Ferrous ions doped calcium carbonate nanoparticles potentiate chemotherapy by inducing ferroptosis

Ferroptosis is a recently identified regulated cell death pathway featured in iron prompted lipid peroxidation inside cells and found to be an effective approach to suppress tumor growth. Motived by the high efficacy of ferrous ions (Fe2+) in initiating intracellular lipid peroxidation via the Fenton reaction, this study herein prepares a pH-responsive Fe2+ delivery nanocarrier by coating calcium carbonate (CaCO3) nanoparticles with a metal-polyphenol coordination polymer composed of gallic acid (GA) and Fe2+. Together with simultaneous encapsulation of succinic acid conjugated cisplatin prodrugs (Pt(IV)-SA) and Fe2+, the yielded nanoparticles, coined as PGFCaCO3, are synthesized and exhibit uniform hollow structure. After PEGylation, the resulted PGFCaCO3-PEG shows increased physiological stability and pH-dependent decomposition, drug release and catalytic capability in initiating lipid peroxidation. After being endocytosed, PGFCaCO3-PEG effectively promoted intracellular generation of cytotoxic reactive oxygen species including lipid peroxide, thereby exhibited superior inhibition effect towards both murine 4T1 and CT26 cancer cells over Pt(IV)-SA and GFCaCO3-PEG. As a result, treatment with systemic administration of PGFCaCO3-PEG effectively suppressed 4T1 tumor growth via combined Fe2+ initiated ferroptosis and Pt(IV)-SA mediated chemotherapy. This work highlights that intracellular delivery of Fe2+ is a robust approach to enhance tumor chemotherapy by inducing ferroptosis.