A CD44-Targeting Programmable Drug Delivery System for Enhancing and Sensitizing Chemotherapy to Drug-Resistant Cancer

Programmable drug delivery systems hold great promise to enhance cancer treatment. Herein, a programmable drug delivery system using a chondroitin sulfate (CS)-based composite nanoparticle was developed for enhancing and sensitizing chemotherapy to drug-resistant cancer. The nanoparticle was composed of a cross-linked CS hydrogel shell and hydrophobic cores containing both free drugs and CS-linked prodrugs. Interestingly, the nanoparticle could mediate tumor-specific CD44 targeting. After specific cellular uptake, the payloads were suddenly released because of the decomposition of the CS shell, and the free drug molecules with synergistic effects induced tumor-specific cytotoxicity rapidly. Subsequently, the inner cores of the nanoparticles sustainedly release their cargos in drug-resistant tumor cells to keep the effective drug concentration against the drug efflux mediated by P-glycoprotein. CS dissociated from the outer shell and sensitized cancer cells to the antitumor drugs through downregulation of Bcl-XL, an antiapoptosis protein. Such a programmable drug delivery system with specific tumor-targeting and sensitized therapy is promising for rational drug delivery and provides more versatility for controlled release in biomedical applications.