Redox-Dependent Copper Carrier Promotes Cellular Copper Uptake and Oxidative Stress-Mediated Apoptosis of Cancer Cells

Transportation of exogenous copper ions into cancer cells by copper carriers has gained increasing interest for cancer chemotherapy. We disclosed herein a redox-dependent copper carrier, 2,2'-dithiodipyridine (DPy), which 1 binds copper ions and carries the cargo into cells. The cellular reducing environment cleaved the disulfide bond in DPy to facilitate unloading copper ions. The elevated copper level then elicits oxidative stress and subsequently promotes the reformation of DPy. Further mechanistic studies revealed that the DPy/copper combination predominantly targets the cellular redox-regulating systems, including the thioredoxin system and the glutathione system, to induce the oxidative stress-mediated death of tumor cells. The discovery of DPy as a cleavable and recyclable copper shuttle provides a proof of concept for designing novel biomaterials for copper transportation as potential anticancer agents.