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

Autor: Liming Zhang, Zhifei Wang, Kaiying Jia, Xiangyu Meng, Kai Sun
Rok vydání: 2021
Předmět:
Zdroj: Chemical Engineering Journal. 415:128947
ISSN: 1385-8947
DOI: 10.1016/j.cej.2021.128947
Popis: 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 ROS-MAPK and NF-κB 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.
Databáze: OpenAIRE
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