Enhanced anticancer effect of doxorubicin by TPGS-coated liposomes with Bcl-2 siRNA-corona for dual suppression of drug resistance  

作　　者：Yinghuan Li Xi Tan Xuhan Liu Lingyan Liu Yan Fang Rong Rao Yuanyuan Ren Xiangliang Yang Wei Liu 

机构地区：[1]School of Pharmaceutical Sciences,Beijing Area Major Laboratory of Peptide and Small Molecular Drugs,Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China,Capital Medical University,Beijing 100069,China [2]College of Life Science and Technology,Huazhong University of Science and Technology,Wuhan 430074,China [3]National Engineering Research Center for Nanomedicine,Huazhong University of Science and Technology,Wuhan 430074,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2020年第5期646-660,共15页亚洲药物制剂科学（英文）

基　　金：financially supported by National Basic Research Program of China(973 Program,2015CB931802);Natural Science Foundation of China(31470968 and 81627901)。

摘　　要：Multiple drug resistance(MDR)is a tough problem in developing hepatocellular carcinoma(HCC)therapy.Here,we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin(Dox)i.e.,Bcl-2 siRNA/Dox-TPGS-LPs,to enhance anticancer effect of Dox in HCC-MDR.TPGS i.e.,d-α-tocopheryl polyethylene glycol 1000 succinate,inhibited Pglycoprotein(P-gp)efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein.The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy.The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGSLPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum.In drug-resistant cells,TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes.In vitro and in vivo anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model.MTT assay confirmed the IC50 value of Dox was 20–50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells.Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels in vitro and in vivo.Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS-(or siRNA-)linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells,and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice.In conclusion,TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.

关 键 词：Multiple drug resistance(MDR) TPGS siRNA-corona Liposomes P-glycoprotein(P-gp) BCL-2 

分 类 号：R943[医药卫生—药剂学]