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 (Cu2+)-tannic acid (TA) complex (denoted as DSF/DOX@ZIF-8@Cu-TA) to achieve enhanced combination chemotherapy. The release of Cu2+ from the outer shell of DSF/DOX@ZIF-8@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 Cu2+ results in the rapid formation of high cytotoxic bis(N, N-diethyl dithiocarbamato)Cu2+ complexes (CuL2) in situ via DSF and Cu2+ chelating reaction, which accompany the production of ROS via Cu+-based Fenton-like reaction. Besides, the anticancer effect of DOX is augmented by CuL2-modulated ROSMAPK and NF-KB signal pathways. The constructed DSF/DOX@ZIF-8@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.

Automated summary

Smart responsive nanomedicines acting as carriers can release chemotherapeutic drugs in the tumor microenvironment to enhance therapeutic efficiency while minimizing toxicity to surrounding normal tissues.