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70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12.05. - 15.05.2019, Würzburg

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The blood brain barrier (BBB) permeability is altered by tumour treating fields (TTFields) in vitro and in vivo

Die Permeabilität der Blut-Hirnschranke wird durch Tumor Treating Fields (TTFields) in vitro und in vivo beeinflusst

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  • Ellaine Salvador - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
  • Almuth F. Keßler - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
  • Clara Schaeffer - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
  • Malgorzata Burek - Universitätsklinikum Würzburg, Experimentelle Anästhesiologie und molekulare Medizin, Würzburg, Deutschland
  • Ursula Ruschig - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, 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, Würzburg, Deutschland
  • Mario Löhr - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
  • Carola Förster - Universitätsklinikum Würzburg, Experimentelle Anästhesiologie und molekulare Medizin, Würzburg, Deutschland
  • Carsten Hagemann - Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie. Würzburg, 12.-15.05.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocV003

doi: 10.3205/19dgnc003, urn:nbn:de:0183-19dgnc0035

Published: May 8, 2019

© 2019 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

Text

Objective: The influx of most compounds from blood to brain is tightly regulated by the blood brain barrier (BBB). As such, delivery of drugs for treatment of malignant brain tumours, particularly glioblastoma multiforme (GBM), may be impeded. Of late, alternating electric fields with intermediate frequency and low intensity, called Tumour Treating Fields (TTFields), have been established as a novel adjuvant treatment approach for GBM. Here, the effect of TTFields on BBB permeability is investigated in vitro and in vivo.

Methods: TTFields (100-300 kHz frequency) were applied to immortalised murine brain capillary endothelial cells (cerebEND) grown on cover slips and transwell inserts. Cell morphology was assessed by immunofluorescent staining of the tight junction proteins Claudin 5 and ZO-1. BBB integrity and permeability were evaluated by transendothelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) staining, respectively. To analyse vessel permeability in vivo, rats were treated with 100 kHz TTFields for 72 hours. At the end of treatment, rats were i.v. injected with Evan’s Blue (EB), which binds Albumin (~70 kDa) upon injection to the blood. EB was extracted after brain homogenisation and quantified at 610 nm.

Results: Upon TTFields application, tight junction proteins were delocalised from the cell membrane to the cytoplasm with maximal effects at 100 kHz. BBB integrity was significantly reduced by 65%. In accordance, BBB permeability for 4 kDa large molecules was significantly increased. Cell morphology recovery was first observed at 48h post-treatment and completely restored to normal after 96h, indicating a reversibility of the TTFields effect on the BBB. Application of TTFields to the rat head significantly increased EB accumulation in the brain.

Conclusion: BBB integrity and permeability alteration as brought about by TTFields application points towards an increased potential to deliver drugs to the brain, even those that are generally unable to cross the barrier. The opening of the barrier by way of TTFields and its subsequent recovery, as demonstrated by the data presented herein, could lead to an innovative method of drug delivery for treatment of brain tumours and other related diseases of the central nervous system. These results should be further validated in clinical studies.