A mixed-valence biotinylated Cu(I/II) complex for tumor-targeted chemodynamic therapy accompanied by GSH depletion

Chemodynamic therapy (CDT), in which highly toxic hydroxyl radicals (OH) could be triggered by a Fenton or Fenton-like reaction to kill cancer cells, has emerged recently. Compared to traditional CDT nanomaterials, herein, an atomically-precise biotinylated Cu(i/ii) complex [(CuCuCl2)-Cu-I-Cl-II(VBio)]center dot CH3OH (VBio = deprotonated O-vanillin biotinylhydrazone), denoted VBio-(CuCuII)-Cu-I, was rationally designed and synthesized successfully. This targeted Fenton-like agent, VBio-(CuCuII)-Cu-I, is constructed from a hydroxyl radical-producible Cu-I ion, a Cu-II center as a GSH depletor for an augmented CDT effect, and a biotin moiety as a cancer-targeting unit. Owing to the obvious cell selectivity discrepancy of biotin towards normal and cancerous cells, VBio-(CuCuII)-Cu-I was able to preferentially accumulate in tumor cells. Meanwhile, the Cu-I metal center could be used as a Fenton-like agent to generate OH. Furthermore, the Cu-II in VBio-(CuCuII)-Cu-I was available for successive OH production via a Cu-I/Cu-II-circulation strategy under a GSH-rich tumor site, thereby improving catalytic efficiency. More importantly, in vivo results further demonstrate that VBio-(CuCuII)-Cu-I could significantly inhibit tumor growth without obvious damage toward major organs. Therefore, this multiple-identity Fenton-like agent could provide an appreciable reference value for the design of atomically precise CDT agents.