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73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

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Reversible blood-brain barrier opening utilising Tumour Treating Fields (TTFields) in a human 3D in vitro model

Reversible Öffnung der Blut-Hirn-Schranke unter Verwendung von Tumor Treating Fields (TTFields) in einem human 3D-In-vitro-Modell

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  • Ellaine Salvador - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Sektion Experimentelle Neurochirurgie, Würzburg, Deutschland
  • Theresa Köppl - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Sektion Experimentelle Neurochirurgie, Würzburg, Deutschland
  • Almuth F. Keßler - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Sektion Experimentelle Neurochirurgie, Würzburg, Deutschland
  • Sebastian Schönhärl - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Sektion Experimentelle Neurochirurgie, Würzburg, Deutschland
  • Malgorzata Burek - Universitätsklinikum Würzburg, Klinik und Poliklinik für Anästhesiologie, Experimentelle Anästhesiologie und Experimentelle Medizin, Würzburg, Deutschland
  • Catherine Tempel Brami - NovoCure Ltd., Haifa, Israel
  • Tali Voloshin-Sela - NovoCure Ltd., Haifa, Israel
  • Moshe Giladi - NovoCure Ltd., Haifa, Israel
  • Ralf-Ingo Ernestus - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Sektion Experimentelle Neurochirurgie, Würzburg, Deutschland
  • Mario Löhr - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Sektion Experimentelle Neurochirurgie, Würzburg, Deutschland
  • Carola Förster - Universitätsklinikum Würzburg, Klinik und Poliklinik für Anästhesiologie, Experimentelle Anästhesiologie und Experimentelle Medizin, Würzburg, Deutschland
  • presenting/speaker Carsten Hagemann - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Sektion Experimentelle Neurochirurgie, Würzburg, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocP158

doi: 10.3205/22dgnc471, urn:nbn:de:0183-22dgnc4717

Published: May 25, 2022

© 2022 Salvador et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Objective: Successful drug delivery to the central nervous system (CNS) is restricted by the blood brain barrier (BBB). Since most therapeutic molecules are not able to breach the BBB, novel methods to disrupt the barrier to enhance drug transport are necessary. We recently demonstrated the ability of TTFields to optimally induce BBB permeability in in vitro and in vivo murine models. TTFields are alternating electric fields of low intensity (1-3V/cm) and intermediate frequency (100-300 kHz), which at 200 kHz are effective and approved for the treatment of glioblastoma (GBM). Since TTFields are already used as a GBM therapeutic modality, we assessed if the same effects we observed in our murine systems translate to a human cell-based entity.

Methods: A 3D-BBB transwell model made up of human brain microvascular endothelial cells (HBMVEC) and human pericytes was established and treated with TTFields at 100-300 kHz for 24-96h using the inovitro™ TTFields Lab Bench System (Novocure®). Afterwards, cells were allowed to recover for 24-96h. To analyze TTFields effects on barrier integrity, transendothelial electrical resistance (TEER) of the HBMVEC monolayer was measured. In addition, permeability was assessed via FITC-dextran assay. Finally, changes in expression and localization of the tight junction protein (TJP) claudin-5 (Cl-5) following application of TTFields were examined via Western blot and immunofluorescence (IF) staining, respectively.

Results: TTFields application of all investigated frequencies significantly decreased TEER across the HBMVEC monolayer after as early as 24h. Nonetheless, strongest effects were seen with 100 kHz after 72h. IF staining revealed delocalization of TJP Cl-5 from the cell boundaries to the cytoplasm. Recovery of the cell barrier was already evident as early as 24h after TTFields cessation, with complete recovery after 48h.

Conclusion: Altogether, the effects of TTFields previously observed in our murine in vitro and in vivo models are validated in the human 3D in vitro model. Reversible opening of the BBB through TTFields is feasible in a human-based entity, as demonstrated by our system. Thus, future translation of this method into a clinical setting could facilitate drug delivery for improved treatment of CNS diseases including devastating brain tumors such as GBM.