High-Dose Exposure to Polymer-Coated Iron Oxide Nanoparticles Elicits Autophagy-Dependent Ferroptosis in Susceptible Cancer Cells

Ferroptosis, a form of iron-dependent, lipid peroxidation-driven cell death, has been extensively investigated in recent years, and several studies have suggested that the ferroptosis-inducing properties of iron-containing nanomaterials could be harnessed for cancer treatment. Here we evaluated the potential cytotoxicity of iron oxide nanoparticles, with and without cobalt functionalization (Fe2O3 and Fe2O3@Co-PEG), using an established, ferroptosis-sensitive fibrosarcoma cell line (HT1080) and a normal fibroblast cell line (BJ). In addition, we evaluated poly (ethylene glycol) (PEG)-poly(lactic-co-glycolic acid) (PLGA)-coated iron oxide nanoparticles (Fe3O4-PEG-PLGA). Our results showed that all the nanoparticles tested were essentially non-cytotoxic at concentrations up to 100 mu g/mL. However, when the cells were exposed to higher concentrations (200-400 mu g/mL), cell death with features of ferroptosis was observed, and this was more pronounced for the Co-functionalized nanoparticles. Furthermore, evidence was provided that the cell death triggered by the nanoparticles was autophagy-dependent. Taken together, the exposure to high concentrations of polymer-coated iron oxide nanoparticles triggers ferroptosis in susceptible human cancer cells.

Automated summary

This study evaluated the cytotoxicity of iron oxide nanoparticles and their Co-functionalized counterparts, and found that cell death with features of ferroptosis occurred at higher concentrations, with the functionalized nanoparticles demonstrating stronger toxicity. Furthermore, it was shown that the cell death triggered by the nanoparticles was autophagy-dependent. Overall, high concentrations of polymer-coated iron oxide nanoparticles induce ferroptosis in susceptible human cancer cells.