Therapeutic Agent Delivery Across the Blood-Brain Barrier Using Focused Ultrasound

Abstract

Specialized features of vasculature in the central nervous system greatly limit therapeutic treatment options for many neuropathologies. Focused ultrasound, in combination with circulating microbubbles, can be used to transiently and noninvasively increase cerebrovascular permeability with a high level of spatial precision. For minutes to hours following sonication, drugs can be administered systemically to extravasate in the targeted brain regions and exert a therapeutic effect, after which permeability returns to baseline levels. With the wide range of therapeutic agents that can be delivered using this approach and the growing clinical need, focused ultrasound and microbubble (FUS+MB) exposure in the brain has entered human testing to assess safety. This review outlines the use of FUS+MB-mediated cerebrovascular permeability enhancement as a drug delivery technique, details several technical and biological considerations of this approach, summarizes results from the clinical trials conducted to date, and discusses the future direction of the field.

Keywords: blood–brain barrier; brain; drug delivery; image-guided therapy; therapy; ultrasound.

Figure 1

Key components of the BBB. Components of the BBB allow fine control over the substances that transit from systemic circulation to brain parenchyma and vice versa. (a) Endothelial cells are surrounded by two basement membranes, an endothelial and a parenchymal basement membrane, composed mainly of collagen IV, laminin, nidogen, and perlecan; pericytes reside in between these layers. Astrocytic endfeet surround the parenchymal basement membrane. Neurons communicate bidirectionally with various cells of the neurovascular unit, primarily astrocytes. (b) Specialized endothelial cells (blue) line cerebral vasculature, linked together by (❶) tight junction proteins (e.g., claudin-5 and occludin), adherens junction proteins (e.g., vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1), gap junctions (e.g., connexin-30), and other junctional molecules (e.g., endothelial cell adhesion molecule and junctional adhesion molecule-A). Routes of transcellular transport across endothelial cells include (❷) passive diffusion (generally, molecular weight <500 Da and log P_OCT = ~2‒4), (❸) receptor-mediated transcytosis (e.g., transferrin receptor-mediated), adsorptive-mediated transcytosis (e.g., histone and tat-derived peptides), solute carriers (e.g., glucose via glucose transporter-1), and ABC-family efflux transporters (e.g., paclitaxel via p-glycoprotein). Abbreviations: ABC, ATP-binding cassette; ATP, adenosine triphosphate; BBB, blood–brain barrier. Figure created based on information detailed by Sweeney et al. (4).

Figure 2

Evaluating FUS+MB-mediated BBB permeability enhancement. A variety of methods have been employed to target desired brain structures and assess cerebrovascular leakage following ultrasound and microbubble exposures. (a,d) MRI spatial coordinates can be coregistered to a transducer positioning system to allow targets (red circles) to be chosen from structural magnetic resonance images (a, rat; d, mouse). In preclinical studies, BBB permeability enhancement has been quantified postsonication using a number of methods, including (b) dynamic contrast–enhanced MRI, (c) contrast-enhanced T1-weighted imaging, (e) T1 mapping following MRI contrast administration, and (f) dextran fluorescence in tissue sections. Images in panels a–c and d–f were collected from the same animal subjects, respectively. Color bars indicate K^trans (min⁻¹) of (b) gadobutrol and (e) T1 in milliseconds. Clinical trials have generally utilized contrast enhanced T1-weighted imaging to confirm changes in BBB permeability. (g) A white arrow indicates a region of increased cerebrovascular leakage generated by FUS+MB exposure targeted to the dorsolateral prefrontal cortex in a participant with Alzheimer’s disease. Image in panel g adapted from Reference . White scale bars: 4 mm. Black scale bar: 400 μm. Abbreviations: BBB, blood–brain barrier; FUS+MB, focused ultrasound and microbubble; MRI, magnetic resonance imaging.

Figure 3

Conceptual illustration of active control strategies. (a) The ramped control scheme, based on ultraharmonic emissions, increases the pressure burst to burst until detection of a threshold (red dashed line) change in emissions from the integrated band around the ultraharmonic frequencies (green boxes, 3/2 f₀). At time X, there is an absence of signal in this band, while at time Y, the presence of ultraharmonic emissions triggers a decrease in applied pressure to a predetermined target level (percentage of the peak reached) for the remainder of the sonication duration. (b) The proportional control scheme, based on harmonic emissions, integrates the harmonic signal over bands around one or multiple harmonics of the driving frequency (illustrated here with a green box around the second harmonic, 2f₀). The applied pressure is adjusted from burst to burst to maintain the harmonic emissions within a target zone (blue band).