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P04.33 Effects of Tumor Treating Fields (TTFields) on blood brain barrier (BBB) permeability
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Abstract
Background
Brain tumors, especially glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, are difficult to treat, because cerebral microvessels strictly regulate the transfer of substances between blood and brain tissue. Thereby they prevent clinical application of several promising drugs. This limitation in drug transport is due to the blood-brain barrier (BBB), mainly formed by intercellular tight junctions (TJ) between brain capillary endothelial cells. Recently, Tumor Treating Fields (TTFields), alternating electric fields with low intensity and intermediate frequency, have been introduced as a new adjuvant treatment modality for GBM. Here, the effect of TTFields on BBB permeability is investigated.
Material and Methods
Immortalized murine brain capillary endothelial cells (cerebEND) were grown on coverslips and transwell inserts. Cells were treated with TTFields at a frequency of 100–300 kHz for up to 72 h. Cell morphology was analyzed by immunofluorescence staining of the TJ proteins Claudin 5 and ZO-1. BBB integrity was determined by transendothelial resistance (TEER) and BBB permeability by flow cytometry analysis with fluoresceine isothiocyanate (FITC).
Results
TTFields application disturbs the BBB by delocalization of tight junction proteins from the cell boundaries to the cytoplasm with most dramatic effects at 100 kHz. The effects appear after 24 h and are most severe after 72 h TTFields treatment. The BBB integrity was significantly reduced by 65% and the BBB permeability for 4 kDa large molecules was significantly increased upon TTFields application. The cell morphology started to recover 48 h and was completed 96 h after end of TTFields treatment pointing to a reversibility of the TTFields-effect on the BBB.
Conclusion
TTFields at a frequency of 100 kHz may potentially permeabilize the BBB. Thereby, TTFields could be utilized to deliver drugs usually unable to cross the BBB to the central nervous system. The presented in vitro data will be verified in an in vivo setting and hopefully may lead to a phase I clinical trial and clinical application in the future.