Affiliation:
1. State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 P. R. China
2. University of Science and Technology of China Hefei 230026 P. R. China
3. College of Materials Science and Chemical Engineering Harbin Engineering University Harbin 150001 P. R. China
Abstract
AbstractDespite its effectiveness in exterminating tumor cells, ferroptosis is seriously hampered by the high expression of antioxidant glutathione (GSH) and the inadequacy of endogenous H2O2 in tumors. Herein, metal‐phenolic nanoformulations (FNCP NFs) composed of sonosensitizer Chlorin e6 (Ce6), the phenolic GSH consumer naphthazarin, and Fe3+, followed by the modification of PEG2000, are strategically designed and fabricated for ultrasound‐boosted ferroptosis in tumor cells through triple regulatory pathways. The carrier‐free FNCP NFs can rapidly dissociate under tumor microenvironment response with the assistance of ultrasound, releasing Fe2+, Ce6, and naphthazarin. Ce6 and Fe2+ are capable of producing singlet oxygen (1O2) and hydroxyl radicals (·OH) by ultrasound‐activated sonodynamic therapy and Fenton reaction‐mediated chemodynamic therapy (CDT), respectively, which not only induce apoptotic cell death but also lead to the effective accumulation of lipid peroxidation (LPO), resulting in ferroptosis. Meanwhile, the released naphthazarin and the self‐cycling valence alternations of Fe3+/Fe2+ promote the significant decrease of intracellular GSH contents, further inducing the inactivation of glutathione peroxidase 4 (GPX4) and the up‐regulation of LPO levels, eventually realizing the synergistically enhanced ferroptosis. This facile and feasible design for versatile metal‐phenolic nanoformulations offers a new strategy for effectively improving ferroptosis efficiency and multimodal cancer therapies.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China