Smart pH-sensitive and sequentially controlled drug delivery system based on PLGA-PEG overcomes multidrug resistance in hepatocellular carcinoma by endocytosis-mediated energy dissipation and energy production decrease

Multiple cycles of transarterial embolization chemotherapy for hepatocellular carcinoma (HCC) can easily cause the overexpression of P-glycoprotein (P-gp), leading to multidrug resistance (MDR) of HCC. Herein, we linked PLA (polylactic acid) with doxorubicin (DOX) through acid-sensitive hydrazone bonds to prepare PLA-ADH/DOX. Then, PLA-ADH/DOX and disulfiram (DSF) were physically encapsulated into PLGA-PEG (polylactic-co-glycolic acid-polyethylene glycol) as the backbone to fabricate a drug delivery system (DOX/DSF NPs) by nanoprecipitation and emulsion solvent evaporation method. The data of physicochemical characterization showed that DOX/DSF NPs enabled excellent stability at room temperature and pH sensitivity in an acidic environment. More importantly, DOX/DSF NPs could avoid P-gp-mediated efflux through endocytosis pathways and inhibit the function of P-gp by DSF, which increases cellular uptake of DOX in HepG2/DOX cells (hepatocellular DOX-resistant cancer cell line) and promotes DOX to enter the nucleus of HepG2/DOX cells for exerting the therapeutic effect in vitro. In addition, DOX/DSF NPs could increase intracellular reactive oxygen species (ROS) levels and reduce intracellular adenosine triphosphate (ATP) levels, thereby further inhibiting the function of P-gp, increasing intracellular concentration of drugs, and ultimately overcoming MDR in HCC. Hence, the combination of DOX and DSF delivered by DOX/DSF NPs with pH-sensitive and sequentially controlled drug release may provide a new way for MDR of HCC.