Smart responsive nanoplatform via in situ forming disulfiram-copper ion chelation complex for cancer combination chemotherapy

Smart responsive nanomedicines serving as carriers can take advantage of the specific tumor microenvironment (TME) to convert non-toxic drugs into effective anticarcinogens and release chemotherapeutic drugs in situ to improve therapeutic efficiency against tumors without inducing off-target toxicity to surrounding normal tissues/cells. Herein, a pH-responsive metal-organic framework nanoparticle is constructed by encapsulating disulfiram (DSF) and doxorubicin (DOX) into the zeolitic imidazolate framework-8 (ZIF-8) and then coating with copper ion (Cu 2+ )-tannic acid (TA) complex (denoted as DSF/ [email protected] @Cu-TA) to achieve enhanced combination chemotherapy. The release of Cu 2+ from the outer shell of DSF/ [email protected] @Cu-TA and the cooperative exposure of DSF and DOX are triggered at multiple stages by mild acidity TME. The accumulation of DSF (non-toxic drugs) and Cu 2+ results in the rapid formation of high cytotoxic bis(N, N-diethyl dithiocarbamato)-Cu 2+ complexes (CuL 2 ) in situ via DSF and Cu 2+ chelating reaction, which accompany the production of ROS via Cu + -based Fenton-like reaction. Besides, the anticancer effect of DOX is augmented by CuL 2 -modulated ROS-MAPK and NF-κB signal pathways. The constructed DSF/ [email protected] @Cu-TA present significantly improved therapeutic efficiency as demonstrated both in vitro and in vivo . The strategy of nontoxicity-to-toxicity transitions with the addictive effect of chemotherapeutics provides a promising paradigm to design novel nanoplatforms for synergistic cancer chemotherapy.