Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.601252
Title: Applications of DOTA-Lanthanide "Click" complexes to sensing and imaging
Author: Hanna, Jill
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2011
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Abstract:
While copper is an essential micronutrient in all living organisms, copper misregulation in humans is associated with neurodegenerative disorders such as Menkes and Wilson’s diseases, amyotrophic lateral sclerosis and Alzheimer’s disease. Furthermore, copper is a widely-produced pollutant and thus the detection of Cu(II) and Cu(I) has received much attention in recent years. Copper can be detected in a number of ways including; quenching of fluorescence upon the binding of paramagnetic Cu(II) (a "turn-off" response); augmentation of fluorescence upon Cu(II) binding due to PET modulation (a "turn-on" response); and selective Cu(II)- or Cu(I)-catalysed reactions where the luminescence of the product is distinctly different to that of the starting material. A review of Cu(I) and Cu(II) sensors is described herein. The Hulme group has previously developed a sensor for ligand-bound copper(I) utilising the copper(I)-catalysed [GS-−Cu(I)] variant of the Huisgen 1,3-dipolar cycloaddition reaction. Cu(I)-catalysed alkyne-azide cycloaddition (CuAAC or “click”) was carried out between an alkynyl Eu(III)-DOTA complex and a dansyl azide yielding a 1,4-triazole with a modest turn-on response (10-fold increase in luminescence). The project described herein aimed to achieve a more significant increase in lanthanide luminescence intensity through alteration of the donor moeity, lanthanide ion, and linker length between donor and acceptor moiety. The synthesis of several lanthanide-DOTA complexes, azido fluorophores and the formation of novel Cu(I)-sensors via CuAAC is described herein. All Cu(I) sensors were excited at their individual λex and their lanthanide luminescence intensity was measured using a timedelayed phosphorimeter. The DOTA structural motif has the ability to complex a plethora of potentially useful radionuclides including; yttrium, indium, gallium, lutetium and gadolinium. In general, DOTA-complexes doped with gadolinium are utilised for the identification of tumour sites while yttrium or indium complexes are used for tumour treatment. Biotin-DOTA conjugates have previously been used for pretargeted cancer imaging and radiotherapy. Biotinidase degradation of the amide bond in some biotin constructs has been reported, rendering them unable to bind to the pre-targeted antibody-(strept)avidin site. A novel biotinyl azide lacking this vulnerable amide bond is reported, with potential for bioconjugation to a variety of biomolecules via “click” chemistry. The synthesis of two novel biotinylated Gd-DOTA complexes, with prospective application as pretargeted MRI contrast agents, are also described.
Supervisor: Bradley, Mark; Hulme, Alison Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.601252  DOI: Not available
Keywords: Lanthanides ; MRI ; Copper
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