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

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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To investigate whether microbubble-enhanced focused ultrasound temporarily suppresses P-glycoprotein expression at the blood–brain barrier and how this suppression depends on sonication conditions and time.

Animal model / Human subject rats, not specified, not specified, not specified

Disease model healthy

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) with microbubbles transiently suppressed P-glycoprotein (Pgp) expression at the blood–brain barrier, with suppression lasting up to 48 hours after 0.55 MPa (recovered by 72 h) and lasting ≥72 hours after 0.81 MPa (though 0.81 MPa produced focal vascular damage/petechiae); suppression magnitude correlated with fourth-harmonic acoustic emissions. Successful parameters: 0.55 MPa (transient Pgp suppression up to 48 h) and 0.81 MPa (longer-lasting suppression ≥72 h).

Duration of biological effect 48 h

Safety-related matter Vascular damage observed at higher pressure.

Brain Region

Visualization unavailable

Ultrasound Parameters

Ultrasound instrument single-element FUS transducer

FUS Frequency 690 kHz

FUS Intensity not reported

FUS Pressure 0.55 MPa

FUS Mode pulsed

Pulse duration not reported

Duration of a single FUS session not reported

Treatment frequency Single session

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