Disulfiram-loaded lactoferrin nanoparticles for treating inflammatory diseases

• Published in: Acta pharmacologica Sinica Vol. 42; no. 11; pp. 1913 - 1920
• Main Authors: Ou, An-Te, Zhang, Jia-Xin, Fang, Yue-Fei, Wang, Rong, Tang, Xue-Ping, Zhao, Peng-Fei, Zhao, Yu-Ge, Zhang, Meng, Huang, Yong-Zhuo
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.11.2021; Springer Singapore
• Subjects: Acetaldehyde Dehydrogenase Inhibitors - pharmacology; Addictions; Animals; Anti-Inflammatory Agents - pharmacology; Biomimetic Materials - pharmacology; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - immunology; COVID-19; COVID-19 - drug therapy; COVID-19 - immunology; Cytokines; Disease Models, Animal; Disulfiram; Disulfiram - pharmacokinetics; Disulfiram - pharmacology; Drug addiction; Drug Carriers - pharmacology; Endotoxins; Humans; Immune response; Immunosuppressive Agents - pharmacology; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory diseases; Lactoferrin; Lactoferrin - metabolism; Lactoferrin - pharmacology; Lipopolysaccharides; Lipopolysaccharides - immunology; Macrophages; Macrophages - drug effects; Macrophages - immunology; Mice; Mice, Inbred C57BL; Nanoparticles; Nanoparticles - therapeutic use; Nanotechnology; Pyroptosis; Pyroptosis - drug effects; SARS-CoV-2; Sepsis; Systemic Inflammatory Response Syndrome - drug therapy; Systemic Inflammatory Response Syndrome - immunology; Systemic Inflammatory Response Syndrome - metabolism; Treatment Outcome; Ulcerative colitis; pyroptosis; macrophage-targeting delivery; inflammation; lactoferrin; disulfiram; ulcerative colitis; sepsis
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00770-w

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.