Artikel
Breaching the blood-brain Barrier (BBB) via Tumour Treating Fields (TTFields)
Durchbrechen der Blut-Hirn-Schranke (BHS) über TTFields
Suche in Medline nach
Autoren
-
Ellaine Salvador
- Universitätsklinikum Julius Maximilians Universität Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland; Universitätsklinikum Julius Maximilians Universität Würzburg, Experimentelle Anästhesiologie und molekulare Medizin, Würzburg, Deutschland
-
Almuth Friederike Keßler
- Universitätsklinikum Julius Maximilians Universität Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
-
Malgorzata Burek
- Universitätsklinikum Julius Maximilians Universität Würzburg, Experimentelle Anästhesiologie und molekulare 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 Julius Maximilians Universität Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
-
Mario Löhr
- Universitätsklinikum Julius Maximilians Universität Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
-
Carola Förster
- Universitätsklinikum Julius Maximilians Universität Würzburg, Experimentelle Anästhesiologie und molekulare Medizin, Würzburg, Deutschland
-
Carsten Hagemann
- Universitätsklinikum Julius Maximilians Universität Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
| Veröffentlicht: | 4. Juni 2021 |
|---|
Gliederung
Text
Objective: BBB tightness accounts for the vast challenge in drug delivery to the brain. Although numerous potent compounds can treat central nervous system (CNS) disorders such as glioblastoma (GBM), failure to cross the BBB render them futile. Thus, novel methods for BBB disruption to enable passage of therapeutics into the CNS are necessary. To date, few such methods approved for clinical use exist. In the light of GBM, the use of TTFields as a treatment modality in combination with chemotherapeutics has increased overall patient survival. Recently, we showed their ability to reversibly open the BBB both in vitro and in vivo. As a follow-up, we herein aimed to further discern the action of TTFields relative to BBB function and disruption.
Methods: TTFields of various intensities at 100 kHz were administered to murine brain endothelial cells (cerebEND) for 24-72h prior to tight junction protein claudin-5 staining. Likewise, mathematical simulations of TTFields delivery and distribution to the rat brain were performed. Median field intensities for the various brain segments were calculated as defined for dynamic contrast-enhanced (DCE) MRI. In addition, tumour-induced rats were treated with TTFields or sham heat, in combination with paclitaxel (PTX). Tumour volume was assessed using MRI. Tumour cell proliferation ratio was quantified using the marker Ki67.
Results: TTFields intensity of 1.62 V/cm RMS disrupted the cerebEND boundaries as shown by claudin-5 delocalisation. No notable physical alteration was displayed at 0.97 and 0.76 V/cm RMS. Furthermore, a significant increase in gadolinium accumulation in the middle and posterior rat brains was observed 72 h post-TTFields. In contrast, no significant accumulation was detected in the anterior brain, which is in accordance with the lower intensities applied to this section based on simulations. Eventually, administration of PTX together with TTFields significantly decreased tumour volume compared to sham or TTFields alone or sham combined with PTX in tumour-induced rats. Moreover, tumour cell proliferation ratio was significantly reduced in TTFields and PTX-treated rats compared to TTFields alone.
Conclusion: Our data point towards the ability of TTFields to open the BBB, suggesting a possible clinical translation. The potential of using TTFields for this purpose would ultimately offer a solution to the current CNS drug delivery problem.
