| Summary: | To evaluate the iron ion release profile of zero-valent iron (ZVI)-based nanoparticles (NPs) and their relationship with lysosomes in cancer cells, silica and mesoporous silica-coated ZVI NPs (denoted as ZVI@SiO<sub>2</sub> and ZVI@mSiO<sub>2</sub>) were synthesized and characterized for the following study of cytotoxicity, intracellular iron ion release, and their underlying mechanisms. ZVI@mSiO<sub>2</sub> NPs showed higher cytotoxicity than ZVI@SiO<sub>2</sub> NPs in the OEC-M1 oral cancer cell line. In addition, internalized ZVI@mSiO<sub>2</sub> NPs deformed into hollow and void structures within the cells after a 24-h treatment, but ZVI@SiO<sub>2</sub> NPs remained intact after internalization. The intracellular iron ion release profile was also accordant with the structural deformation of ZVI@mSiO<sub>2</sub> NPs. Burst iron ion release occurred in ZVI@mSiO<sub>2</sub>-treated cells within an hour with increased lysosome membrane permeability, which induced massive reactive oxygen species generation followed by necrotic and apoptotic cell death. Furthermore, inhibition of endosome−lysosome system acidification successfully compromised burst iron ion release, thereby reversing the cell fate. An in vivo test also showed a promising anticancer effect of ZVI@mSiO<sub>2</sub> NPs without significant weight loss. In conclusion, we demonstrated the anticancer property of ZVI@mSiO<sub>2</sub> NPs as well as the iron ion release profile in time course within cells, which is highly associated with the surface coating of ZVI NPs and lysosomal acidification.
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