Temporal Characterization of Blood-Brain Barrier Disruption with High-Frequency Electroporation.

Matthew Lee,Yukitaka Kani,John H Rossmeisl,Fang-Chi Hsu,John L Robertson,Rafael V Davalos,Scott S Verbridge,Joy Adler,Melvin F Lorenzo,Sean C Thomas,Jonathan Hinckley

doi:10.3390/cancers11121850

Abstract

Treatment of intracranial disorders suffers from the inability to accumulate therapeutic drug concentrations due to protection from the blood–brain barrier (BBB). Electroporation-based therapies have demonstrated the capability of permeating the BBB, but knowledge of the longevity of BBB disruption (BBBD) is limited. In this study, we quantify the temporal, high-frequency electroporation (HFE)-mediated BBBD in an in vivo healthy rat brain model. 40 male Fisher rats underwent HFE treatment; two blunt tipped monopolar electrodes were advanced into the brain and 200 bursts of HFE were delivered at a voltage-to-distance ratio of 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye) at time points of 1, 24, 48, 72, and 96 h after HFE. Contrast enhanced T1W scans demonstrated BBBD for 1 to 72 h after HFE but intact BBB at 96 h. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated that brief BBBD was induced with low magnitude electric fields, and BBBD duration increased with field strength. These data suggest the spatiotemporal characteristics of HFE-mediated BBBD may be modulated with the locally applied electric field.

Highlights

The blood–brain barrier (BBB) is an active and highly selective biological barrier made up by the complex interactions between brain capillary endothelial cells (BCECs), astrocytes, tight junction (TJ) proteins, and other supportive cells; together these components regulate molecular transport across the microvasculature in the central nervous system (CNS) [1,2]
BBB permeability was assessed by intraperitoneal injection of a solution formulated with gadopentetate dimeglumine and Evans blue dye (Gd-EBD); this solution was administered 1 hour prior to sacrifice to allow for circulation and clearance of the Gd-EBD solution
While the BBBD temporal thresholds (BTTs) determined in this study describe BBB disruption (BBBD) pertaining to Gd (~950 Da) and EBD, these thresholds may vary depending on the size and mobility of the molecule/drug in question

Summary

Introduction

The blood–brain barrier (BBB) is an active and highly selective biological barrier made up by the complex interactions between brain capillary endothelial cells (BCECs), astrocytes, tight junction (TJ) proteins, and other supportive cells; together these components regulate molecular transport across the microvasculature in the central nervous system (CNS) [1,2]. Coupled with molecular efflux transporters (such as P-glycoproteins and multidrug resistance protein 1) expressed on the surface of specialized BCECs, the intact BBB acts to maintain brain homeostasis and isolates the CNS from circulating pathogens. Though effective in this regard, the BBB hinders transport of therapeutic. Cancers 2019, 11, 1850 drugs and large molecules, thereby impeding treatment of intracranial malignancies [3,4]. One potential solution for intracranial drug delivery is convection-enhanced delivery (CED), which seeks to bypass the BBB by direct therapeutic administration to the brain parenchyma and target tissue. CED is limited by the occurrence of perfusate reflux and by the requirement for lengthy treatment sessions due to relatively slow infusion rates

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Discussion

Conclusion