Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

Abstract

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB.

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

“…In general, it has been well-accepted that the successful BBBD can be facilitated once the strength of stable cavitation achieves a certain threshold. However, if the exposure level is too high, the likelihood of inertial cavitation increases, which has been reported to be associated with vascular/neuronal damage (7).…”

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

“…The linkage sequesters the peptide, but the peptide can be released inside the aorta by fragmenting the microbubbles with ultrasound pulses transmitted by a 1.1‐MHz focused transducer (Figure 5A). Stresses generated during bubble oscillation and destruction can permeabilize the endothelium reversibly48 and allow the peptide to cross the intima and reach smooth muscle cells in the media of the aorta. In Figure 5C, lower panel, the tissue has been ultrasound‐loaded, and the green peptide is seen appearing in cells at least half way across the thickness of the vessel wall.…”

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

“…A variety of therapeutic agents including small molecules, antibodies, plasmid DNA, and siRNA, either alone or packaged in liposomes, have been successfully delivered across the BBB using FUS and microbubbles. 15,16 This method is noninvasive and can achieve brain-specific delivery; thus, it has several advantages over other strategies to circumvent the BBB.…”