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.