Engineering copper (II) in situ reduction and delivery by a novel amphiphilic diacylhydrazone for chemodynamic therapy.

Chemodynamic treatment (CDT) possesses the ability to disturb intracellular redox equilibrium, thus inhibiting tumor development. The copper-induced CDT generally needs the delivery of copper (II) ions to tumor cells and reacting with local GSH, to produce Cu+, and thus generating toxic hydroxyl radicals (·OH) via a Fenton-like reaction. Due to an insufficient amount of endogenous GSH, it remains a great challenge to achieve satisfactory anticancer efficacy and the development of a receptor with the capability of both binding and reducing Cu (II) ions is valuable. In this study, we synthesized a novel amphiphilic diacylhydrazone (compound 1) by a brief chemical reaction. Compound 1 was not only capable of complexation with copper(II) ions but able to reduce the divalent copper ions partially to the monovalent ones. The generated assembly (complex 1) containing mixed Cu (I)/Cu (II) presents a spherical-like nanoparticle, which could easily enter the HCT-116 cells and release both Cu+ and Cu2+ in a mildly acidic environment. The complex 1 therefore inhibited the growth of HCT-116 cells due to the mitochondrial damage initiated by the enhanced Fenton-like effect and the growth inhibition rate of in vivo colon cancer proliferation reached 85.12 %, significantly higher than that of its components of either compound 1 or Cu(ClO4)2, as well as paclitaxel (the positive control). Meanwhile, complex 1 had relatively low toxicity. This work provided a reference for transit Cu (I/II)-mediated precision-targeted CDT therapeutic regimen.