Dynamic study of blood-brain barrier closure after its disruption using ultrasound: a quantitative analysis.

Benjamin Marty (1) , Benoit Larrat (1, 2) , Maxime van Landeghem (3) , Caroline Robic (4) , Philippe Robert (4) , Marc Port (4) , Denis Le Bihan (5) , Mathieu Pernot (2) , Mickael Tanter (2) , Franck Lethimonnier (1) , Sébastien Mériaux (1)

1 LRMN - Laboratoire d'Imagerie et de Spectroscopie
2 IL - Institut Langevin - Ondes et Images (UMR7587)
3 PPMD - Laboratoire de Physico-Chimie des Polymères et des Milieux Dispersés
4 Laboratoire Guerbet / Guerbet Research
5 NEUROSPIN - Service NEUROSPIN

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 T(1) 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.

Mots clés: BBB disruption; MR contrast agent; MRI; nanoparticles; T1 mapping; ultrasound

Domaines: Imagerie

Benjamin Marty, Benoit Larrat, Maxime van Landeghem, Caroline Robic, Philippe Robert, et al.. Dynamic study of blood-brain barrier closure after its disruption using ultrasound: a quantitative analysis.. Journal of Cerebral Blood Flow and Metabolism, 2012, 32 (10), pp.1948-58. ⟨10.1038/jcbfm.2012.100⟩. ⟨cea-00739117⟩