Different Valence States of Copper Ion Delivery against Triple-Negative Breast Cancer

Different valence states of copper (Cu) ions are involved in complicated redox reactions in vivo, which are closely related to tumor proliferation and death pathways, such as cuproptosis and chemodynamic therapy (CDT). Cu ion mediated Fenton-like reagents induced tumor cell death which presents compelling attention for the CDT of tumors. However, the superiority of different valence states of Cu ions in the antitumor effect is unknown. In this study, we investigated different valence states of Cu ions in modulating tumor cell death by Cu-chelated cyanine dye against triple-negative breast cancer. The cuprous ion (Cu⁺) and copper ion (Cu²⁺) were chelated with four nitrogen atoms of dipicolylethylenediamine-modified cyanine for the construction of Cu⁺ and Cu²⁺ chelated cyanine dyes (denoted as CC1 and CC2, respectively). Upon 660 nm laser irradiation, the CC1 or CC2 can generate reactive oxygen species, which could disrupt the cyanine structure, achieving the rapid release of Cu ions and initiating the Fenton-like reaction for CDT. Compared with Cu²⁺-based Fenton-like reagent, the CC1 with Cu⁺ exhibited a better therapeutic outcome for the tumor due to there being no need for a reduction by glutathione and a shorter route to generate more hydroxyl radicals. Our findings suggest the precision delivery of Cu⁺ could achieve highly efficient antitumor therapy.