A Nanodrug Self-Assembled from a Redox-Responsive Cabazitaxel–Zosuquidar Conjugate and DSPE-PEG_2k Reverses Multidrug Resistance in Nonsmall Cell Lung Cancer

Multidrug resistance (MDR) is a significant factor contributing to chemotherapy failure in the clinical treatment of nonsmall cell lung cancer (NSCLC). The combination of P-glycoprotein (P-gp) inhibitors with chemotherapeutic agents can effectively overcome MDR by inhibiting drug efflux from NSCLC cells. However, achieving a satisfactory therapeutic effect through the codelivery of chemotherapeutic agents and P-gp inhibitors remains challenging due to their different pharmacokinetics and physicochemical properties. In this study, we constructed a redox-responsive drug-inhibitor conjugate (CTX-SS-Zos) using cabazitaxel (CTX, a cytotoxin) and zosuquidar (Zos, a third-generation P-gp inhibitor) through a linkage containing a disulfide bond. Subsequently, this conjugate can self-assemble into uniform and stable nanoparticles (CZNPs) in the presence of DSPE-PEG_2k with a molar percentage of 10%. Administered via tail vein injection, CZNPs can accumulate at tumor sites. Upon internalization by cancer cells, the high intracellular concentration of glutathione triggers the disassembly of CZNPs and the cleavage of the redox-sensitive CTX-SS-Zos conjugate. As a result, CTX and Zos are simultaneously released, thereby reversing tumor MDR and synergistically inhibiting the growth of drug-resistant NSCLC. The in vivo tumor inhibition rate of CZNPs reaches up to 86.91% in A549/PTX tumor-bearing mice without obvious toxic side effects. These smart CZNPs may offer a promising clinical treatment approach for drug-resistant NSCLC.