Tumor-responsive copper-activated disulfiram for synergetic nanocatalytic tumor therapy
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Tumor-responsive copper-activated disulfiram for synergetic nanocatalytic tumor therapy Hao Chen1,§, Xi Li1,§, Minfeng Huo3 (), Liying Wang4, Yu Chen2,3 (), Wei Chen1, and Bailiang Wang1 () School of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China School of Life Sciences, Shanghai University, Shanghai 200444, China 3 State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China 4 Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China § Hao Chen and Xi Li contributed equally to this work. 1 2
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 19 March 2020 / Revised: 18 August 2020 / Accepted: 22 August 2020
ABSTRACT 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.
KEYWORDS disulfiram, metal-organic frameworks, chemotherapy, Fenton-like reaction, tumor suppression
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Introduction
Traditional chemotherapy has been clinically favorable treatment approach in cancer therapy for almost a century [1–3]. A variety of chemodrugs has been explored and developed as chemotherapeutic drugs for carcinoma destruction [4, 5]. In a large extent, chemotherapy has made a great step towards cancer healing. However, due to the intrinsic biological toxicities of most chemotherapeutic drugs, the non-tumo
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