Abstract
The blood-brain barrier (BBB) is a specialized vascular system that impedes entry of all large and the vast majority of small molecules including the most potent central nervous system (CNS) disease therapeutic agents from entering from the lumen into the brain parenchyma. Microbubble-enhanced, focused ultrasound (ME-FUS) has been previously shown to disrupt noninvasively, selectively, and transiently the BBB in small animals in vivo. For the first time, the feasibility of transcranial ME-FUS BBB opening in non-human primates is demonstrated with subsequent BBB recovery. Sonications were combined with two different types of microbubbles (customized 4–5 µm and Definity®). 3T MRI was used to confirm the BBB disruption and to assess brain damage.
Highlights
The main limiting factor towards the development of novel treatments of neurological and neurodegenerative diseases is the blood-brain barrier (BBB): more than 98% of small-molecule drugs and most large-molecule drugs do not cross this anatomic barrier [1,2]
Global breaching of the BBB can be a risky process, as it increases influx of all molecules and therapeutic agents in untargeted areas of the brain [5] even if this approach has been proven to be successful for some applications such as metastatic lung cancer [6]
Applying ME-FUS BBB opening in large animals is very challenging as focusing inside the brain is impeded by the presence of the skull along the beam path
Summary
The main limiting factor towards the development of novel treatments of neurological and neurodegenerative diseases is the blood-brain barrier (BBB): more than 98% of small-molecule drugs and most large-molecule drugs do not cross this anatomic barrier [1,2]. Our group has shown, along with others, that microbubble-enhanced, focused ultrasound (ME-FUS) is capable of disrupting the BBB noninvasively, transiently and selectively in small animals [7,8,9] typically at frequencies above 1 MHz. the exact mechanism of BBB opening remains to be determined, the interaction of the ultrasound beam with microbubbles results in mechanical perturbation of the microvasculature and thereby changes in the integrity of the BBB components. Applying ME-FUS BBB opening in large animals is very challenging as focusing inside the brain is impeded by the presence of the skull along the beam path.
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