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.
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Acknowledgements
We are thankful for the support from National Key Research and Development Program of China (2021YFE0103100, China), NFSC (81925035 and 81521005), and National Special Project for Significant New Drugs Development (2018ZX09711002-010-002), and Shanghai SciTech Innovation Initiative (19431903100, 18430740800) and Shanghai Collaborative Innovation Group of Early Diagnosis and Precise Treatment of Hemangiomas and Vascular Malformations (SSMU-ZDCX20180701) for the support. We thank the Molecular Imaging Center and TEM Facility at SIMM and the National Center for Protein Science Shanghai, CAS, for the technical support at flow cytometry and MALDI-TOF MASS Facility.
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ATO: Investigation, Data curation, Formal analysis, Writing original draft. JXZ and YFF: Investigation, Visualization, Methodology. RW and XPT: Investigation, Validation. PFZ, YGZ, MZ: Methodology, Validation. YZH: Formal analysis, Project administration, Supervision, Writing—review & editing.
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Ou, At., Zhang, Jx., Fang, Yf. et al. Disulfiram-loaded lactoferrin nanoparticles for treating inflammatory diseases. Acta Pharmacol Sin 42, 1913–1920 (2021). https://doi.org/10.1038/s41401-021-00770-w
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DOI: https://doi.org/10.1038/s41401-021-00770-w
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