Enhancing Intracellular Uptake of Ivermectin through Liposomal Encapsulation

DOI record: { "DOI": "10.1208/s12249-025-03113-8", "ISSN": [ "1530-9932" ], "URL": "http://dx.doi.org/10.1208/s12249-025-03113-8", "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 &gt; 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>", "alternative-id": [ "3113" ], "article-number": "123", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "19 November 2024" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "10 April 2025" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "2 May 2025" }, { "group": { "label": "Declarations", "name": "EthicsHeading" }, "name": "Ethics", "order": 1 }, { "group": { "label": "Conflict of interest", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "The authors declare no conflict of interest." } ], "author": [ { "ORCID": "https://orcid.org/0000-0002-4165-6191", "affiliation": [], "authenticated-orcid": false, "family": "Kocas", "given": "Meryem", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-3503-8696", "affiliation": [], "authenticated-orcid": false, "family": "Yamashita", "given": "Fumiyoshi", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-4221-5814", "affiliation": [], "authenticated-orcid": false, "family": "Comoglu", "given": "Tansel", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-8440-2071", "affiliation": [], "authenticated-orcid": false, "family": "Zhang", "given": "Qiyue", "sequence": "additional" } ], "container-title": "AAPS PharmSciTech", "container-title-short": "AAPS PharmSciTech", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2025, 5, 2 ] ], "date-time": "2025-05-02T16:07:57Z", "timestamp": 1746202077000 }, "deposited": { "date-parts": [ [ 2025, 5, 2 ] ], "date-time": "2025-05-02T17:02:50Z", "timestamp": 1746205370000 }, "funder": [ { "name": "Social Science University of Ankara" } ], "indexed": { "date-parts": [ [ 2025, 5, 3 ] ], "date-time": "2025-05-03T04:09:38Z", "timestamp": 1746245378192, "version": "3.40.4" }, "is-referenced-by-count": 0, "issue": "5", "issued": { "date-parts": [ [ 2025, 5, 2 ] ] }, "journal-issue": { "issue": "5", "published-online": { "date-parts": [ [ 2025, 6 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 5, 2 ] ], "date-time": "2025-05-02T00:00:00Z", "timestamp": 1746144000000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 5, 2 ] ], "date-time": "2025-05-02T00:00:00Z", "timestamp": 1746144000000 } } ], "link": [ { "URL": "https://link.springer.com/content/pdf/10.1208/s12249-025-03113-8.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/article/10.1208/s12249-025-03113-8/fulltext.html", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/content/pdf/10.1208/s12249-025-03113-8.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1208", "published": { "date-parts": [ [ 2025, 5, 2 ] ] }, "published-online": { "date-parts": [ [ 2025, 5, 2 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1016/j.pt.2014.07.005", "author": "S Omura", "doi-asserted-by": "publisher", "first-page": "445", "issue": "9", "journal-title": "Trends Parasitol", "key": "3113_CR1", "unstructured": "Omura S, Crump A. 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