Significance: Focused ultrasound is currently the only method of reversible blood–brain barrier disruption for targeted drug delivery without incision or radiation. A significant challenge for its clinical translation is a lack of reliable real-time treatment control. Here a closed-loop, real-time control paradigm is shown capable of sustaining stable microbubble oscillations at a preset level while minimizing microbubble behavior that may result in vascular damage. Tested at clinically relevant frequency in healthy and tumor-bearing rats, our approach enables targeted delivery of predefined drug concentrations within a therapeutically effective range in both normal tissue and glioma, while maintaining a safe exposure level. It can be readily implemented clinically for delivering chemotherapeutics or other agents and potentially applied to other cavitation-enhanced ultrasound therapies.

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.