Cu–Ferrocene‐Functionalized CaO(2) Nanoparticles to Enable Tumor‐Specific Synergistic Therapy with GSH Depletion and Calcium Overload

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.