TY  - JOUR
A1  - Salvador, Ellaine
A1  - Köppl, Theresa
A1  - Hörmann, Julia
A1  - Schönhärl, Sebastian
A1  - Bugaeva, Polina
A1  - Kessler, Almuth F.
A1  - Burek, Malgorzata
A1  - Ernestus, Ralf-Ingo
A1  - Löhr, Mario
A1  - Hagemann, Carsten
T1  - Tumor Treating Fields (TTFields) induce cell junction alterations in a human 3D in vitro model of the blood-brain barrier
JF  - Pharmaceutics
N2  - 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.
KW  - blood-brain barrier
KW  - Tumor-Treating Fields (TTFields)
KW  - CNS disorders
KW  - human brain microvascular endothelial cells (HBMVEC)
KW  - human cells
KW  - 3D in vitro model
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304830
SN  - 1999-4923
VL  - 15
IS  - 1
ER  - 
TY  - JOUR
A1  - Salvador, Ellaine
A1  - Kessler, Almuth F.
A1  - Domröse, Dominik
A1  - Hörmann, Julia
A1  - Schaeffer, Clara
A1  - Giniunaite, Aiste
A1  - Burek, Malgorzata
A1  - Tempel-Brami, Catherine
A1  - Voloshin, Tali
A1  - Volodin, Alexandra
A1  - Zeidan, Adel
A1  - Giladi, Moshe
A1  - Ernestus, Ralf-Ingo
A1  - Löhr, Mario
A1  - Förster, Carola Y.
A1  - Hagemann, Carsten
T1  - Tumor Treating Fields (TTFields) reversibly permeabilize the blood–brain barrier in vitro and in vivo
JF  - Biomolecules
N2  - Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy.
KW  - blood–brain barrier
KW  - TTFields
KW  - CNS disorders
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288057
SN  - 2218-273X
VL  - 12
IS  - 10
ER  -