Enhancement and Monitoring of Drug Delivery for CNS with Noninvasive Focused Ultrasound and Ultrasound Contrast Agent
Date Issued
2009
Date
2009
Author(s)
Lee, Yung-Shin
Abstract
Previous studies showed that focused ultrasound (FUS) with ultrasound contrast agent (UCA) could non-invasively open blood-brain barrier of targeted region to do local drug delivery. In this study, we investigated the effects of ultrasound sonication on the delivery enhancement of Evans Blue (EB) and iron oxide nanocarriers (about 60 nm) into rat brain after the blood-brain barrier was temporarily opened by FUS with UCA. Wistar rats averaging about 380g were used in this study and the hair on their heads was removed thoroughly. After an intravenous injection of microbubbles (200μl/kg, Artison, Artison Corp., Inola, USA), 1.0 MHz focused ultrasound was immediately sonicated through the skull to the target region at 1.2 MPa pressure, 50ms burst length, 1 Hz repetition frequency, and 60s duration, to disrupt the blood-brain barrier. Ten minutes later, EB and/or iron oxide nanocarrier were injected, and then a second sonication was exposed at the same location. All rats were sacrificed about 4 hrs after the second sonication. The brains were removed and sectioned for extraction and detection of EB/nanocarrier extravasation and distribution. The results of EB extraction showed that the density of EB in the brains with a second sonication is 98.43±35.48μg/ (g of brain tissue) compared to 9.46±2.94μg/g for those without a second sonication. The spatial distributions of EB stain and fluorescent dye (Fluorescein isothiocyanate, FITC) for nanocarrier in the sonicated regions showed that a larger and much deeper region was produced for the cases with a second sonication. A second sonication without the injection of microbubbles can effectively enhance the delivery of molecules (EB) and nanoparticles (iron oxide nanocarrier) into the region with BBB temporarily disrupted. It indicated that this sonication strategy is potentially employed to improve the drug delivery within a limited duration.
Subjects
focused ultrasound
ultrasound contrast agent
blood-brain barrier
enhanced drug delivery
nanoparrticles
Type
thesis
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