Artikel
TTFields disruption of the blood brain barrier – a potential CNS drug delivery approach
Öffnung der Blut-Hirn-Schranke durch TTFields – eine potentielle Methode zum Drug-delivery in das ZNS
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Autoren
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Ellaine Salvador
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Tumorbiologisches Labor, Würzburg, Deutschland
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Almuth F. Keßler
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Tumorbiologisches Labor, Würzburg, Deutschland
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Julia Hörmann
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Tumorbiologisches Labor, Würzburg, Deutschland
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Malgorzata Burek
- Universitätsklinikum Würzburg, Klinik und Poliklinik für Anästhesiologie, Würzburg, Deutschland
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Catherine T. Brami
- Novocure GmbH, Haifa, Israel
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Tali V. Sela
- Novocure GmbH, Haifa, Israel
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Moshe Giladi
- Novocure GmbH, Haifa, Israel
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Ralf-Ingo Ernestus
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Tumorbiologisches Labor, Würzburg, Deutschland
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Mario Löhr
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Tumorbiologisches Labor, Würzburg, Deutschland
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Carola Förster
- Universitätsklinikum Würzburg, Klinik und Poliklinik für Anästhesiologie, Würzburg, Deutschland
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Carsten Hagemann
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Tumorbiologisches Labor, Würzburg, Deutschland
| Veröffentlicht: | 26. Juni 2020 |
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Gliederung
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Objective: Despite the availability of potent drugs, modern medicine is still faced with the problem of effectively delivering them into the central nervous system (CNS) due to the tight regulation of the blood brain barrier (BBB). Of late, tumour treating fields (TTFields) have emerged as an effective treatment modality for glioblastoma. Moreover, TTFields combined with chemotherapy significantly improve overall survival in patients. The influence of TTFields on the BBB, however, has so far not yet been investigated. Our recent findings demonstrate that TTFields administration has the potential to open up the BBB in vitro with an optimal frequency of 100 kHz. Consequently, in this study, we aimed to validate our data in vivo.
Methods: Rats were subjected to 100 kHz TTFields or heat treatment for 72 h and subsequently i.v. injected with Evan´s Blue (EB). Afterwards, rats were sacrificed, EB was extracted from the brain and quantified. Likewise, in separate experiments, rats were injected with TRITC-dextran (TD), and brain slices were photographed to localise the staining. In addition, cryosections of rat brains were prepared after TTFields administration. Sections were stained for intercellular junction proteins claudin-5, occludin and PECAM-1 as well as immunoglobulin G (IgG) to assess vessel structure. Finally, serial dynamic contrast-enhanced (DCE) MRI with gadolinium (Gd) contrast agent was performed pre- and post TTFields application.
Results: Accumulation of both EB and TD in the brain increased with TTFields administration. Also, brain cryosections demonstrated delocalisation of claudin-5 and occludin but not PECAM-1 and build-up of IgG in the brain parenchyma. Validating these observations, DCE-MRI displayed significantly increased Gd in the brain post TTFields application. These effects, however, reverted back to normal 96 h after end of treatment as no difference in contrast enhancement between controls and TTFields-treated rats was found.
Conclusion: TTFields of 100 kHz alter BBB integrity and permeability leading to opening of the latter. This suggests the possibility of using TTFields for drug delivery to the CNS. Moreover, subsequent BBB recovery post-treatment demonstrate transient effects, thus potentiating a novel clinical approach of using TTFields to open the BBB for enhanced and more effective drug delivery strategy targeting CNS disorders.
