Disulfiram-loaded lactoferrin nanoparticles for treating inflammatory diseases.

Abstract

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.

• Authors: An-Te Ou, Jia-Xin Zhang, Yue-Fei Fang, Rong Wang, Xue-Ping Tang, Peng-Fei Zhao, Yu-Ge Zhao, Meng Zhang, Yong-Zhuo Huang
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 42 Issue 11 Pg. 1913-1920 (11 2021) ISSN: 1745-7254 [Electronic] United States
• PMID: 34561552 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Acetaldehyde Dehydrogenase Inhibitors
• Anti-Inflammatory Agents
• Drug Carriers
• Immunosuppressive Agents
• Lipopolysaccharides
• Lactoferrin
• Disulfiram

Topics

• Acetaldehyde Dehydrogenase Inhibitors (pharmacology)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Biomimetic Materials (pharmacology)
• COVID-19 (immunology)
• Colitis, Ulcerative (drug therapy, immunology)
• Disease Models, Animal
• Disulfiram (pharmacokinetics, pharmacology)
• Drug Carriers (pharmacology)
• Humans
• Immunosuppressive Agents (pharmacology)
• Lactoferrin (metabolism, pharmacology)
• Lipopolysaccharides (immunology)
• Macrophages (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Nanoparticles (therapeutic use)
• Pyroptosis (drug effects)
• SARS-CoV-2
• Systemic Inflammatory Response Syndrome (drug therapy, immunology, metabolism)
• Treatment Outcome
• COVID-19 Drug Treatment