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

作者：Yu Tian, Li Chen, Ming He, Hu Du, Xiaoling Qiu, Xinwu Lai, Suya Bao, Weixi Jiang, Jianli Ren, An Zhang · 发表于：ACS Applied Materials & Interfaces · 年份：2024 · DOI：10.1021/acsami.3c17659 · 被引用次数：9 · 研究领域：Heme Oxygenase-1 and Carbon Monoxide、Respiratory Support and Mechanisms、Alcohol Consumption and Health Effects

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 AR...