A Fe(III)-porphyrin-oxaliplatin(IV) nanoplatform for enhanced ferroptosis and combined therapy

Since there are several limitations in cancer treatment for traditional chemotherapy, such as side effects, poor prognosis and drug resistance, developing new combined therapy is urgently needed. In this work, a biocompatible, simple and tumor microenvironment-responsive nanotheranostics (PCN-Oxpt/PEG) was built to favor the chemotherapy/ferroptosis/immunomodulation synergism in cancer. This nanotheranostics is constructed by modifying oxaliplatin prodrug and PEG on Fe(III) - porphyrin metal-organic frameworks (PCN(Fe) MOFs). After intravenous injection, the cloak of PEG leads to long circulation, and the Fe(III)-porphyrin MOFs enables dual-model guidance with fluorescence (FL) and magnetic resonance imaging (MRI). Inside the tumor, the intracellular H₂O₂ would be transferred into hydroxyl radicals (•OH) by iron ions released from MOFs, which could trigger the lethal ferroptosis to cancer cells. Meanwhile, oxaliplatin(II) transformed from the loaded oxaliplatin prodrug would result in the chemotherapy, as well as immunogenic cell death (ICD), and the prodrug strategy could also avoid the occurring of liver damage by the direct administration of oxaliplatin(II). It was noticed that the ferroptosis effect was enhanced by triple-assistance during the combined therapy, as followed: (1) glutathione (GSH) would be consumed in the process of oxaliplatin(II) generation from oxaliplatin prodrug; (2) the increased CD8⁺ T cells induced by ICD were able to produce interferon-γ (IFN-γ), which could inhibit the transport of cystine by tumor cells, and impair the activation of glutathione peroxidase 4 (GPX4); (3) the amount of H₂O₂ could be increased by the internalized oxaliplatin and thus further promote the Fenton reaction and ferroptosis. Both in vivo and in vitro results revealed that tumor growing was significantly inhibited by PCN-Oxpt/PEG, taken together, the concomitant of oxaliplatin-mediated chemotherapy and ICD with triple-enhanced ferroptosis offer great prospect in the clinical treatment of cancer.