Targeted Delivery of Triptolide Via Folate-Functionalized Pluronic Micelles Enhances Anti-Melanoma Activity by Inducing Reactive Oxygen Species Accumulation.

Melanoma remains a highly lethal malignancy, often associated with limited therapeutic efficacy and substantial systemic toxicity caused by conventional chemotherapy. Triptolide (TP) exhibits potent antitumor activity, but its clinical application is limited by poor aqueous solubility and a narrow therapeutic window. In this study, folate-decorated Pluronic nanomicelles (TP-FPNPs) were developed to enhance TP delivery. The resulting spherical micelles, with an average diameter of 152 nm, exhibited an encapsulation efficiency of 79% and sustained drug release for up to 48 h. By targeting folate receptors (FRs), TP-FPNPs increased cellular uptake in B16F10 and reduced the IC50 to 18.94 nm (2.08-fold decrease). Conversely, the IC50 in HUVECs increased from 19.51 to 37.89 nm (1.94-fold), indicating reduced toxicity toward normal endothelial cells. Mechanistically, TP-FPNPs downregulated glutathione peroxidases (GPx), increased intracellular Reactive Oxygen Species (ROS) levels, and promoted apoptosis. In vivo, TP-FPNPs achieved a tumor inhibition rate of 89.6% with negligible toxicity, significantly outperforming free TP. These results suggest that TP-FPNPs are a promising targeted delivery system that improves the therapeutic index of TP for melanoma therapy.