Cu–Ferrocene‐Functionalized CaO₂ Nanoparticles to Enable Tumor‐Specific Synergistic Therapy with GSH Depletion and Calcium Overload

Abstract The conversion of endogenous H 2 O 2 into toxic hydroxyl radical ( • OH) via catalytic nanoparticles is explored for tumor therapy and received considerable success. The intrinsic characteristics of microenvironment in tumor cells, such as limited H 2 O 2 and overexpressed glutathione (GSH), hinder the intracellular • OH accumulation and thus weaken therapeutic efficacy considerably. In this study, fine CaO 2 nanoparticles with Cu–ferrocene molecules at the surface (CaO 2 /Cu–ferrocene) are successfully designed and synthesized. Under an acidic condition, the particles release Ca 2+ ions and H 2 O 2 in a rapid fashion, while they can remain stable in neutral. In addition, agitated production of • OH occurs following the Fenton reaction of H 2 O 2 and ferrocene molecules, and GSH is consumed by Cu 2+ ions to avoid the potential • OH consumption. More interestingly, in addition to the exogenous Ca 2+ released by the particles, the enhanced • OH production facilitates intracellular calcium accumulation by regulating Ca 2+ channels and pumps of tumor cells. It turns out that promoted • OH induction and intracellular calcium overload enable significant in vitro and in vivo antitumor phenomena.

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