Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo
Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery....
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| Format: | Article |
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MDPI AG
2022-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/10/1348 |
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| author | Ellaine Salvador Almuth F. Kessler Dominik Domröse Julia Hörmann Clara Schaeffer Aiste Giniunaite Malgorzata Burek Catherine Tempel-Brami Tali Voloshin Alexandra Volodin Adel Zeidan Moshe Giladi Ralf-Ingo Ernestus Mario Löhr Carola Y. Förster Carsten Hagemann |
| author_facet | Ellaine Salvador Almuth F. Kessler Dominik Domröse Julia Hörmann Clara Schaeffer Aiste Giniunaite Malgorzata Burek Catherine Tempel-Brami Tali Voloshin Alexandra Volodin Adel Zeidan Moshe Giladi Ralf-Ingo Ernestus Mario Löhr Carola Y. Förster Carsten Hagemann |
| author_sort | Ellaine Salvador |
| collection | DOAJ |
| description | Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy. |
| first_indexed | 2024-03-09T20:38:12Z |
| format | Article |
| id | doaj.art-b91b48214a2d4b4198e80fa053ef9dd0 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T20:38:12Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-b91b48214a2d4b4198e80fa053ef9dd02023-11-23T23:07:13ZengMDPI AGBiomolecules2218-273X2022-09-011210134810.3390/biom12101348Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In VivoEllaine Salvador0Almuth F. Kessler1Dominik Domröse2Julia Hörmann3Clara Schaeffer4Aiste Giniunaite5Malgorzata Burek6Catherine Tempel-Brami7Tali Voloshin8Alexandra Volodin9Adel Zeidan10Moshe Giladi11Ralf-Ingo Ernestus12Mario Löhr13Carola Y. Förster14Carsten Hagemann15Department of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University of Würzburg, D-97080 Würzburg, GermanyNovocure Ltd., Haifa 3190500, IsraelNovocure Ltd., Haifa 3190500, IsraelNovocure Ltd., Haifa 3190500, IsraelNovocure Ltd., Haifa 3190500, IsraelNovocure Ltd., Haifa 3190500, IsraelDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University of Würzburg, D-97080 Würzburg, GermanyDepartment of Neurosurgery, Section Experimental Neurosurgery, University of Würzburg, D-97080 Würzburg, GermanyDespite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy.https://www.mdpi.com/2218-273X/12/10/1348blood–brain barrierTTFieldsCNS disorders |
| spellingShingle | Ellaine Salvador Almuth F. Kessler Dominik Domröse Julia Hörmann Clara Schaeffer Aiste Giniunaite Malgorzata Burek Catherine Tempel-Brami Tali Voloshin Alexandra Volodin Adel Zeidan Moshe Giladi Ralf-Ingo Ernestus Mario Löhr Carola Y. Förster Carsten Hagemann Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo Biomolecules blood–brain barrier TTFields CNS disorders |
| title | Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo |
| title_full | Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo |
| title_fullStr | Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo |
| title_full_unstemmed | Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo |
| title_short | Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo |
| title_sort | tumor treating fields ttfields reversibly permeabilize the blood brain barrier in vitro and in vivo |
| topic | blood–brain barrier TTFields CNS disorders |
| url | https://www.mdpi.com/2218-273X/12/10/1348 |
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