Enhancing Intracellular Uptake of Ivermectin through Liposomal Encapsulation
et al., AAPS PharmSciTech, doi:10.1208/s12249-025-03113-8, May 2025
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,200+ studies for
200+ treatments. c19early.org
|
In vitro study showing enhanced intracellular uptake of ivermectin through liposomal encapsulation in Vero E6 cells with reduced cytotoxicity. While free ivermectin showed a half-maximal cytotoxic concentration (CC50) of 10 μM, liposomal formulations exhibited CC50 values exceeding 110 μM, demonstrating significantly reduced toxicity. Cellular uptake of ivermectin-loaded liposomes ranged from 13-60%, compared to only 2% for free ivermectin. This improved delivery approach builds on the authors' previous study that demonstrated enhanced antiviral efficacy of liposomal ivermectin against SARS-CoV-2 in Vero E6 cells. Liposomal encapsulation offers advantages including enhanced solubility for the highly hydrophobic ivermectin, passive targeting of immune cells, sustained release, and improved tissue penetration.
74 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 H7N771, Dengue37,72,73 , HIV-173, Simian virus 4074, Zika37,75,76 , West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
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Kocas et al., 2 May 2025, peer-reviewed, 4 authors.
Contact: comoglu@pharmacy.ankara.edu.tr.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Enhancing Intracellular Uptake of Ivermectin through Liposomal Encapsulation
AAPS PharmSciTech, doi:10.1208/s12249-025-03113-8
Ivermectin (IVM), an antiparasitic drug approved by the Food and Drug Administration (FDA), is widely used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies. Additionally, IVM has shown potential as a potent inhibitor of certain RNA viruses, such as SARS-CoV-2. However, IVM is highly hydrophobic, essentially insoluble in water, which limits its bioavailability and therapeutic effectiveness. The use of liposomes as drug carriers offers several advantages, including enhanced solubility for lipophilic drugs, passive targeting of immune system cells, sustained release, and improved tissue penetration. To address the limitations of IVM, including its poor solubility and bioavailability, liposomal formulations were developed using a combination of soyphosphatidylcholine (SPC), dioleylphosphatidylcholine (DOPC), cholesterol (Ch), and diethylphosphate (DCP) in two distinct molar ratios (1.85:1:0.15 and 7:2:1) via the ethanol injection method. The physicochemical properties of the placebo and IVM-loaded liposomes were extensively characterized in our earlier study, including the particle size, polydispersity index, and zeta potential. The present work adds a deeper level of investigation into how to effect cellular uptake and cytotoxicity in vitro of both free IVM and IVM-loaded liposomes in Vero E6 cells. The half-maximal cytotoxic concentrations (CC 50 ) for free IVM and IVM-loaded liposomes were 10 μM and > 110 μM, respectively and the cellular uptake of IVM-loaded liposomes ranged from 13 to 60%, whereas free IVM showed a significantly lower uptake of only 2%. These results demonstrate that liposomal encapsulation effectively enhances IVM's cellular uptake while reducing its cytotoxicity, thus offering a promising strategy for improving the effectiveness of IVM.
Supplementary Information The online version contains supplementary material available at https:// doi . org/ 10. 1208/ s12249-025-03113-8. Author Contributions Meryem Kocas (ORCID: 0000-0002-4165-6191): The author contributed to the conception or design of the study; acquisition, analysis and interpretation of data for the study. She has also drafted or critically revised the manuscript for important intellectual content; and has agreed to be responsible for final approval of the version to be published and for all aspects of the publication. Fumiyoshi Yamashita (ORCID: 0000-0002-3503-8696): The author contributed to the conception or design of the study; acquisition, analysis and interpretation of data for the study. He has also drafted or critically revised the manuscript for important intellectual content; and has agreed to be responsible for final approval of the version to be published and for all aspects of the publication. Tansel Comoglu (ORCID: 0000-0002-4221-5814): The author contributed to the conception or design of the study; acquisition, analysis and interpretation of data for the study. She has also drafted or critically revised the manuscript for important intellectual content; and has agreed to be responsible for final approval of the version to be published and for all aspects of the publication. Qiyue Zhang (ORCID: 0000-0001-8440-2071): The author contributed to the conception or design of the study; acquisition, analysis and interpretation of data for the..
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>Ivermectin (IVM), an antiparasitic drug approved by the Food and Drug Administration (FDA), is widely used to treat several neglected tropical diseases, including onchocerciasis, helminthiases, and scabies. Additionally, IVM has shown potential as a potent inhibitor of certain RNA viruses, such as SARS-CoV-2. However, IVM is highly hydrophobic, essentially insoluble in water, which limits its bioavailability and therapeutic effectiveness. The use of liposomes as drug carriers offers several advantages, including enhanced solubility for lipophilic drugs, passive targeting of immune system cells, sustained release, and improved tissue penetration. To address the limitations of IVM, including its poor solubility and bioavailability, liposomal formulations were developed using a combination of soyphosphatidylcholine (SPC), dioleylphosphatidylcholine (DOPC), cholesterol (Ch), and diethylphosphate (DCP) in two distinct molar ratios (1.85:1:0.15 and 7:2:1) via the ethanol injection method. The physicochemical properties of the placebo and IVM-loaded liposomes were extensively characterized in our earlier study, including the particle size, polydispersity index, and zeta potential. The present work adds a deeper level of investigation into how to effect cellular uptake and cytotoxicity <jats:italic>in vitro</jats:italic> of both free IVM and IVM-loaded liposomes in Vero E6 cells. The half-maximal cytotoxic concentrations (CC<jats:sub>50</jats:sub>) for free IVM and IVM-loaded liposomes were 10 μM and > 110 μM, respectively and the cellular uptake of IVM-loaded liposomes ranged from 13 to 60%, whereas free IVM showed a significantly lower uptake of only 2%. These results demonstrate that liposomal encapsulation effectively enhances IVM’s cellular uptake while reducing its cytotoxicity, thus offering a promising strategy for improving the effectiveness of IVM.</jats:p>\n <jats:p>\n <jats:bold>Graphical Abstract</jats:bold>\n </jats:p>",
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