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

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

doi:10.1016/j.ajps.2019.10.003

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

Asian J Pharm Sci. 2020 Sep;15(5):646-660. doi: 10.1016/j.ajps.2019.10.003. Epub 2019 Nov 12.

Authors

Yinghuan Li¹, Xi Tan², Xuhan Liu², Lingyan Liu¹, Yan Fang², Rong Rao², Yuanyuan Ren², Xiangliang Yang^{2

3}, Wei Liu^{2

3}

Affiliations

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.

Abstract

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 P-glycoprotein (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-TPGS-LPs 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.

Keywords: Bcl-2; Liposomes; Multiple drug resistance (MDR); P-glycoprotein (P-gp); TPGS; siRNA-corona.