首页|Repurposing disulfiram with CuET nanocrystals:Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases

Repurposing disulfiram with CuET nanocrystals:Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases

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Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs.Recently,disulfiram(DSF),a drug primarily used for alcohol addiction treatment,has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis,a form of pro-grammed cell death.The therapeutic activity of DSF can be further enhanced by the presence of Cu2+,although the underlying mechanism of this enhancement remains unclear.In this study,we inves-tigated the mechanistic basis of Cu2+-induced enhancement and discovered that it is attributed to the for-mation of a novel copper ethylthiocarbamate(CuET)complex.CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action.However,despite its potent activity,CuET suffered from poor solubility and limited permeability,as revealed by our drugg-ability studies.To overcome these intrinsic limitations,we developed a scalable method to prepare CuET nanocrystals(CuET NCs)using a metal coordination-driven self-assembly approach.Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability.Notably,CuET NCs exhibited high biodistribution in the intestine,suggesting their potential application for the treatment of inflammatory bowel diseases(IBDs).To evaluate their therapeutic efficacy in vivo,we employed a mu-rine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms.Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent,and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.

Drug repurposingPyroptosisNanoparticlesBioavailabilityDisulfiramDSS-induced colitisNLRP3 inflammasomeCuET

Xueming Xu、Yuanfeng Han、Jiali Deng、Shengfeng Wang、Shijie Zhuo、Kai Zhao、Wenhu Zhou

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Hematology and Department of Critical Care Medicine,The Third Xiangya Hospital,Central South University,Changsha 410013,China

Xiangya School of Pharmaceutical Sciences,Central South University Changsha 410013,China

Hunan Chidren's Hospital,Changsha 410007,China

Department of Pharmacy,The Third Xiangya Hospital,Central South University,Changsha 410013,China

Key Laboratory of Biological Nanotechnology of National Health Commission,Changsha 410008,China

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National Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNatural Science Foundation of Hunan Province ChinaNatural Science Foundation of Hunan Province ChinaScience and Technology Innovation Program of Hunan Province,ChinaCentral South University Graduate Students Independent Exploration and Innovation Project,ChinaWisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University(China)

2021YFC250080282071986820737998177182782272207822023982021JJ200842021JJ200902021RC30202021zzts0984

2024

10.1016/j.apsb.2024.03.003

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(6)
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