Ferrocene conjugated glutathione consumption for enhanced ferroptosis therapy and chemotherapy

As the backbone of tumor therapy, chemotherapy is prone to tumor resistance due to its apoptotic pathway. Ferroptosis, as an effective form of non-apoptotic cell death, can overcome chemotherapy apoptosis-induced resistance. Therefore, the combination of chemotherapy and ferroptosis is a highly promising tumor treatment strategy. However, high glutathione (GSH) and insufficient intracellular iron content in the tumor environment limit the efficiency of ferroptosis-mediated anticancer. Not only that, simultaneous intracellular delivery of iron sources, ferroptosis inducers, and chemotherapeutic agents remains a major challenge. Here, we constructed a self-assembled nano prodrug system to co-deliver iron sources, ferroptosis inducers, and anti-cancer drugs for combined ferroptosis and chemotherapy. In the tumor microenvironment, high levels of GSH triggered redox-responsive disulfide bonding, which induced the disassembly of this nano prodrug system (PFSH@HCPT), releasing hydroxycamptothecin (HCPT), honokiol (HNK) and ferrocene (Fc). HCPT induced cell death via apoptosis and Fc triggered the Fenton reaction, which induced ferroptosis. HNK inhibited the activity of glutathione peroxidase 4 (GPX4) to enhance ferroptosis, and on the other hand, it further induced cell death via apoptosis. Meanwhile, the combined strategy of HNK-mediated resistance and ferroptosis-induced resistance mechanism further overcame the resistance of HCPT and significantly improved the therapeutic efficacy. This nano prodrug system realized the “multi-machine integrated” therapeutic efficacy and showed great therapeutic potential, which may open up a new way for effective cancer treatment.