Reactive oxygen species-activated self-amplifying prodrug nanoagent for tumor-specific Cu-chelate chemotherapy and cascaded photodynamic therapy

Disulfiram (DSF), an effective FDA-approved anti-alcoholism drug, shows potent antitumor activity by producing Cu(DTC)₂, a chelate of its metabolite diethyldithiocarbamate (DTC) and copper. However, the rapid metabolism and unselective distribution of DSF and the insufficient endogenous copper severely restrict enough bioactive Cu(DTC)₂ generation in tumor tissues to achieve satisfactory antitumor effect. Moreover, directly Cu(DTC)₂ administration also suffers from serious systemic toxicity. Herein, a Reactive Oxygen Species (ROS)-activatable self-amplifying prodrug nanoagent (HA-DQ@MOF) was developed for the stable co-delivery of DTC prodrug and Cu-quenched photosensitizer, aiming to achieve tumor-specific dual-activation of highly-toxic Cu(DTC)₂-mediated chemotherapy and cascaded photodynamic therapy (PDT). The ROS-cleavable hyaluronic acid-conjugated DTC prodrug (HA-DQ) was decorated on Cu²⁺ and photosensitizer Zn-TCPP coordinated MOF (PDT-shielded state) to construct HA-DQ@MOF. HA-DQ@MOF could specifically activated in ROS-overexpressed tumor cells to rapidly release DTC, while remaining relatively stable in normal cells. The free DTC immediately grabbed Cu²⁺ from MOF to in situ generate highly-cytotoxic Cu(DTC)₂ chelate, accompanied by MOF dissociation to restore the PDT effect of Zn-TCPP. Importantly, ROS produced by PDT could in turn trigger more DTC release, which further promoted Zn-TCPP liberation, forming a self-amplifying prodrug/photosensitizer activation positive feedback loop. Experimental results confirmed the dual-activated and combined tumor-killing effect of Cu(DTC)₂-mediated chemotherapy and Zn-TCPP-based PDT with little systemic toxicity. This work provides a dual-activated "low toxic-to-toxic" transformable treatment pattern for tumor-specific chemo-photodynamic therapy.