Redox-responsive drug-inhibitor conjugate encapsulated in DSPE-PEG micelles for overcoming multidrug resistance to chemotherapy.

Multidrug resistance (MDR) is a major cause of chemotherapy failure in cancer treatment. P-glycoprotein (P-gp) inhibitors are helpful for chemotherapy drugs to overcome tumor MDR effectively. With the traditional physical mixing of chemotherapy drugs and inhibitors, it is difficult to achieve satisfactory results due to the different pharmacokinetics and physicochemical properties between the two of them. Herein, we prepared a novel drug-inhibitor conjugate prodrug (PTX-ss-Zos) from a cytotoxin (PTX) and a third-generation P-gp inhibitor (Zos) linked with a redox-responsive disulfide. Then, PTX-ss-Zos was encapsulated in DSPE-PEG micelles to form stable and uniform nanoparticles (PTX-ss-Zos@DSPE-PEG NPs). PTX-ss-Zos@DSPE-PEG NPs could be cleaved by the high-concentration GSH in cancer cells and release PTX and Zos simultaneously to inhibit MDR tumor growth synergistically without apparent systemic toxicity. The evaluation experiments exhibited that the tumor inhibition rates (TIR) of PTX-ss-Zos@DSPE-PEG NPs were high up to 66.5% for HeLa/PTX tumor-bearing mice. This smart nanoplatform would bring new hope for cancer treatment in clinical trials.