Tumor Treating Fields (TTFields) Induce Cell Junction Alterations in a Human 3D In Vitro Model of the Blood-Brain Barrier

Abstract

In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies.

TTFields Prolonged the PFS of Epithelioid Glioblastoma Patient: A Case Report

“…TTFields therapy uses alternating electric fields with a specific frequency (100~300 kHZ) to interfere with cell mitosis, and at the same time, the electrically charged material undergoes dielectrophoresis to rupture the cell membrane and kill the tumor. Furthermore, Kessler et al showed that TTFields increase the permeability of the blood–brain barrier (BBB) by reducing the expression of tight junction proteins between neurovascular endothelial cells [ 29 ]. Kirson et al combined TTFields with TMZ and found that TTFields could improve tumor sensitivity to chemotherapy [ 30 ].…”

Therapeutic potential of tumor treating fields for malignant brain tumors

“…Recently, TTFields have been proven to temporarily increase the permeability of the BBB in a human in vitro model. 61 TTField‐induced opening of BBB is similarly reversible and expands the range of intracranial drug applications.…”

“… 60 Till now, the presence of BBB has posed limitations for the treatment of brain malignancies and the cerebral application of some agents. Recently, TTFields have been proven to temporarily increase the permeability of the BBB in a human in vitro model 61 . TTField‐induced opening of BBB is similarly reversible and expands the range of intracranial drug applications.…”

Platelet-derived extracellular vesicles for drug delivery

“…16 CD41 and P-selectin have been identified on most PEV surfaces. 33 Phosphatidylserine could be found on some PEV surfaces. 34 Platelets also package mRNAs and non-coding RNAs inside PEVs to interact with other cells.…”