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

作　　者：Xueming Xu Yuanfeng Han Jiali Deng Shengfeng Wang Shijie Zhuo Kai Zhao Wenhu Zhou 

机构地区：[1]Hematology and Department of Critical Care Medicine,The Third Xiangya Hospital,Central South University,Changsha 410013,China [2]Xiangya School of Pharmaceutical Sciences,Central South University,Changsha 410013,China [3]Hunan Chidren's Hospital,Changsha 410007,China [4]Department of Pharmacy,The Third Xiangya Hospital,Central South University,Changsha 410013,China [5]Key Laboratory of Biological Nanotechnology of National Health Commission,Changsha 410008,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2698-2715,共18页药学学报（英文版）

基　　金：supported by National Key Research and Development Program of China(2021YFC2500802);National Natural Science Foundation of China(Nos.82071986,82073799,81771827,82272207,and 82202398);Natural Science Foundation of Hunan Province China(Nos.2021JJ20084 and 2021JJ20090);the Science and Technology Innovation Program of Hunan Province(2021RC3020,China);the Central South University Graduate Students Independent Exploration and Innovation Project(No.2021zzts0984,China);the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University(China).

摘　　要：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 programmed cell death.The therapeutic activity of DSF can be further enhanced by the presence of Cu^(2+),although the underlying mechanism of this enhancement remains unclear.In this study,we investigated the mechanistic basis of Cu^(2+)-induced enhancement and discovered that it is attributed to the formation 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 druggability 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 murine 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.

关 键 词：Drug repurposing PYROPTOSIS Nanoparticles BIOAVAILABILITY DISULFIRAM DSS-induced colitis NLRP3 inflammasome CuET 

分 类 号：R96[医药卫生—药理学]