Oxaliplatin-Loaded Mil-100(Fe) for Chemotherapy–Ferroptosis Combined Therapy for Gastric Cancer

Abstract

Oxaliplatin (Oxa) is a commonly used chemotherapy drug in the treatment of gastric cancer, but its toxic side effects and drug resistance after long-term use have seriously limited its efficacy. Loading chemotherapy drugs with nanomaterials and delivering them to the tumor site are common ways to overcome the above problems. However, nanomaterials as carriers do not have therapeutic functions on their own, and the effect of single chemotherapy is relatively limited, so there is still room for progress in related research. Herein, we construct Oxa@Mil-100(Fe) nanocomposites by loading Oxa with a metal−organic framework (MOF) Mil-100(Fe) with high biocompatibility and a large specific surface area. The pore structure of Mil-100(Fe) is conducive to a large amount of Oxa loading with a drug-loading rate of up to 27.2%. Oxa@Mil-100(Fe) is responsive to the tumor microenvironment (TME) and can release Oxa and Fe 3+ under external stimulation. On the one hand, Oxa can inhibit the synthesis of DNA and induce the apoptosis of gastric cancer cells. On the other hand, Fe 3+ can clear overexpressed glutathione (GSH) in TME and be reduced to Fe 2+ , inhibiting the activity of glutathione peroxidase 4 (GPX4), leading to the accumulation of intracellular lipid peroxides (LPO), and at the same time releasing a large number of reactive oxygen species (ROS) through the Fenton reaction, inducing ferroptosis in gastric cancer cells. With the combination of apoptosis and ferroptosis, Oxa@Mil-100(Fe) shows a good therapeutic effect, and the killing effect on gastric cancer cells is obvious. In a nude mouse model of subcutaneous tumor transplantation, Oxa@Mil-100(Fe) shows a significant inhibitory effect on tumor growth, with an inhibition rate of nearly 60%. In addition to its excellent antitumor activity, Oxa@Mil-100(Fe) has no obvious toxic or side effects. This study provides a new idea and method for the combined treatment of gastric cancer.

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

“…Moreover, the iron oxide nanoparticles AFN@CM synthesized from ATO can target-induce ferroptosis in tumor cells, with excellent anti-cancer effects and almost no side effects. In addition to the synergistic effect of ATO and Fe, the stronger antitumor effect of AFN@CM may also be USPBNPs@MCSNs (UPM) Inhibit Xc − -GSH-GPX4 √ [269] FeE@PEG NPs Increase Fe 2+ and release EGCG √ [270] HNK@Ir-HMONs-LOD(HIHL) Release HNK and Ir √ [271] sora@Fe-MIL Increase Fe 2+ and release sorafenib √ [272] Oxa@Mil-100(Fe) Induce apoptosis and release Fe 3+ √ [273] AsIr@PDA Relase IrFN √ [274] MitCuOHA Inhibit GSH √ [275] https://doi.org/10.2147/DDDT.S472178…”