Activate the endogenous Cu 2+ switch for Zn(DDC) 2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC) ₂ to overcome the limitations, like the poor water solubility. However, Cu (DDC) ₂ liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn ²⁺ to form zinc diethyldithiocarbamate (Zn (DDC) ₂ ). Furthermore, this study prepared stable and homogeneous Zn (DDC) ₂ liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC) ₂ was converted to Cu (DDC) ₂ with the help of endogenous Cu ²⁺ -switch enriched in the TME, which has a higher stability constant compared with Zn (DDC) ₂ . In other words, the Cu ²⁺ -switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC) ₂ to the more cytotoxic Cu (DDC) ₂ for effective tumor therapy so that the Zn (DDC) ₂ liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC) ₂ liposomes in cancer therapy.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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