Disulfiram-loaded lactoferrin nanoparticles for treating inflammatory diseases.
Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.
['Ou|An-Te|AT|', 'Zhang|Jia-Xin|JX|', 'Fang|Yue-Fei|YF|', 'Wang|Rong|R|', 'Tang|Xue-Ping|XP|', 'Zhao|Peng-Fei|PF|', 'Zhao|Yu-Ge|YG|', 'Zhang|Meng|M|', 'Huang|Yong-Zhuo|YZ|']
D065086:Acetaldehyde Dehydrogenase Inhibitors D000818:Animals D000893:Anti-Inflammatory Agents D040761:Biomimetic Materials D000086382:COVID-19 D003093:Colitis, Ulcerative D004195:Disease Models, Animal D004221:Disulfiram D004337:Drug Carriers D006801:Humans D007166:Immunosuppressive Agents D007781:Lactoferrin D008070:Lipopolysaccharides D008264:Macrophages D051379:Mice D008810:Mice, Inbred C57BL D053758:Nanoparticles D000069292:Pyroptosis D000086402:SARS-CoV-2 D018746:Systemic Inflammatory Response Syndrome D016896:Treatment Outcome
lactoferrin sepsis disulfiram pyroptosis ulcerative colitis inflammation macrophage-targeting delivery