Non-Invasive Low Pulsed Electrical Fields for Inducing BBB Disruption in Mice—Feasibility Demonstration

Abstract

The blood–brain barrier (BBB) is a major hurdle for the treatment of central nervous system disorders, limiting passage of both small and large therapeutic agents from the blood stream into the brain. Thus, means for inducing BBB disruption (BBBd) are urgently needed. Here, we studied the application of low pulsed electrical fields (PEFs) for inducing BBBd in mice. Mice were treated by low PEFs using electrodes pressed against both sides of the skull (100–400 square 50 µs pulses at 4 Hz with different voltages). BBBd as a function of treatment parameters was evaluated using MRI-based treatment response assessment maps (TRAMs) and Evans blue extravasation. A 3D numerical model of the mouse brain and electrodes was constructed using finite element software, simulating the electric fields distribution in the brain and ensuring no significant temperature elevation. BBBd was demonstrated immediately after treatment and significant linear regressions were found between treatment parameters and the extent of BBBd. The maximal induced electric field in the mice brains, calculated by the numerical model, ranged between 62.4 and 187.2 V/cm for the minimal and maximal applied voltages. These results demonstrate the feasibility of inducing significant BBBd using non-invasive low PEFs, well below the threshold for electroporation.

Albumin–Methotrexate Prodrug Analogues That Undergo Intracellular Reactivation Following Entrance into Cancerous Glioma Cells

“…Those were found to be inactive antiproliferative prodrugs which efficiently regained their cytotoxic efficacy following entrance into cancerous cells. The antiproliferative efficacy of these conjugates was studied in cancerous cell lines of brain glioma origin, to complement another activity of our laboratory aiming to transfer chemotherapeutically active macromolecules from the blood to the brain via the blood-brain barrier (BBB) for treating major brain disorders such as glioblastoma multiforme [14][15][16][17].…”

“…In this study, we describe our synthetic procedures for obtaining a variety of BSA-MTX conjugates, their cell-free DHFR-inhibitory potencies in the absence and in the presence of glutathione or cysteine, and their antiproliferative efficacies in several lines of cancerous cells relative to that of methotrexate. Two glioma cell lines are investigated here, for the first time, in the context of albumin conjugates to align with other research in our lab, in which new compounds and methods that enable blood-brain barrier (BBB) opening, and thus, the entrance of large therapeutic molecules such as albumin are being developed [14][15][16][17][18].…”

Drug Design: Where We Are and Future Prospects

“…The most widely used method for direct brain delivery is convection-enhanced delivery (CED), whereby specially designed catheters are introduced into target tissue, and the infusate is delivered slowly over a prolonged period of time. CED enables the delivery of conventional, nano-, bio-, gene, and even cellular therapies [61][62][63][64][65][66][67][68][69][70][71][72][73]. Hopefully, in the near future, it will be possible to deliver more small molecules in a therapeutic useful concentration and antibodies to the CNS.…”

Opening the Blood Brain Barrier with an Electropermanent Magnet System

“…The blood brain barrier (BBB) is composed of brain endothelial cells, pericytes, and astrocytes in tight junctions without fenestrations [ 1 , 2 , 3 , 4 ]. The BBB prevents 98% of small molecules, and an even greater percentage of large molecules, from reaching their intended brain targets [ 5 , 6 ] and is therefore considered the most significant barrier to the efficient and targeted delivery of therapeutics to the brain [ 3 ]. Due to its significance, numerous approaches have focused on safely and temporarily opening the BBB.…”

“…In cell culture models of the BBB, pulsed electric fields have been shown to be capable of destabilizing cell membranes and inducing the formation of nanoscale aqueous pores in the membranes, which may reseal (i.e., reversible electroporation) or may lead to cell death (irreversible electroporation) [ 6 , 14 , 16 , 17 ]. Drug infusion during reversible electroporation (using electric fields in the V/m range) has been used to improve survival and reduce tumor growth in glioma-bearing rats and dogs [ 18 , 19 , 20 ].…”