Triple-Responsive Cross-Linked Micelles for Synergistic Chemo-Photothermal Cancer Therapy

We have developed a novel triple-responsive (pH/reduction/near-infrared (NIR) light) cross-linked polymer micelle PEG-P(LL/LL-LA)-PCL-IR820 for enhanced synergistic cancer therapy. This micelle was synthesized using a triblock amphiphilic polymer based on polylysine, functionalized with maleic anhydride (LA) as a cross-linking site and polycaprolactone (PCL) for encapsulating the anticancer drug doxorubicin (DOX). The photosensitizer IR820 was grafted onto PCL to enable photothermal and photodynamic effects under NIR irradiation. The DOX-loaded cross-linked micelles (DCMs) demonstrated exceptional stability under physiological conditions, effectively preventing premature drug release. Rapid DOX release was triggered by the intracellular high glutathione (GSH) level and acidic pH in tumor cells. Under NIR irradiation, DCM micelles exhibited significant photothermal and photodynamic effects, which markedly enhanced the cytotoxicity against B16 tumor cells. In B16 tumor-bearing mice, the DCM-treated group achieved superior tumor growth inhibition and prolonged survival under NIR irradiation compared to un-cross-linked micelles (DUCM) or free DOX, with minimal systemic toxicity. The tumor volume in the DCM + NIR group was significantly inhibited compared with other groups, reaching only about 300 mm³ within 15 days, while for the PBS-treated group, it reached approximately 1400 mm³. The survival rate of the DCM + NIR group was also significantly higher, with an over 70% survival rate within a 40-day observation period. This work presents a robust nanoplatform that combines stability, microenvironment responsiveness, and multimodal therapy, offering a promising strategy for targeted cancer treatment.