A smart P-gp inhibitor-drug conjugate nanomedicine overcomes administration challenges and multidrug resistance in breast cancer therapy

Abstract

Docetaxel (DTX), a first-line taxane chemotherapeutic agent, is widely used in the treatment of breast cancer. However, its clinical efficacy is often limited by multidrug resistance (MDR), primarily driven by P-glycoprotein (P-gp)-mediated drug efflux, as well as dose-limiting systemic toxicities. In a previous study, our group developed a novel DTX derivative, DTX-AI, via structural modification at the C10 position. This modification enables DTX-AI to partially evade P-gp recognition, thereby enhancing both antitumor efficacy and safety. Nevertheless, the clinical translation of DTX-AI remains hindered by its hydrophobicity and the emergence of MDR following prolonged treatment. Herein, we further developed an inhibitor-drug conjugate (Zos-SS-DTX-AI) by covalently linking the third-generation P-gp inhibitor zosuquidar (Zos) to DTX-AI via a glutathione (GSH)-responsive disulfide bond. This conjugate co-assembled with a small amount of DSPE-PEG_2k to form nanoparticles (Zos-SS-DTX-AI@DSPE-PEG_2k NPs) that exhibited colloidal stability in circulation and possessed enhanced tumor accumulation capability. After cellular internalization, the elevated intracellular GSH level triggered disulfide cleavage, resulting in the disassembly of Zos-SS-DTX-AI@DSPE-PEG_2k NPs to synchronously release DTX-AI and Zos. Subsequently, Zos inhibited P-gp-mediated efflux, thereby promoting intracellular retention of DTX-AI and reversing MDR. In vivo, Zos-SS-DTX-AI@DSPE-PEG_2k NPs achieved a tumor inhibition rate of 83.5% in MCF-7/PTX drug-resistant breast cancer xenograft mice, with no obvious systemic toxicity. Collectively, this smart nanomedicine platform effectively addresses the delivery challenges of DTX-AI and overcomes MDR, offering a promising therapeutic strategy for the treatment of drug-resistant breast cancer.