Tumor-responsive copper-activated disulfiram for synergetic nanocatalytic tumor therapy

Exploring alternative biomedical use of traditional drugs in different disease models is highly important as it can reduce the cost of drug development and overcome several critical issues of traditional chemodrugs such as low chemotherapeutic efficiency, severe side effect, and drug resistance. Disulfiram (DSF), a clinically approved alcohol-aversion drug, was recently demonstrated to feature tumor-growth suppression effect along with the co-administration of Cu²⁺ species, but direct Cu²⁺ administration mode might cause severe toxicity originating from low Cu²⁺ accumulation into the tumor and nonspecific Cu²⁺ distribution-induced cytotoxicity. Based on the intriguing drug-delivery performance of nanoscale metal-organic frameworks (MOFs), we herein construct HKUST nMOFs as the Cu²⁺ self-supplying nanocarriers for efficient delivery of the DSF drug. The mildly acidic condition of tumor microenvironment initially triggered the release of Cu ions from HKUST nMOFs, which further reacted with the encapsulated DSF to form toxic Cu(DDTC)₂ (activation) for tumor chemotherapy. Especially, during the Cu(DDTC)₂ complexation, Cu⁺ species were formed concomitantly, triggering the intratumoral nanocatalytic therapy for the generation of reactive oxygen species to synergistically destroying the tumor cells/tissue. As a result, synergetic tumor-responsive chemotherapy and nanocatalytic therapy are enabled by DSF@HKUST nanodrugs, as demonstrated by the dominant anticancer efficacy with satisfied biocompatibility both in vitro and in vivo. The present work offers a sophisticated strategy for tumor-responsive nontoxic-to-toxic therapeutic with high biocompatibility.