Targeting ferroptosis with polymerized platinum (IV) prodrugs nanoparticles with everolimus for enhancing therapeutic efficacy on cholangiocarcinoma

Strategies to induce ferroptosis in tumor cells have been widely adopted for the treatment of cancer. Traditional single-target ferroptosis inducers, however, have shown limited efficacy. Tumor cells often counteract these drugs through mechanisms by high levels of glutathione (GSH) detoxification of lipid peroxidases. To address these challenges, we have developed a GSH-responsive amphiphilic polymer with polymerized platinum(IV) prodrugs (Poly-CisPt (IV)), capable of encapsulating everolimus (a mTORC1 inhibitor) into nanoparticles (NP@Ev). This strategy facilitates the concurrent depletion of GSH and the release of cisplatin and everolimus. On the one hand, the released cisplatin simultaneously induces cell apoptosis and impairs the GPX4 enzyme. On the other hand, everolimus disrupts the mTOR signaling pathway, inhibiting tumor cell proliferation and inducing the production of reactive oxygen species (ROS) and lipid peroxides, which leads to mitochondrial dysfunction and ferroptosis. Our study indicated that NP@Ev effectively induced ferroptosis and significantly inhibited the progression of human cholangiocarcinoma in murine models, with limited toxicity. These findings underscore the potential of NP@Ev as a promising avenue for the clinical multimodal treatment of cholangiocarcinoma.