Binary and ternary complexes based on polycaprolactone-graft-poly (N, N-dimethylaminoethyl methacrylate) for targeted siRNA delivery

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• 作者：Yuanyu Huang^a ; ¹ ; Daoshu Lin^b ; ¹ ; Qian Jiang^a ; Wendi Zhang^b ; Shutao Guo^b ; Ping Xiao^c ; Shuquan Zheng^c ; Xiaoxia Wang^a ; Hongbo Chen^a ; Hong-Yan Zhang^c ; Liandong Deng^b ; Jinfeng Xing^b ; Quan Du^a ; ^{quan.du@pku.edu.cn} ; Anjie Dong^b ; ^{ajdong@tju.edu.cn} ; Zicai Liang^a ; ^{liangz@pku.edu.cn}
• 关键词：siRNA delivery ; Tumor targeting ; Liver targeting ; Ternary complex ; PCL-g-PDMAEMA ; Non-viral carriers
• 刊名：Biomaterials
• 出版年：2012
• 期刊代码：7_01429612
• 类别：ms
• 出版时间：June, 2012
• 卷：33
• 期：18
• 页码：4653-4664
• 文件大小：3860 K

摘要

Small interfering RNA (siRNA) is a powerful gene silencing tool and has promising prospects in basic research and the development of therapeutic reagents. However, the lack of an effective and safe tool for siRNA delivery hampers its application. Here, we introduced binary and ternary complexes that effectively mediated siRNA-targeted gene silencing. Both complexes showed excellent siRNA loading even at the low N/P/C ratio of 3:1:0. FACS and confocal microscopy demonstrated that nearly all cells robustly internalized siRNAs into the cytoplasm, where RNA interference (RNAi) occurred. Luciferase assay and Western blot verified that silencing efficacy reached >80%, and introducing folate onto the ternary complexes further enhanced silencing efficacy by about 10%over those without folate at the same N/P/C ratio. In addition, the coating of PGA-g-mPEG decreased the zeta potential almost to electroneutrality, and the MTT assay showed decreased cytotoxicity. In聽vivo distribution measurement and histochemical analysis executed in C57BL/6 and Hela tumor-bearing BALB/c nude mice showed that complexes accumulated in the liver, lungs, pancreas and tumors and were released slowly for a long time after intravenous injection. Furthermore, ternary complexes showed higher siRNA fluorescence intensity than binary complexes at the same N/P ratio in tumor tissues, those with folate delivered more siRNAs to tumors than those without folate, and more folate induced more siRNA transport to tumors. In addition, in聽vivo functional study showed that both binary and ternary complexes mediated down-regulation of ApoB in liver efficiently and consequently blocked the secretion of fatty acids into the blood, resulted in lipid accumulation in liver, liver steatosis and hepatic dysfunction. In conclusion, these complexes provided a powerful means of administration for siRNA-mediated treatment of liver-related diseases and various cancers, especial for pancreatic and cervical cancer.