Drug Delivery to the Brain by Focused Ultrasound and Microbubble Mediated Blood-brain Barrier Disruption: Vascular-level Investigation using Two-photon Fluorescent Microscopy
Year: 2015
Type: dissertation
Abstract: The use of focused ultrasound (FUS) in combination with microbubbles (MBs) to transiently and noninvasively disrupt the blood-brain barrier (BBB) has been an active research topic which could ultimately revolutionize the way drugs are delivered into the brain parenchyma for treatment of central nervous system (CNS) pathologies. Stemmed from its prospective clinical application, the overarching goal of this research is to explore the underlying physical mechanisms and fundamental biological effects via the use of two-photon fluorescence microscopy (2PFM). In addition, this research aims to draw the connection between the kinetics of blood-brain barrier disruption (BBBD) and the localized drug deposition in the treated brain. To provide a robust solution for dorsal approach of FUS exposure and in vivo 2PFM imaging of the cerebral microvasculature, a ring-shaped transducer has been designed and characterized. Two modes of vibration (thickness and height) were investigated for their effectiveness at inducing BBBD in a rat model. By operating the transducer in thickness mode, we induced BBBD at different acoustic pressure levels and delivered fluorescent dyes into the rat's blood circulatory system while capturing a series of 2PFM images. These microscopic data allowed for quantitative measurement of the enhanced permeability of blood vessels upon BBBD. The dependency of the vascular permeability on the substance size and the applied acoustic pressured was established. We identified two types of leakage kinetics - fast and slow - that exhibit distinctive permeability constants, temporal disruption onsets, and pertinent vessel diameter. To translate these preclinical findings into the clinical setting, we developed a mathematical framework that depicts the kinetics of BBBD and rendered the spatio-temporal distribution of the intended drug at a targeted brain region. Here, we considered Doxorubicin (Dox) as the drug of choice. The constructed model predicts Dox concentrations within the plasma, extracellular and intracellular compartments that are governed by various transport processes. By examining several clinical treatment parameters, our simulation outputs were validated against experimental findings in a rat model. Considering the flexibility of the FUS+MBs assisted BBBD technique, this simulation study can be adapted for other drugs to assist the treatment planning process for different CNS conditions.
Source: TSpace (University of Toronto)
Author: Tam Nhan
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W2603001757