Abstract
Abstract The use of low-intensity pulsed ultrasound with concomitant injection of microbubbles (LIPU/MB) achieves local and reversible opening the blood-brain barrier (BBB), enhancing the delivery of systemically administered drugs to the brain parenchyma. Electron microscopic studies conducted in animals proposed that LIPU/MB enhances paracellular diffusion across the cerebral vasculature, by disrupting tight junction proteins between endothelial cells, as well as enhancement of caveolar transcytosis. The effects of LIPU/MB on the ultrastructure of the human BBB and cerebral endothelial phenotype have not been systematically investigated. Here we report a first in-human electron microscopic study, examining endothelial phenotype and BBB ultrastructure in the peri-tumoral brain of humans after undergoing LIPU/MB-enhanced drug delivery. Non-eloquent peritumoral brain was biopsied at different time points (4-63 minutes) following an intraoperative LIPU/MB procedure in three patients who underwent a surgical resection of recurrent glioblastoma through a phase I clinical trial [NCT04528680]. Transmission electron microscopy was used to examine cross sections of the microvasculature and associated components of the BBB. We observed a significant (P = 0.0397) time-dependent decrease in the frequency of endothelial caveolae immediately after sonication compared to non-sonicated control vessels, which resolved within 1 hour of treatment. We also observed a time-dependent increase in membrane-bound vacuoles in the endothelial cytoplasm following sonication (P = 0.0002, one-way ANOVA). Sonicated blood vessels occasionally showed swollen astrocytes, convoluted luminal protections, and lightening of otherwise dense tight junction proteins, not frequently observed in non-sonicated biopsies from the same patients. Our study shows that LIPU/MB changes the endothelial phenotype within the cerebral vasculature, and suggests the accumulation of vacuoles in endothelial cells after BBB opening.
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