Image-Guided Focused-Ultrasound CNS Molecular Delivery: An Implementation via Dynamic Contrast-Enhanced Magnetic-Resonance Imaging.
Authors: Chai WY, Chu PC, Tsai CH, Lin CY, Yang HW, Lai HY, Liu HL
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<sup>st</sup> stage, a relationship among the imaging index K<sub>trans</sub>, exposure level and molecular size was calibrated and established. In the 2<sup>nd</sup> stage, various exposure levels and distinct molecules were applied to evaluate the estimated molecular concentration discrepancy with the quantified ones. High correlation (r<sup>2</sup> = 0.9684) between K<sub>trans</sub> and transcranial mechanical index (MI) implies K<sub>trans</sub> 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<sup>2</sup> = 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.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine whether DCE-MRI (Ktrans) can be used to estimate concentrations of molecules of varying sizes delivered into the brain via focused ultrasound-induced BBB opening across different exposure levels.
Animal model / Human subject
Rat, Sprague Dawley, 8 weeks, male, 250-300 g
MRI or image guidance method
MRI guided
Target coordinates
AP: 0.0 mm; ML: -3.5 mm
Cargo name and characteristics
Gd-DTPA (1 kDa); Dextran; Evans blue-albumin; trypan blue-albumin; bevacizumab
Route of administration
Intravenous
Outcomes and Safety
Summary of Outcomes
Ktrans correlate with transcranial MI and accurately predicted delivered brain concentrations for molecules ranging from 1-149 kDa
Safety-related matter
FUS exposure with MI > 0.6 may cause erythrocyte extravasations or brain damage.
Brain Region
Ultrasound Parameters
Ultrasound instrument
0.4 MHz transducer (Imasonic, France); 0.5 MHz transducer (H104MR, Sonic Concepts); 1 MHz transducer (RK-300, FUS Instruments)
FUS Frequency
0.4, 0.5, 1 MHz
FUS Pressure
0.32-0.88 Mpa (0.4 MHz); 0.44 Mpa (0.5 MHz); 0.65-1.25 Mpa (1 MHz)
FUS Mode
pulsed
Pulse duration
10 ms
Duration of a single FUS session
90-120 s
Focal Characteristics
Focal depth: None; Focal length: 80 mm (0.4 MHz); 63 mm (0.5 MHz); 20 mm (1 MHz); Aperture size: 60 mm (0.4 MHz); 64 mm (0.5 MHz); 25 mm (1 MHz)
Treatment frequency
Single session
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