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The design and synthesis of fluorescent peptides and disaccharides for tumour imaging.

Main, Marcus John (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

Chapter 1: Peptide targeting of integrin αvβ3 Integrins are cellular surface receptor proteins involved in numerous cellular signalling and adhesion processes. The integrin αvβ3 subtype is up-regulated around sites of malignancy especially solid tumour masses. This is due to its expression on the endothelial and smooth muscle cells which are concentrated in areas of cancer where the uncontrolled proliferation and longeitivity of cells characterises the malignant process. Sustaining such a process is achieved through the development of a labyrinth of new vessels to supply nutrients and remove waste from the accumulating tumour mass. This is the process of angiogenesis, where endothelial and smooth muscle cells accumulate to form new blood vessels. Crystallographic studies have determined that the tri-amino acid sequence RGD is crucial for the recognition and binding of extracellular proteins in the αvβ3 integrin binding site. Cyclic penta-peptides bearing this RGD motif have been found to exhibit preferential in vivo stability properties over their linear counterparts without affecting recognition and binding. In this study the cyclic peptide cRGDfK was synthesised using solid phase peptide chemistry and the lysine (K) residue proved an efficient means of attaching a fluorophore for potential diagnostic imaging applications. Targeted fluorescent imaging is the backbone of this study. Novel lanthanide metal complexes with a variety of appended chromophores were synthesised via the Ugi four-component condensation reaction. The plan was to discern the most effective energy transfer mediated long-lifetime luminescent combinations, for subsequent attachment to the cyclic peptide as long-lifetime imaging agents which would allow the use of time-gated technology to eliminate troublesome background fluorescence. This chemistry was published. Near-IR emissive organic fluorophores were also appended to the cyclic peptide and intraveneously injected into live lung tumour bearing mice. This interesting work investigated the in vivo potential of these targeted probes. Chapter 2: β-Galactoside targeting of galectin-3 Galectins are a family of intra and extra-cellular proteins which bind specifically to the β-galactoside carbohydrate residues of cellular glycoproteins. Several galectins, but most significantly galectin-3, have been found to mediate important inter- and intra-cellular processes particular to cancer cells including their signalling, proliferation and also in the metastasis of malignancy. Galectin-3 targeted lactosamine derivatives were synthesised with various organic fluorophores appended via an N-caproic spacer unit. These compounds were then tested against galectin-3 expressing cell lines and the binding and subsequent emission visualised through fluorescence microscopy.

Type of Work:Ph.D. thesis.
Supervisor(s):Snaith, J. S.
School/Faculty:Colleges (2008 onwards) > College of Engineering & Physical Sciences
Department:School of Chemistry
Subjects:QD Chemistry
Institution:University of Birmingham
ID Code:997
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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