Preclinical Research on Focused Ultrasound-Mediated Blood-Brain Barrier Opening for Neurological Disorders: A Review

Abstract

Several therapeutic agents for neurological disorders are usually not delivered to the brain owing to the presence of the blood-brain barrier (BBB), a special structure present in the central nervous system (CNS). Focused ultrasound (FUS) combined with microbubbles can reversibly and temporarily open the BBB, enabling the application of various therapeutic agents in patients with neurological disorders. In the past 20 years, many preclinical studies on drug delivery through FUS-mediated BBB opening have been conducted, and the use of this method in clinical applications has recently gained popularity. As the clinical application of FUS-mediated BBB opening expands, it is crucial to understand the molecular and cellular effects of FUS-induced microenvironmental changes in the brain so that the efficacy of treatment can be ensured, and new treatment strategies established. This review describes the latest research trends in FUS-mediated BBB opening, including the biological effects and applications in representative neurological disorders, and suggests future directions.

Keywords: blood–brain barrier; drug delivery; focused ultrasound; neurological disorders.

Figure 1

Schematic representation of the various pathways for transport across the BBB. Receptor-mediated transport (Clathrin-mediated endocytosis): only receptor-specific substances are transported through this process, and cells take up metabolites, hormones, proteins, and in some cases, viruses by an internal invasion of the plasma membrane. Carrier-mediated transport is an energy-dependent pathway normally used by small hydrophilic molecules. Carrier membranes have specific receptors that recognize target molecules and pass through cells, and mainly amino acids, monosaccharides, and peptides are delivered in this process. Adsorptive-mediated transport: this is accomplished by the electrostatic interaction of negatively charged plasma membrane with oppositely charged ligands. Paracellular-mediated transport is a passive transport process across the epithelium through the intercellular space between endothelial cells, in which various tight junction proteins are intricately attached. Cell-mediated transcytosis: cells such as monocytes or macrophages migrate through the paracellular space or across the BBB by transcytosis into the brain to release specific proteins or viruses. Passive diffusion: most small molecules cross the BBB and reach the brain by passive diffusion.

Figure 2

Confirmation of FUS-induced BBB opening using MRI. The hippocampi (yellow dotted line) of mouse were targeted per sonication. (A,B) Transverse T1-weighted pre-/post-gadolinium MR images were taken to confirm the increased BBB permeability. (C–F) Coronal T1-weighted pre-/post-gadolinium MR images after FUS. (E,F) Coronal T1-weighted post-gadolinium MR images after FUS.

Figure 3

Schematic representation of focused ultrasound-mediated focused blood–brain barrier opening. When FUS is sonicated in a specific area of the brain, an acoustic cavitation effect is induced, in which MB injected into the blood repeats contraction and expansion due to the pressure of FUS. The binding force between the vascular endothelial cells is loosened at this time. The loosened binding force lasts about 6 h, during which drugs can be delivered into the brain parenchyma.