A fibroblast activation protein α-activatable nanoagent co-delivering diethyldithiocarbamate and copper for tumor therapy and imaging

Disulfiram (DSF), an FDA-approved drug for treating alcoholism, has been verified with Cu²⁺-dependent anticancer activity by forming Cu(DTC)₂, the complex of one of its metabolites diethyldithiocarbamate (DTC) and Cu²⁺. Nevertheless, the antitumor effect is limited by insufficient Cu(DTC)₂ formation in suit and off-target system toxicity. Herein, we developed a fibroblast activation protein α (FAPα) activatable nanoagent (HfD-HID-Cu) for co-delivery of DTC polymeric prodrug and exogenous Cu²⁺ to achieve enhanced cancer-specific therapy and activatable in situ fluorescence imaging meanwhile. HfD-HID-Cu was simply constructed through the co-assembly of the DTC polymeric prodrug (HA-fap-DTC) and the copper-loaded IR808-conjugated polymer (HA-IR-DPA-Cu), which could serve as the “OFF-to-ON” switch for chemotherapy and fluorescence. With the high expression of FAPα in tumor tissues, HA-fap-DTC could be activated specifically to release DTC, while maintaining inactive in normal tissues. The liberated DTC within tumor tissues could contend for Cu²⁺ from HA-IR-DPA-Cu, resulting in the formation of highly cytotoxic Cu(DTC)₂ in situ for chemotherapy, concomitant with the fluorescence recovery of cyanine dye for tumor imaging. This work provides an effective strategy for co-delivery of DTC prodrug and Cu²⁺ for tumor theranostic with improved selectivity and minimal side effects.

Statement of significance

DSF-based antitumor therapy is highly dependent on Cu²⁺. However, the non-synchronous distribution of DSF/DTC and Cu²⁺ in tumor tissues attenuates the antitumor efficacy. The insufficient Cu(DTC)₂ formation in suit and off-target distribution greatly limit the anti-tumor application. This study provides a nanoagent for co-delivery of DTC polymeric prodrug and Cu²⁺ by simple co-assembly to achieve their synchronous tumor distribution. It can be selectively activated by FAPα, forming cytotoxic Cu(DTC)₂ in suit for tumor-specific chemotherapy and reducing the systemic toxicity. In addition to chemotherapy, the nanoagent can emit fluorescence under the sequential triggering of FAPα and released DTC for tumor imaging. Overall, this study renders a promising strategy for improved Cu(DTC)₂-based antitumor therapy and imaging.