A Highly‐Active Chemodynamic Agent Based on In Situ Generated Copper Complexes from Copper Hexacyanoferrate Nanoparticles

Copper hexacyanoferrate (Cu₂Fe(CN)₆) nanocubes with a homogeneous size under 100 nm are synthesized by self-assembly from Cu²⁺ and Fe(CN)₆ ^3- precursors. Similar to previous reports with catalysts containing Cu and Fe, the objective is to produce a nanoparticle catalyst that can promote glutathione (GSH) oxidation thanks to the Cu contribution, plus some ROS production through Fenton-like processes fostered by Fe. Unexpectedly, the catalytic activity for GSH oxidation are much higher (≈50%) than those obtained with equal Cu amounts provided as CuCl₂. Furthermore, in the presence of GSH concentrations characteristic of the tumor microenvironment, the nanocubes disassembled homogeneously, without a noticeably change of composition. These results suggest that this strong increase of catalytic activity arises from synergistic coordination of the released Cu²⁺ and Fe(CN)₆ ^3- ions that facilitate GSH deprotonation, accelerating its oxidation. Given the role of GSH in the nanoparticle disassembly process, a selective action of the catalyst can be obtained: lethal doses as low as 18 ppm of Cu are obtained for U251-MG cancer cells while healthy fibroblasts are largely spared.