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Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery

Xu et al., Pharmaceutics, doi:10.3390/pharmaceutics16050601
Apr 2024  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
 
*, now with p < 0.00000000001 from 104 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments. c19ivm.org
Non-COVID-19 In Vitro study showing enhanced antiviral activity of ivermectin against porcine epidemic diarrhea virus when loaded into nanostructured lipid carriers. Ivermectin-loaded nanostructured lipid carriers (IVM-NLCs) inhibited viral proliferation by up to 3 orders of magnitude compared to free ivermectin. IVM-NLCs also reduced reactive oxygen species accumulation, mitigated mitochondrial dysfunction, and decreased apoptosis in infected cells compared to free ivermectin. The enhanced efficacy is attributed to improved intracellular delivery of ivermectin by the nanostructured lipid carriers.
While this is not a COVID-19 study, the IVM-NLCs may potentially have similar advantages for COVID-19. As SARS-CoV-2 replicates inside host cells, improved intracellular delivery of ivermectin could be beneficial for COVID-19 treatment. IVM-NLCs reduced reactive oxygen species accumulation, mitigated mitochondrial dysfunction, and decreased apoptosis in PEDV-infected cells. These effects could potentially help to reduce the severity of COVID-19 by limiting virus-induced cell damage.
68 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N766, Dengue32,67,68, HIV-168, Simian virus 4069, Zika32,70,71, West Nile71, Yellow Fever72,73, Japanese encephalitis72, Chikungunya73, Semliki Forest virus73, Human papillomavirus52, Epstein-Barr52, BK Polyomavirus74, and Sindbis virus73.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins66,68,69,75, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing33, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination36,76, shows dose-dependent inhibition of wildtype and omicron variants31, exhibits dose-dependent inhibition of lung injury56,61, may inhibit SARS-CoV-2 via IMPase inhibition32, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation5, inhibits SARS-CoV-2 3CLpro49, may inhibit SARS-CoV-2 RdRp activity24, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages55, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation77, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1954,78, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage4, may minimize SARS-CoV-2 induced cardiac damage35,43, increases Bifidobacteria which play a key role in the immune system79, has immunomodulatory46 and anti-inflammatory65,80 properties, and has an extensive and very positive safety profile81.
Xu et al., 29 Apr 2024, China, peer-reviewed, 12 authors. Contact: gdawei0123@njau.edu.cn (corresponding author).
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery
Xiaolin Xu, Shasha Gao, Qindan Zuo, Jiahao Gong, Xinhao Song, Yongshi Liu, Jing Xiao, Xiaofeng Zhai, Haifeng Sun, Mingzhi Zhang, Xiuge Gao, Dawei Guo
Pharmaceutics, doi:10.3390/pharmaceutics16050601
Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of -31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.
to biological tests, IVM-NLCs exhibited stronger antiviral activity against PEDV than free IVM and reduced PEDV-induced mitochondrial dysfunction, which prevented ROS generation and improved viability of infected Vero cell. Moreover, IVM-NLCs also reduced PEDV-induced cell apoptosis rate. In view of the in vitro results, it would be necessary to carry out in vivo tests as soon as possible, to explore its potential in the clinical treatment of PEDV. Consequently, IVM-NLCs were demonstrated to be a potential drug against PEDV, which might provide a basis for the development of novel drugs to antagonize PEDV. Supplementary Materials: The following supporting information can be downloaded at: https://www. mdpi.com/article/10.3390/pharmaceutics16050601/s1, Figure S1 : Cytotoxicity of Vero cells treated with different concentration of IVM at the appointed time via CCK-8 assay; Figure S2 : Antiviral activity of IVM-NLCs was measured by CCK-8 assay; Table S1 Characterization of as-prepared IVM-NLCs. Author Contributions: Conceptualization, D.G. and X.X.; methodology, X.X., S.G., Q.Z., J.G. and X.S.; formal analysis, X.X., S.G., Q.Z., J.G., X.S., Y.L., J.X., M.Z. and X.G.; investigation, X.X., S.G., Q.Z. and D.G.; resources, Y.L., J.X. and M.Z.; data curation, X.Z. and H.S.; writing-original draft preparation, X.X., S.G., Q.Z., X.S. and J.X.; writing-review and editing, D.G., J.G., Y.L., H.S., X.Z., M.Z. and X.G.; supervision, D.G., X.G., X.Z. and H.S,; project administration,..
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