic efficiency in a variety of diseases including diabetes. Here we synthesized a new highly intracellular stimuli-sensitive chitosan-graft-metformin (CS-MET) prodrug by imine reaction between oxidative chitosan and metformin for type 2 diabetes (T2D) therapy. Hypothetically, CS-MET functions dually as an anti-diabetes prodrug as well as a gene delivery vector without superfluous materials. CS-MET formed nanocomplexes with therapeutic gene through electrostatic interactions and entered cells by Organic Cation Transporter (OCT)-independent endocytosis. The incorporation of metformin into chitosan has been found to increase endosomal escape via the proton sponge effect. When vector carrying a short-hairpin RNA (shRNA) silencing sterol regulatory element-binding protein (SREBP), a major transcription factor involved in de novo lipogenisis, it reduced the SREBP mRNA and proteins efficiently. Furthermore, by intraperitoneal injection, CS-MET/shSREBP nanocomplexes effectively knocked down SREBP in livers of western-type diet (WD)-induced obese C57BL/6J mice, markedly reversed insulin resistance and alleviated the fatty liver phenotype without obvious toxic effects. Thus we were able to show that the intracellular stimuli-sensitive CS-MET prodrug renders a potential platform to increase the anti-diabetes activity with synergistic enhancement of gene therapy.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Feng-Zhen
authors.initials: FZ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacognosy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhi-Shen
authors.initials: ZS
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xing
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Bing-Feng
authors.initials: BF
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jia-Liang
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jian-Bin
authors.initials: JB
authors.lastname: Qiao
authors.affiliation: Department of Orthopedics, Xuzhou Central Hospital, Xuzhou 221009, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Shi
authors.affiliation: Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
authors.affiliation: Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea; Department of Nano Fusion Technology, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 443-270, South Korea; Graduate Group of Tumor Biology, Seoul National University, Seoul 151-742, South Korea; Advanced Institute of Convergence Technology, Seoul National University, Suwon 443-270, South Korea.
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xiaojunxu2000@163.com.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacognosy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: liping2004@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jianghulin3@163.com.
authors.forename: Hu-Lin
authors.initials: HL
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy*; D004705:Endocytosis; D005234:Fatty Liver / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D007097:Imines / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008687:Metformin / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018613:Microscopy, Confocal; D049329:Nanostructures / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D011108:Polymers / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D055672:Static Electricity; D051780:Sterol Regulatory Element Binding Protein 1 / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D007097:Imines; D008055:Lipids; D011108:Polymers; D011355:Prodrugs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1; D048271:Chitosan; D008687:Metformin; D010100:Oxygen
keywords: Combination therapy; Diabetes; Prodrug; Stimuli-sensitive