Dynamic Study of Blood–Brain Barrier Closure after its Disruption using Ultrasound: A Quantitative Analysis

• Published in: Journal of cerebral blood flow and metabolism Vol. 32; no. 10; pp. 1948 - 1958
• Main Authors: Marty, Benjamin, Larrat, Benoit, Van Landeghem, Maxime, Robic, Caroline, Robert, Philippe, Port, Marc, Le Bihan, Denis, Pernot, Mathieu, Tanter, Mickael, Lethimonnier, Franck, Mériaux, Sébastien
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.10.2012; Nature Publishing Group; Sage Publications Ltd
• Subjects: Animal models; Animals; Bioengineering; Biological and medical sciences; Blood-Brain Barrier - cytology; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - radiation effects; Contrast Media - chemistry; Contrast Media - pharmacokinetics; Drug Delivery Systems; Endothelial Cells - cytology; Endothelial Cells - radiation effects; Imaging; Investigative techniques, diagnostic techniques (general aspects); Life Sciences; Magnetic Resonance Imaging; Male; Medical sciences; Models, Biological; Nervous system; Neurology; Original; Rats; Rats, Sprague-Dawley; Sound; Ultrasonic investigative techniques; Vascular diseases and vascular malformations of the nervous system; nanoparticles; MR contrast agent; MRI; BBB disruption; ultrasound; T1 mapping; Cartography; Nervous system diseases; mapping; Blood brain barrier; Nuclear magnetic resonance imaging; Cerebral disorder; T; Central nervous system disease; Ultrasound; Cerebrovascular disease; Contrast media
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2012.100

Delivery of therapeutic or diagnostic agents to the brain is majorly hindered by the blood–brain barrier (BBB). Recently, many studies have demonstrated local and transient disruption of the BBB using low power ultrasound sonication combined with intravascular microbubbles. However, BBB opening and closure mechanisms are poorly understood, especially the maximum gap that may be safely generated between endothelial cells and the duration of opening of the BBB. Here, we studied BBB opening and closure under magnetic resonance (MR) guidance in a rat model. First, MR contrast agents (CA) of different hydrodynamic diameters (1 to 65 nm) were employed to estimate the largest molecular size permissible across the cerebral tissues. Second, to estimate the duration of the BBB opening, the CA were injected at various times post-BBB disruption (12 minutes to 24 hours). A T1 mapping strategy was developed to assess CA concentration at the ultrasound (US) focal point. Based on our experimental data and BBB closure modeling, a calibration curve was obtained to compute the half closure time as a function of CA hydrodynamic diameter. These findings and the model provide an invaluable basis for optimal design and delivery of nanoparticles to the brain.