Effects on P-Glycoprotein Expression after Blood-Brain Barrier Disruption Using Focused Ultrasound and Microbubbles

Abstract

Many blood-borne substances attempting to pass through the luminal membrane of brain endothelial cells are acted upon by a variety of metabolizing enzymes or are actively expelled back into the capillary lumen by embedded efflux transporters, such as Permeability-glycoprotein (Pgp). Overexpression of this protein has also been linked to multidrug resistance in cancer cells. Previous studies have shown that focused ultrasound (FUS), when combined with a microbubble agent, has ability to temporarily disrupt blood-brain barrier (BBBD). In this work, we investigated whether modulation of Pgp expression is part of the FUS-induced effects. We found that ultrasound can temporarily suppress Pgp expression. When BBBD was produced at 0.55 MPa, Pgp was suppressed up to 48 hours and restored by 72 hours. At 0.81 MPa, suppression can last 72 hours or longer. These findings support the idea that microbubble-enhanced FUS disrupts the functional components of the BBB through suppression of drug efflux.

Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib

“…Using similar conditions to ours, Cho and colleagues reported a decrease in ABCB1 expression at the BBB of the sonicated area, 24 h after FUS [28]. Aryal et al, confirmed this observation and showed that the effect was maximum 48 h post FUS (~50% decrease) [27]. These studies suggest a connection between the regulation of the "physical" and the "functional" components of the BBB in vivo.…”

“…It can be hypothesized that ABC-transporter function may be modulated by BBB integrity. Recent studies have reported an impact of FUS-induced BBB disruption on the rat microvascular transcriptome [26] and a delayed decrease in ABCB1 expression in the sonicated area, 24 to 48 h after FUS [27,28]. This suggests that erlotinib, which brain distribution is mainly governed by ABC-transporter mediated efflux at the BBB, may benefit from the immediate and/or delayed impact of FUSinduced BBB disruption as a strategy to locally improve its brain delivery.…”

Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption

“…It is possible that the sonications resulted in suppression of one or more drug efflux pumps. Indeed, others have shown that the efflux pump P-glycoprotein can be suppressed by ultrasound [42,43], and our laboratory has reported that such suppression may occur in blood vessels in the brain after BBB disruption [44]. DOX is known to be a substrate for P-glycoprotein.…”

Ultrasound-Mediated Diagnosis and Therapy based on Ultrasound Contrast Agents

“…For guiding and monitoring HIFU therapy, an MR‐guided HIFU system can be a potential alternative to the previous therapy . It can give information on a desired region with outstanding cross‐sectional imaging and temperature elevation within seconds . Furthermore, in combination with CT, the HIFU technique can refine the transducer array to monitor a dose moving through the brain and record the temperature rise, and consequently make it more focused and sophisticated…”