Harnessing Dual-Responsive Polymeric Micelles for Precision Oxidative Stress Amplification in Targeted Cancer Therapy

Targeting the altered redox balance in cancer cells, this study explores a strategy to induce selective cancer cell death by combining reactive oxygen species (ROS) generation with glutathione (GSH) depletion. We developed oxidative stress-amplifying polymeric (pCB) micelles that function both as therapeutic agents and carriers for GSH-depleting retinoic acid prodrug (BRDP). pCB incorporating ROS-generating cinnamaldehyde and a GSH-depleting quinone methide precursor could self-assemble into micelles encapsulating BRDP, delivering both ROS generators and GSH-depleting drugs. The micelles were surface-functionalized with the tripeptide Arg-Gly-Asp (RGD) for targeted delivery to integrin-overexpressing tumors. In a mouse xenograft model, RGD-decorated BRDP-loaded micelles significantly accumulated in tumor sites, enhancing anticancer efficacy without toxicity to normal tissues. This study marks significant advancement in the field of oxidative stress-amplifying polymeric precursors, presenting a novel and highly effective anticancer therapeutic approach that integrates multiple tumor-specific triggers and ROS-mediated mechanisms.