Dynamic effects of point source electroporation on the rat brain tissue Shirley Sharabi a,b , David Last a , David Guez a , Dianne Daniels a,b , Mohammad Ibrahim Hjouj c,d , Sharona Salomon a , Elad Maor e,f , Yael Mardor a,b, ⁎ a The Advanced Technology Center, Sheba Medical Center, Ramat-Gan 52621, Israel b Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel c Center for Bioengineering in the Service of Humanity and Society, School of Computer Science and Engineering, Hebrew University, Jerusalem, Israel d The Medical Imaging Department, Al Quds University, Abu Dis Jerusalem, Israel e Leviev Heart Center, Sheba Medical Center, Ramat-Gan 52621, Israel f Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Ramat-Gan 52621, Israel abstract article info Article history: Received 4 December 2013 Received in revised form 22 April 2014 Accepted 8 June 2014 Available online 17 June 2014 Keywords: Blood brain barrier Electroporation Brain Tumor MRI In spite of aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme due to tumor infiltration into the surrounding brain as well as poor blood–brain barrier penetration of most therapeutic agents. In this paper we present a novel approach for a minimally invasive treatment and a non-invasive response assess- ment methodology consisting of applying intracranial point-source electroporation and assessing treatment effect volumes using magnetic resonance imaging. Using a unique setup of a single intracranial electrode and an external surface electrode we treated rats' brains with various electroporation protocols and applied magnetic resonance imaging to study the dependence of the physiological effects on electroporation treatment parame- ters. The extent of blood–brain barrier disruption and later volumes of permanent brain tissue damage were found to correlate significantly with the treatment voltages (r 2 = 0.99, p b 0.001) and the number of treatment pulses (r 2 = 0.94, p b 0.002). Blood–brain barrier disruption depicted 3.2 ± 0.3 times larger volumes than the final permanent damage volumes (p b 0.0001). These results indicate that it may be beneficial to use more than one modality of electroporation when planning a treatment for brain tumors. © 2014 Elsevier B.V. All rights reserved. 1. Introduction The current standard of care in glioma therapy includes surgery, radiation and temozolomide chemotherapy. However, this multimodal treatment still offers a poor prognosis for glioblastoma multiforme (GBM) patients. Peripheral administration of therapeutic agents for the treatment of CNS pathologies is mostly inefficient due to poor penetration of most drugs across the blood–brain barrier (BBB). Direct drug delivery methods are restricted by the limited diffusion of drug through the tissue, in the order of a few mm. In addition, GBM cells are also highly resistant to therapeutic apoptotic stimuli. However, they exhibit a para- doxical propensity for extensive cellular necrosis [1,2]. On top of these challenges, malignant brain gliomas are able to evade and suppress the immune system [3]. Due to the extreme adaptability of GBM cells, residual tumor, including the infiltrating zone surrounding the tumor should be treated with high efficacy as well, to prevent sub-lethal hits of tumor cells leading to the growth of more malignant clonal cell populations [4]. In order to obtain these goals a combined approach, consisting of inducing significant/rapid necrosis in the tumor mass in parallel to de- livery of high chemotherapy doses to the tumor and infiltrating zone is suggested. Since GBMs are among the most highly vascularized solid tumors [5,6], the tumor own vasculature may be used for delivering the drug. While disrupting the BBB in the local vicinity of the tumor. Tis- sue necrosis within the massive region of the tumor, and surrounding BBB disruption can be obtained by applying electroporation. Electroporation is the use of intense electric pulses to make the cell membrane transiently porous and increase permeability to ions and macromolecules. It has been shown that electric fields control the per- meabilization of cell membrane [7]. The electric fields induce a change in membrane potential which depends on physiological parameters such as tissue type and cell size as well as pulse parameters including pulse strength, shape, duration, number of pulses, and frequency. As a function of the induced membrane potential, the electroporation pulse can either: have no effect on the cell membrane, reversibly permeabilize the cell membrane (reversible electroporation) or permeabilize the cell Bioelectrochemistry 99 (2014) 30–39 Abbreviations: BBB, blood brain barrier; GBM, glioblastoma multiforme; NTIRE, Non-thermal irreversible electroporation; MRI, magnetic resonance imaging; BDVs, BBB disruption volumes; ETVs, early tissue response volumes; IRVs, irreversible damage volumes; SIMVs, simulation volumes. ⁎ Corresponding author at: The Advanced Technology Center, Sheba Medical Center Tel-Hashomer, 52621, Israel. Tel.: +972 3 5302993, +972 52 6667274 (cellular); fax: +972 3 5303146. E-mail address: yael.mardor@sheba.health.gov.il (Y. Mardor). http://dx.doi.org/10.1016/j.bioelechem.2014.06.001 1567-5394/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Bioelectrochemistry journal homepage: www.elsevier.com/locate/bioelechem