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Title: Dual-modal imaging agents for zinc ion sensing
Author: Rivas, Charlotte
ISNI:       0000 0004 5920 6775
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The area of MRI/optical imaging has received a lot of attention as their combination brings together the high spatial resolution of MRI with the high sensitivity of optical imaging. Changes in pancreatic β-cell mass contribute to the development of both type 1 and type 2 diabetes. Whilst the processes of β-cell loss are fairly well established for type 1, both the extent of the loss and the underlying mechanisms are relatively unknown for type 2. Zinc ions are highly concentrated in the insulin granules that are contained within β-cells. Few robust approaches currently exist to monitor changes in β-cell mass in vivo, and as such, this project aims to develop responsive lanthanide complexes to bind selectively and respond to zinc levels in this target area. The introductory chapter considers the fundamental aspects of molecular imaging, with a particular focus on magnetic resonance and optical imaging, as well as the intrinsic properties of the lanthanide elements, such as magnetism and luminescence. The subsequent results chapters contain more detailed introductions, relevant to the topics covered within the chapter. The synthesis of dual-modal MR/optical probes is described in chapter two. Three rhodamine-based [GdDO3A] complexes are described and their relaxivity and fluorescence properties are established. The Eu3+ and Tb3+ analogues are also studied. Two of the complexes, which show superior water solubilities, are further studied in in vitro and in vivo experiments. One probe displays a fluorescence pH sensitivity that allows for the differentiation of healthy cells from malignant cells due to their difference in pH whilst the other probe displays fluorescence at all pH's. Both probes show accumulation in the mitochondria. Chapter three discusses the synthesis of an MR zinc sensor using a BPEN chelator as the zinc-binding moiety. Showing high selectivity for zinc, this probe is then further functionalised with the rhodamine fluorophore derivative previously described to give a dual- modal MR/fluorescent zinc sensor. This probe only shows an MR response in the presence of zinc. In vitro experiments show the localisation of the probe to differ from the results of the dual-modal probes discussed in chapter two, showing cytosol localisation. Finally, chapter four concerns the synthesis of a fluorescent zinc sensor and its conjugation to a [GdDO3A] scaffold to give a dual-modal MR/optical zinc sensor. This probe displays an improved response to zinc showing increases in both relaxivity and fluorescence. In vitro experiments with both INS1 and HEK cells show the probe to localise in the lysosome and mitochondria respectively.
Supervisor: Long, Nicholas Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available