posted on 2024-02-29, 15:08authored byYu Tian, Li Chen, Ming He, Hu Du, Xiaoling Qiu, Xinwu Lai, Suya Bao, Weixi Jiang, Jianli Ren, An Zhang
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.