Biocompatible polymeric nanocomplexes as an intracellular stimuli-sensitive prodrug for type-2 diabetes combination therapy

• Published in: Biomaterials 2015-12, Vol.73, p.149-159
• Main Authors: Wang, Feng-Zhen, Xie, Zhi-Shen, Xing, Lei, Zhang, Bing-Feng, Zhang, Jia-Liang, Cui, Peng-Fei, Qiao, Jian-Bin, Shi, Kun, Cho, Chong-Su, Cho, Myung-Haing, Xu, Xiaojun, Li, Ping, Jiang, Hu-Lin
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Biocompatible Materials - chemistry; Cell Line, Tumor; Chemical compounds; Chitosan; Chitosan - administration & dosage; Combination therapy; Dentistry; Diabetes; Diabetes Mellitus, Type 2 - therapy; Drugs; Endocytosis; Fatty Liver - metabolism; Genetic Therapy - methods; Genetic Vectors; Glucose Tolerance Test; Hep G2 Cells; Homeostasis; Humans; Imines - chemistry; Lipids - chemistry; Mathematical analysis; Metformin; Metformin - administration & dosage; Metformin - chemistry; Mice; Mice, Inbred C57BL; Mice, Obese; Microscopy, Confocal; Nanostructure; Nanostructures - chemistry; Oxygen - chemistry; Phenotype; Polymers - chemistry; Prodrug; Prodrugs - chemistry; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Static Electricity; Sterol Regulatory Element Binding Protein 1 - chemistry; Stimuli-sensitive; Therapy
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2015.09.013

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.