Minimally invasive targeted drug delivery in the brain enhanced by closed-loop focused ultrasound control

Abstract

Minimally invasive systemic drug delivery in the brain offers several advantages over conventional invasive approaches (e.g. Ommaya reservoir). However, effective delivery still remains a major challenge. This is due to the low drug penetration across the blood-brain barrier (BBB) – a specialized neuro-vascular unit evolved to keep the brain “safe”. Low-intensity focused ultrasound (FUS) combined with ultrasound (vascular) contrast agents called ‘microbubbles’ (MBs) provides a physical method to spatially and temporally modulate the BBB permeability and improve the delivery of a range of therapeutic agents in the brain. Here, using closed-loop methods based on the detection of the oscillating microbubble acoustic emissions (AE), we show that it is possible to monitor and locally control the cerebrovascular microbubble dynamics. This capability not only allows to modulate the level of drug delivered in the brain, but also makes this minimally invasive technology completely “tunable”. These capabilities are incorporated to a portable and cost-effective system and demonstrated in small animal experiments. Following the proof-of-concept experiments, this system will be scaled to clinical level with the goal to accelerate the clinical translation of this promising technology for targeted drug delivery against a range of brain diseases, including Alzheimer’s and brain cancer.