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In vivo evaluation of the efficacy and safety of rapid short-pulse sequences for ultrasound-medicated delivery of agents to the brain

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Title: In vivo evaluation of the efficacy and safety of rapid short-pulse sequences for ultrasound-medicated delivery of agents to the brain
Authors: Morse, Sophie
Item Type: Thesis or dissertation
Abstract: The blood-brain barrier is essential to the maintenance of homeostasis in the brain, but it also prevents 98% of small molecule drugs and imaging agents from entering the brain. Focused ultrasound in combination with microbubbles is a method that can increase the permeability of the blood-brain barrier in a non-invasive, localised and transient manner, allowing drugs and imaging agents into the brain. In conventional ultrasound methods, a sequence of long pulses is applied to the brain, which can cause undesired effects, such as uneven drug distributions and a barrier altered for several hours, exposing the brain to unwanted bloodborne substances. In this thesis, we have investigated whether the efficacy and safety of drug delivery can be improved in vivo by emitting ultrasound in a Rapid Short-Pulse (RaSP) sequence. We first investigated the differences in performance and safety between emitting a RaSP sequence and a long pulse sequence to deliver a dextran model drug. We found that a more uniform drug distribution was achieved using RaSP, with a delivered dose comparable to that of long pulses. The barrier permeability was altered for less than 10 minutes, minimising the amount of endogenous proteins entering the brain, while no tissue damage was observed. We then investigated whether RaSP could deliver large 100 nm liposomes into the brain. We showed that RaSP can achieve this with an improved safety profile, although higher pressures were needed compared to long pulses. Finally, we evaluated whether a dual-modal MRI-optical probe could be delivered into the brain, using long pulses, to image neurons. We confirmed uptake within neurons and detected both fluorescence and MRI signals ex vivo. This work demonstrates that ultrasound sequences can be designed to improve the efficacy and safety of drug delivery for the diagnosis and treatment of brain diseases.
Content Version: Open Access
Issue Date: Jul-2020
Date Awarded: Oct-2020
URI: http://hdl.handle.net/10044/1/97208
DOI: https://doi.org/10.25560/97208
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Choi, James
Long, Nicholas
Sponsor/Funder: Engineering and Physical Sciences Research Council (EPSRC)
Funder's Grant Number: EP/L015226/1
Department: Bioengineering
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Bioengineering PhD theses



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