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

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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.

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Acknowledgements

We greatly acknowledge the financial support from the National Key R&D Program of China (Nos. 2016YFA0203700 and 2016YFC1101201), the National Natural Science Foundation of China (Nos. 31771026, 81771984, and 51672303), Excellent Young Scientist Foundation of NSFC (No. 51722211), Program of Shanghai Subject Chief Scientist (No. 18XD1404300), and International Collaboration Project of Chinese Academy of Sciences (No. GJHZ2072).

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  1. Hao Chen and Xi Li contributed equally to this work.

Authors and Affiliations

  1. School of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China

    Hao Chen, Xi Li, Wei Chen & Bailiang Wang

  2. School of Life Sciences, Shanghai University, Shanghai, 200444, China

    Yu Chen

  3. State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, China

    Minfeng Huo & Yu Chen

  4. Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Liying Wang

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  1. Hao Chen
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  2. Xi Li
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  3. Minfeng Huo
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  5. Yu Chen
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  6. Wei Chen
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Correspondence to Minfeng Huo, Yu Chen or Bailiang Wang.

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Chen, H., Li, X., Huo, M. et al. Tumor-responsive copper-activated disulfiram for synergetic nanocatalytic tumor therapy. Nano Res. 14, 205–211 (2021). https://doi.org/10.1007/s12274-020-3069-1

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