Image: Fluorescence images of the murine hippocampus after diffusion of Dextran through the FUS opened BBB (Left), compared to contralateral that shows no uptake (Right) (Photo courtesy of Dr. Elisa Konofagou/ Columbia University).
A new technique uses a focused ultrasound (FUS) beam to control the size of molecules penetrating the blood-brain barrier (BBB).
Researchers at Columbia University (New York, NY, USA) conducted a study that applied FUS onto a mouse hippocampus in the presence of systemically administered microbubbles (MBs) containing fluorescently labeled dextrans with molecular weights of 3-2,000 kDa (2.3–54.4 nm in diameter), to examine the possibility of trans-BBB dextran delivery. Outcomes were evaluated using ex vivo fluorescence imaging, and cavitation detection was employed to concomitantly monitor the MB activity associated with the delivery of the dextrans.
The results showed that FUS-induced BBB opening size—defined by the size of the largest molecule that can permeate through the BBB—can be controlled by acoustic pressure. BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, reached 70 kDa (10.2 nm) at 0.51 MPa, and was as large as 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa). The study was published in the July 2014 issue of the Journal of Cerebral Blood Flow & Metabolism.
“Most small and all large molecule drugs do not currently penetrate the blood-brain barrier that sits between the vascular bed and the brain tissue,” said study coauthor professor of biomedical engineering and radiology Elisa Konofagou, PhD, of Columbia Engineering. “This is an important breakthrough in getting drugs delivered to specific parts of the brain precisely, noninvasively, and safely, and may help in the treatment of central nervous system diseases like Parkinson's and Alzheimer's.”
FUS in conjunction with MBs—gas-filled bubbles coated by protein or lipid shells—is so far the only technique can permeate the BBB safely and noninvasively. When MBs are hit by an FUS beam, they start oscillating due to cavitation, the formation of vapor cavities in the liquid phase; depending on the magnitude of the pressure, they continue oscillating or collapse. The study showed that the pressure of the FUS can be adjusted depending on the size of the drug that needs to be delivered to the brain - small molecules at lower pressures and larger molecules at higher pressures.