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

Abstract

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 [Cu^ICu^IICl₂(VBio)]·CH₃OH (VBio = deprotonated O-vanillin biotinylhydrazone), denoted VBio-Cu^ICu^II, was rationally designed and synthesized successfully. This targeted Fenton-like agent, VBio-Cu^ICu^II, 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-Cu^ICu^II 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-Cu^ICu^II 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-Cu^ICu^II 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.