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High-Frequency Irreversible Electroporation (H-FIRE) Induced Blood-Brain Barrier Disruption Is Mediated by Cytoskeletal Remodeling and Changes in Tight Junction Protein Regulation

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dc.contributor.authorPartridge, Brittanie R.en
dc.contributor.authorKani, Yukitakaen
dc.contributor.authorLorenzo, Melvin F.en
dc.contributor.authorCampelo, Sabrina N.en
dc.contributor.authorAllen, Irving C.en
dc.contributor.authorHinckley, Jonathanen
dc.contributor.authorHsu, Fang-Chien
dc.contributor.authorVerbridge, Scott S.en
dc.contributor.authorRobertson, John L.en
dc.contributor.authorDavalos, Rafael V.en
dc.contributor.authorRossmeisl, John H. Jr.en
dc.date.accessioned2022-06-23T18:49:30Zen
dc.date.available2022-06-23T18:49:30Zen
dc.date.issued2022-06-11en
dc.date.updated2022-06-23T12:11:18Zen
dc.description.abstractGlioblastoma is the deadliest malignant brain tumor. Its location behind the blood–brain barrier (BBB) presents a therapeutic challenge by preventing effective delivery of most chemotherapeutics. H-FIRE is a novel tumor ablation method that transiently disrupts the BBB through currently unknown mechanisms. We hypothesized that H-FIRE mediated BBB disruption (BBBD) occurs via cytoskeletal remodeling and alterations in tight junction (TJ) protein regulation. Intracranial H-FIRE was delivered to Fischer rats prior to sacrifice at 1-, 24-, 48-, 72-, and 96 h post-treatment. Cytoskeletal proteins and native and ubiquitinated TJ proteins (TJP) were evaluated using immunoprecipitation, Western blotting, and gene-expression arrays on treated and sham control brain lysates. Cytoskeletal and TJ protein expression were further evaluated with immunofluorescent microscopy. A decrease in the F/G-actin ratio, decreased TJP concentrations, and increased ubiquitination of TJP were observed 1–48 h post-H-FIRE compared to sham controls. By 72–96 h, cytoskeletal and TJP expression recovered to pretreatment levels, temporally corresponding with increased claudin-5 and zonula occludens-1 gene expression. Ingenuity pathway analysis revealed significant dysregulation of claudin genes, centered around claudin-6 in H-FIRE treated rats. In conclusion, H-FIRE is capable of permeating the BBB in a spatiotemporal manner via cytoskeletal-mediated TJP modulation. This minimally invasive technology presents with applications for localized and long-lived enhanced intracranial drug delivery.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationPartridge, B.R.; Kani, Y.; Lorenzo, M.F.; Campelo, S.N.; Allen, I.C.; Hinckley, J.; Hsu, F.-C.; Verbridge, S.S.; Robertson, J.L.; Davalos, R.V.; Rossmeisl, J.H. High-Frequency Irreversible Electroporation (H-FIRE) Induced Blood-Brain Barrier Disruption Is Mediated by Cytoskeletal Remodeling and Changes in Tight Junction Protein Regulation. Biomedicines 2022, 10, 1384.en
dc.identifier.doihttps://doi.org/10.3390/biomedicines10061384en
dc.identifier.urihttp://hdl.handle.net/10919/110901en
dc.language.isoenen
dc.publisherMDPIen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjecthigh-frequency irreversible electroporation (H-FIRE)en
dc.subjectblood–brain barrieren
dc.subjectgliomaen
dc.subjectintracranial drug deliveryen
dc.titleHigh-Frequency Irreversible Electroporation (H-FIRE) Induced Blood-Brain Barrier Disruption Is Mediated by Cytoskeletal Remodeling and Changes in Tight Junction Protein Regulationen
dc.title.serialBiomedicinesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Scholarly Works, Biomedical Engineering and Mechanics
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