Repurposing Disulfiram to Combat Acute Respiratory Distress Syndrome with Targeted Delivery by LET-Functionalized Nanoplatforms.
Yu TianLi ChenMing HeHu DuXiaoling QiuXinwu LaiSuya BaoWeixi JiangJianLi RenAn ZhangPublished in: ACS applied materials & interfaces (2024)
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.
Keyphrases
- acute respiratory distress syndrome
- endothelial cells
- extracorporeal membrane oxygenation
- high glucose
- mechanical ventilation
- lps induced
- cancer therapy
- oxidative stress
- pulmonary hypertension
- drug delivery
- inflammatory response
- reactive oxygen species
- induced apoptosis
- vascular endothelial growth factor
- nlrp inflammasome
- type diabetes
- body mass index
- high dose
- diabetic rats
- intensive care unit
- cell proliferation
- immune response
- low dose
- quantum dots
- toll like receptor
- high fat diet induced
- amino acid
- mass spectrometry
- protein protein
- wound healing
- anti inflammatory
- physical activity
- insulin resistance
- skeletal muscle
- oxide nanoparticles