A new insight into the reversal of multidrug resistance in cancer by nanodrugs

Abstract

Although nanodrugs have been shown to evade P-glycoprotein (P-gp) recognition and reverse multi-drug resistance (MDR) in cancer, a specific mechanism of how nanodrugs reverse MDR is still unclear. Herein, we investigate the underlying MDR reversal mechanism by studying the in vitro behaviors of model nanodrugs, including internalization, intracellular drug release and intracellular drug enrichment. Comprehensive experimental results showed that the internalization process of nanodrugs can change the distribution of P-gp in MDR cells and significantly reduce the P-gp level in the cell membrane, which might be the key step for MDR reversal. This work offers novel mechanistic insights into MDR reversal by nanodrugs, and this process involves reducing the P-gp distribution ratio in the cell membrane through unique cell internalization behavior rather than merely evading P-gp recognition. Moreover, we further demonstrated that the MDR reversal capacity of nanodrugs follows a size-dependent pattern.