Abstract 6251: Blood brain barrier opening by TTFields: a future CNS drug delivery strategy

Abstract

Introduction: Although a number of effective drugs are available to treat central nervous system (CNS) disorders, their ability to breach the tight regulation of the blood brain barrier (BBB) still remains a major challenge. Recently, the use of tumor treating fields (TTFields) has become an effective treatment approach for glioblastoma. Furthermore, its combination with chemotherapy significantly improved overall patient survival. Nonetheless, how TTFields could affect the BBB has not yet been studied. Our recent findings exhibit the potential of TTFields administration to open up the BBB in vitro with an optimal frequency of 100 kHz. Consequently, in this study, we therefore aimed to validate our data in vivo. Experimental procedures: Subsequent to 100 kHz TTFields or heat treatment for 72 h, rats were i.v. injected with Evan´s Blue (EB). Next, they were sacrificed to extract and quantify EB from the brain. In the same manner, rats were injected with TRITC-dextran (TD), after which permeation was visualized in sectioned brains. Cryosections of rat brains were also prepared post-TTFields treatment. These were stained for intercellular junction proteins claudin-5, occludin and PECAM-1 as well as immunoglobulin G (IgG) to assess vessel structure. Finally, serial dynamic contrast-enhanced (DCE) MRI with gadolinium (Gd) contrast agent was performed before and after TTFields administration. Results: Permeation of both EB and TD was observed in the brain after TTFields application. Moreover, brain cryosections displayed claudin-5 and occludin delocalization but not PECAM-1. Accumulation of IgG in the brain parenchyma was also noted. Confirming these observations, increased Gd in the brain was shown by DCE-MRI post TTFields treatment. A reversion to normal conditions was, however, detected 96 h after end of treatment demonstrated by no difference in contrast enhancement between control and TTFields-treated rats. Conclusions: Administration of 100 kHz TTFields in rats led to alterations in BBB integrity and permeability, which signal its opening. The subsequent recovery of the BBB at the end of treatment demonstrates transient effects, hence presenting TTFields as a possible novel clinical strategy to open the BBB for enhanced and more effective drug delivery strategy for CNS disorders. Citation Format: Ellaine Salvador, Almuth F. Kessler, Julia Hörmann, Malgorzata Burek, Catherine T. Brami, Tali V. Sela, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann. Blood brain barrier opening by TTFields: a future CNS drug delivery strategy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6251.

Permeabilizing Cell Membranes with Electric Fields

“…Thus, it is possible that loss-of-function mutations in PTEN could potentiate the inhibition of microtubule polymerization and mitotic spindle apparatus assembly that are known to result from TTFields exposure. Ultimately, future investigations should provide insights towards a unified understanding of the mechanism of action of TTFields-induced cytoskeletal changes, cancer cell membrane permeabilization, and permeabilization of the blood-brain barrier [ 95 ].…”

The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy

“…The blood-brain barrier is a vital structure to maintain the stability of the internal environment of brain. Chemotherapy for brain tumors usually lacks of effectiveness because most chemotherapeutic drugs are difficult to penetrate the blood-brain barrier [ 75 ]. In vivo experiments show that Evans Blue, TRITC-dextran, and magnetic resonance contrast agent Gd-DTPA increase in the brain [ 75 – 78 ].…”

“…Chemotherapy for brain tumors usually lacks of effectiveness because most chemotherapeutic drugs are difficult to penetrate the blood-brain barrier [ 75 ]. In vivo experiments show that Evans Blue, TRITC-dextran, and magnetic resonance contrast agent Gd-DTPA increase in the brain [ 75 – 78 ]. Meanwhile, in vitro experiments showed that Claudin-5 and Occludin translocation in capillary endothelial cells [ 76 , 79 ] points out that TTFields increases the permeability of the blood-brain barrier.…”

“…Meanwhile, in vitro experiments showed that Claudin-5 and Occludin translocation in capillary endothelial cells [ 76 , 79 ] points out that TTFields increases the permeability of the blood-brain barrier. The current studies have shown that 100 kHz is the best frequency for opening the blood–brain barrier in the rat [ 75 – 80 ]. Permeability is generally most pronounced 24 hours after TTFields exposure [ 80 ].…”

“…Permeability is generally most pronounced 24 hours after TTFields exposure [ 80 ]. The blood-brain barrier recovery starts 48 hours after termination of TTFields and is fully recovered at 96 hours [ 75 – 80 ].…”