Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood-Brain Barrier In Vitro and In Vivo

Area of Science:

• Neuroscience
• Biomedical Engineering
• Oncology

Background:

• The blood-brain barrier (BBB) restricts the passage of most therapeutic agents into the central nervous system (CNS), limiting treatment options for neurological disorders.
• Novel strategies are required to enhance drug delivery across the BBB for effective CNS therapies.

Purpose of the Study:

• To investigate the effect of Tumor Treating Fields (TTFields) on the integrity and permeability of the blood-brain barrier (BBB).
• To evaluate the potential of TTFields as a novel strategy for improving drug delivery to the brain, particularly for glioblastoma (GBM).

Main Methods:

• In vitro: Murine microvascular cerebellar endothelial cells (cerebEND) were treated with TTFields (100-300 kHz) and analyzed for barrier protein expression.
• In vivo: TTFields (100 kHz) were administered to rats, and the brain's permeability to normally restricted compounds was assessed using MRI and immunohistochemistry.
• In vivo efficacy: GBM-bearing rats were treated with paclitaxel (PTX) combined with TTFields (100 kHz) to evaluate tumor volume reduction.

Main Results:

• TTFields (100 kHz) were found to transiently disrupt BBB function in vitro via a Rho kinase-mediated pathway affecting claudin-5 phosphorylation.
• In vivo, TTFields (100 kHz) increased BBB permeability, allowing normally restricted compounds to enter the brain.
• Combined TTFields and paclitaxel treatment significantly reduced GBM tumor volume in rats compared to either treatment alone.

Conclusions:

• TTFields demonstrate a novel mechanism for transiently increasing BBB permeability.
• This BBB modulation by TTFields holds potential as a new strategy for enhancing CNS drug delivery.
• TTFields could improve the efficacy of chemotherapeutics like paclitaxel in treating brain tumors such as GBM.