RESUMO
Ferroptosis has been proposed as one form of iron-dependent cell death, overgeneration of high-toxicity hydroxyl radicals (ËOH) tumor sites via Fenton reactions induced cell membrane damage. However, the insufficient intracellular concentrations of both iron and H2O2 limited the anticancer performance of ferroptosis. In this study, ROS-sensitive prodrug nanoassemblies composed of a PEG2000-ferrous compound and a single thioether bond bridged dihydroartemisinin-paclitaxel prodrug were constructed, which fully tapped ex/endogenous iron, ferroptosis inducers, and chemotherapeutic agents. Following cellular uptake, the intracellular oxidizing environment accelerated the self-destruction of nanoassemblies and triggered drug release. In addition to the chemotherapeutic effect, the activated dihydroartemisinin was capable of acting as a toxic ËOH amplifier via the reinforced Fenton reaction, simultaneously depleting intracellular GSH, as well as inducing glutathione peroxidase 4 inactivation, further enhancing ferroptosis-dependent cancer cell proliferation inhibition. Meanwhile, the ROS generation-inductive and cell cycle arrest effect from the paclitaxel augmented synergetic ferroptotic-chemotherapy of cancer. Thus, the prodrug integrating dihydroartemisinin with paclitaxel via a single thioether bond represents a potent nanoplatform to exert amplified ferroptotic-chemotherapy for improved anticancer efficacy.