The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.

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Systemic injections of chemotherapeutics often deliver only minor fractions of the administered dose to the targeted pathology, resulting in unwanted toxicity towards healthy tissue. In brain tissue, drug delivery is impaired by the highly selective nature of the blood brain barrier impeding the influx of most substances. Acoustic Cluster Therapy (ACT®) is a platform for targeted therapeutic enhancement, facilitating increased local drug transfer. The platform is comprised of ACT® clusters, a mix of microbubbles and microdroplets and low intensity (diagnostic) ultrasound insonation. Intravenously injected ACT® clusters circulate freely through the body before activation by localised insonation at the targeted pathology. In the ultrasound field, microbubbles transfer energy to microdroplets, which undergo a liquid-to-gas phase transition, forming larger ACT® bubbles that transiently deposit in the targeted microvasculature. Further exposure to ultrasound results in controlled volume oscillation of the ACT® bubbles, inducing a range of biomechanical effects. The effects lead to enhanced extravasation across the endothelial barrier, facilitating the transport of co-administered chemotherapeutics to the targeted tissue. Proof of concept studies showed an increased therapeutic efficacy of standard of care drugs, when combined with ACT® treatment. Furthermore, ACT® treatment induced a controlled and temporal opening of the blood brain barrier observed by the extravasation of fluorescent macromolecules into brain tissue.

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