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

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.