Repurposing Disulfiram to Combat Acute Respiratory Distress Syndrome with Targeted Delivery by LET-Functionalized Nanoplatforms

作者全名："Tian, Yu; Chen, Li; He, Ming; Du, Hu; Qiu, Xiaoling; Lai, Xinwu; Bao, Suya; Jiang, Weixi; Ren, Jianli; Zhang, An"

作者地址："[Tian, Yu; Chen, Li; He, Ming; Du, Hu; Qiu, Xiaoling; Lai, Xinwu; Bao, Suya; Zhang, An] Chongqing Med Univ, Affiliated Hosp 2, Dept Crit Care Med, Chongqing 400010, Peoples R China; [Jiang, Weixi; Ren, Jianli] Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China"

通信作者："Zhang, A (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Crit Care Med, Chongqing 400010, Peoples R China.; Jiang, WX; Ren, JL (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China."

来源：ACS APPLIED MATERIALS & INTERFACES

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:001178597900001

JCR分区：Q1

影响因子：8.3

年份：2024

卷号：16

期号：10

开始页：12244

结束页：12262

文献类型：Article

关键词：disulfiram; lung endothelial cell; acute respiratorydistress syndrome; lung-targeted therapy; vascularendothelial cell pyroptosis

摘要："Acute respiratory distress syndrome (ARDS) is a serious respiratory condition characterized by a damaged pulmonary endothelial barrier that causes protein-rich lung edema, an influx of proinflammatory cells, and treatment-resistant hypoxemia. Damage to pulmonary endothelial cells and inflammation are pivotal in ARDS development with a key role played by endothelial cell pyroptosis. Disulfiram (DSF), a drug that has long been used to treat alcohol addiction, has recently been identified as a potent inhibitor of gasdermin D (GSDMD)-induced pore formation and can thus prevent pyroptosis and inflammatory cytokine release. These findings indicate that DSF is a promising treatment for inflammatory disorders. However, addressing the challenge posed by its intrinsic physicochemical properties, which hinder intravenous administration, and effective delivery to pulmonary vascular endothelial cells are crucial. Herein, we used biocompatible liposomes incorporating a lung endothelial cell-targeted peptide (CGSPGWVRC) to produce DSF-loaded nanoparticles (DTP-LET@DSF NPs) for targeted delivery and reactive oxygen species-responsive release facilitated by the inclusion of thioketal (TK) within the liposomal structure. After intravenous administration, DTP-LET@DSF NPs exhibited excellent cytocompatibility and minor systemic toxicity, effectively inhibited pyroptosis, mitigated lipopolysaccharide (LPS)-induced ARDS, and prevented cytokine storms resulting from excessive immune reactions in ARDS mice. This study presents a straightforward nanoplatform for ARDS treatment that potentially paves the way for the clinical use of this nanomedicine."

基金机构：The 2022 Emergency Special Project for COVID-19 Infection [2023IITXG06]

基金资助正文：This work was supported by The 2022 Emergency Special Project for COVID-19 Infection (#2023IITXG06 to A.Z.).