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Title: Functionalised microbubbles for dual-modality imaging
Author: Harriss, Bethany Ivy
ISNI:       0000 0004 8499 3301
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Medical imaging is ubiquitous in disease diagnosis and monitoring, with many different methods available. The aim of dual-modal contrast agents is to synergistically combine two of these into one probe in order to enhance the information obtained. Early and accurate detection of diseases is crucial in improving patient prognosis and survival rates. For this reason, this thesis aims to develop cancer-specific contrast agents which combine multiple imaging modalities into one probe. Ultrasound is a commonly used imaging modality as it is cheap, easy to use, portable and provides real-time images. It is frequently used to assess the abdominal organs and monitor foetus development, however cancerous tissues can be difficult to observe under normal conditions. Microbubbles are clinically used ultrasound contrast agents that can improve the visualisation of tumours. These are composed of a gas core stabilised by a surface coating such as a phospholipid and are the ideal platform for further functionalisation. During this project, phospholipids have been functionalised with the cancer-targeting peptide RGD and fully characterised using NMR, MALDI-TOF and UPC2-ES+. These were then formed into microbubbles and their selective binding proved through in vivo work. Phospholipids were then functionalised with moieties to allow for coordination to 68Ga, a PET isotope. Initial experiments involved the radiolabelling of a small molecule followed by functionalisation of the microbubble surface. Unfortunately this did not yield radiolabelled microbubbles, therefore latter experiments focussed on direct radiolabelling of a phospholipid and subsequent formation into microbubbles. This route resulted in radiolabelled microbubbles, with further development underway to improve this reaction. Phospholipid functionalisation with pH sensitive and pH insensitive fluorophores was also performed, their fluorescence properties assessed and incorporation of modified phospholipids into microbubbles proved by microscope visualisation under laser irradiation. These were then formed into nanodroplets, with the goal of using the optical absorbers to induce selective vaporisation into microbubbles. Further work will assess the vaporisation properties of these nanodroplets. Finally, small molecule fluorescence-MRI and fluorescence-PET probes were developed for use with microbubbles to mediate delivery across the blood-brain-barrier. Preliminary results indicate successful, selective delivery using this technique, with further testing underway.
Supervisor: Long, Nicholas Sponsor: Imperial College London ; Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral