Regulation of P-glycoprotein and Breast Cancer Resistance Protein Expression Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption: A Pilot Study

Abstract

The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which limit the passage of substrate molecules from blood circulation to the brain. Focused ultrasound (FUS) with microbubbles can create a local and reversible detachment of the TJs. However, very little is known about the effect of FUS on the expression of efflux transporters. We investigated the in vivo effects of moderate acoustic pressures on both P-gp and BCRP expression for up to two weeks after sonication. Magnetic resonance-guided FUS was applied in the striatum of 12 rats. P-gp and BCRP expression were determined by immunohistochemistry at 1, 3, 7, and 14 days postFUS. Our results indicate that FUS-induced BBB opening is capable of (i) decreasing P-gp expression up to 3 days after sonication in both the treated and in the contralateral brain regions and is capable of (ii) overexpressing BCRP up to 7 days after FUS in the sonicated regions only. Our findings may help improve FUS-aided drug delivery strategies by considering both the mechanical effect on the TJs and the regulation of P-gp and BCRP.

Imaging the impact of blood-brain barrier disruption induced by focused ultrasound on P-glycoprotein function

“…It should, however, be noticed that only a partial -45% decrease in P-gp expression was achieved. This result is consistent with previous studies reporting a significant but partial down-regulation of P-gp at the BBB from 24h to 48h after FUS [17][18][19][20]. These studies used different acoustic pressure and FUS conditions.…”

“…Other studies have consistently reported a significant decrease in the expression of P-gp at the BBB from 24h to 48h after FUS [17][18][19][20]. However, it remains to be evaluated whether delayed FUS-induced down-regulation of the P-gp may locally enhance the brain delivery of P-gp substrates.…”

Exosome-based delivery strategies for tumor therapy: an update on modification, loading, and clinical application

“…This restricted passage of antitumor drugs through the BBB is mainly attributed to active efflux transporters (AETs) [ 194 ]. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the two most common AETs that are associated with drug resistance in multiple tumors and limit the brain penetration of antineoplastic drugs [ 195 ]. More than half of the commercially available antitumor drugs are recognized by P-gp, which prevents drug entry into the brain parenchyma via the transcytosis pathway.…”

State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound

“…This leads to the loosening of tight junctions in between endothelial cells, allowing large molecules to enter the brain in the sonicated area (Hynynen et al 2001, Sheikov et al 2004, Cammalleri et al 2020. In addition, MB-assisted focused-US can also alter the gene expression of essential BBB efflux transport proteins, such as downregulation of the P-glycoprotein, which enhances medication localization in the parenchyma (Aryal et al 2017, Jangjou et al 2021, Conti et al 2022. However, it is difficult to understand the precise mechanism of interactions between MB and tissues leading to BBB disruption (Barzegar-Fallah et al 2022).…”