Enhancement of Nanoparticle and Macromolecule Delivery into Brain Tissue with Ultrasound and Microbubbles and Monitoring with MR Image
Date Issued
2010
Date
2010
Author(s)
Wu, Hsin-Yu
Abstract
The blood-brain barrier (BBB) is the major limiting factor to delivering therapeutic agents to the brain for disease treatment. Focused ultrasound (FUS) was shown to be able to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened BBB. In this study, we investigated the delivery enhancement of nanoparticles and macromolecules into brain tissue using additional sonication after the BBB was temporarily opened by FUS with microbubbles. We examined the BBB opening induced by FUS and microbubbles dependence on the agent’s molecular weight with MR image and inductively coupled plasma mass spectrometry (ICP-MS).
After the injection of microbubbles, one MHz FUS immediately sonicated at the target location of the brains of 300-400g Wistar rats through skulls to noninvasively open the BBB. After the complete decay of microbubbles, an additional sonication was applied without further microbubble injection to enhance the delivery of iron oxide (70 nm) or dextran (3 kDa or 70 kDa) particles into the sonicated brain tissues. The amount of particles in the brain tissue was measured using ICP-MS and microplate reader.
ICP-MS results showed that FUS with a low dosage of microbubbles could only result in a small amount of iron oxide nanoparticles delivered into the brain tissues (extracellular space~50nm). However, an additional FUS sonication could enhance nanoparticles delivered into brain tissues up to 20-fold. The result of microplate reader showed that 3 kDa and 70 kDa dextrans were both diffusively distributed throughout the targeted brain region, while 70 kDa dextran appeared more punctuative. The amount of 70 kDa dextran significantly increased with an additional sonication, but not for 3 kDa dextran. This sonication strategy can effectively enhance the delivery of nanoparticles and macromolecules into the sonicated brain tissues, and it is more effectively to larger macromolecules and to nanoparticle with low dose of microbubble injection.
Subjects
focused ultrasound
microbubbles
blood-brain barrier
drug delivery
nanoparticles
Type
thesis
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