Drug delivery across the blood-brain barrier using focused ultrasound

Abstract

Introduction: The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a noninvasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain.

Areas covered: The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed.

Expert opinion: The introduction of magnetic resonance imaging guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development.

Figure 1

Timeline for FUS experiments. Animals are prepared for FUS treatment by using chemical depilatory to remove the hair from the head and by inserting a catheter into the tail vein. A T2-MR image is acquired and the target locations for sonication are chosen (denoted by red dots). Microbubble contrast agent is diluted and injected immediately prior to the onset of sonication. FUS is applied using standard parameters (10ms pulses, 1 Hz pulse repetition frequency, 120s total duration). Following FUS, MRI contrast agent is injected and a contrast enhanced (CE)-T1 weighted MR images is acquired. The regions of hyperintensity correspond to areas where contrast agent move from the vasculature into the brain parenchyma and is used to confirm effective BBB opening with FUS.

Figure 2

MRI has been the primary imaging modality for targeting and evaluating FUS treatments. Top panel – MR images from a mouse brain were taken using a 3.0T MR scanner (GE Healthcare). T2 weighted images were used to choose 4 sonication points in each hemisphere (red dots). Contrast enhanced T1 weighted images were used to confirm BBB opening had occurred in the target locations (red arrows). Bottom panel – MR images from a mouse brain were taken using a 7.0T MR scanner (Bruker). T2 weighted images were used to target the bilateral hippocampus using 2 sonciations in each hemisphere (red dots). T1 weighted images were used to confirm BBB opening had occurred on target (red arrows).