Image-Guided Focused-Ultrasound CNS Molecular Delivery: An Implementation via Dynamic Contrast-Enhanced Magnetic-Resonance Imaging

Focused ultrasound (FUS) exposure with microbubbles can transiently open the blood-brain barrier (BBB) to deliver therapeutic molecules into CNS tissues. However, delivered molecular distribution/concentration at the target need to be controlled. Dynamic Contrast-Enhanced Magnetic-Resonance Imaging (DCE-MRI) is a well-established protocol for monitoring the pharmacokinetic/pharmacodynamic behavior of FUS-BBB opening. This study investigates the feasibility of using DCE-MRI to estimate molecular CNS penetration under various exposure conditions and molecule sizes. In the 1(st) stage, a relationship among the imaging index K(trans), exposure level and molecular size was calibrated and established. In the 2(nd) stage, various exposure levels and distinct molecules were applied to evaluate the estimated molecular concentration discrepancy with the quantified ones. High correlation (r(2) = 0.9684) between K(trans) and transcranial mechanical index (MI) implies K(trans) can serve as an in vivo imaging index to mirror FUS-BBB opening scale. When testing various molecules with the size ranging 1–149 kDa, an overall correlation of r(2) = 0.9915 between quantified and predicted concentrations was reached, suggesting the established model can provide reasonably accurate estimation. Our work demonstrates the feasibility of estimating molecular penetration through FUS-BBB opening via DCE-MRI and may facilitate development of FUS-induced BBB opening in brain drug delivery.