Overcoming Multidrug Resistance by Codelivery of MDR1-Targeting siRNA and Doxorubicin Using EphA10-Mediated pH-Sensitive Lipoplexes: In Vitro and In Vivo Evaluation.

The therapeutic efficacy of chemotherapy is dramatically hindered by multidrug resistance (MDR), which is induced by the overexpression of P-glycoprotein (P-gp). The codelivery of an antitumor drug and siRNA is an effective strategy recently applied in overcoming P-gp-related MDR. In this study, a multifunctional drug delivery system with both pH-sensitive feature and active targetability was designed, in which MDR1-siRNA and DOX were successfully loaded. The resulting carrier EphA10 antibody-conjugated pH-sensitive doxorubicin (DOX), MDR1-siRNA coloading lipoplexes (shortened as DOX + siRNA/ePL) with high serum stability had favorable physicochemical properties. DOX + siRNA/ePL exhibited an incremental cellular uptake, enhanced P-gp downregulation efficacy, as well as a better cell cytotoxicity in human breast cancer cell line/adriamycin drug-resistant (MCF-7/ADR) cells. The results of the intracellular colocalization study indicated that DOX + siRNA/ePL possessed the ability for pH-responsive rapid endosomal escape in a time-dependent characteristic. Meanwhile, the in vivo antitumor activities suggested that DOX + siRNA/ePL could prolong the circulation time as well as specifically accumulate in the tumor cells via receptor-mediated endocytosis after intravenous administration into the blood system. The histological study further demonstrated that DOX + siRNA/ePL could inhibit the proliferation, induce apoptosis effect, and downregulate the P-gp expression in vivo. Altogether, DOX + siRNA/ePL was expected to be a suitable codelivery system for overcoming the MDR effect.