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Title: Palladium catalysts for cancer imaging
Author: Cowling, Paul Timothy
ISNI:       0000 0004 9349 2445
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2020
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Lung cancer is one of the most devastating diseases with a 5-year survival rate of 17 %. The reason for this poor prognosis is that the disease is often detected at a late stages because of the reliance on low accuracy/low sensitivity diagnostic techniques such as, X-rays and CTscans. These techniques give non-specific answers as to the exact causes of a patient’s symptoms; in that they can detect if an abnormality is present, but not what it is. There is a clear need for new diagnostic techniques which can deduce the presence of lung cancer in an efficient and cost-effective manner. Molecular imaging with targeted fluorescent probes has been demonstrated as a highly sensitive approach for visualising active diseases, with several probes currently in clinical trials. To image lung cancer, this work aims to recreate the concept of antibody directed enzyme prodrug therapy (ADEPT) except replacing the enzyme catalyst with a palladium catalyst. These antibody-catalyst conjugates would be able to catalyst depropargylation reactions of protected fluorophores such as Rhodamine 110 and Dichlorofluorescein, thus giving a mechanism to “switch on” fluorescent signals that can be used to image the location of cancer cells. To deliver this, a library of palladium-N-heterocyclic carbene complexes were created through novel resin-based synthetic methodologies, enabling rapid multi-reaction synthesis with one purification step. All the catalysts contained moieties that could subsequently be used for bioconjugation, therefore the catalysts developed could be attached to targeting molecules such as antibodies. The catalysts were shown to be biocompatible and catalytically active in biological environments, with a lead catalyst shown to activate a prodrug in a 3D cancer spheroid model. Subsequently, the synthesised Pd-catalysts were for the first time, conjugated onto antibodies in a world first discovery. The Pd-antibody conjugates were shown to catalyse the activation of a fluorescent reporter, and optimisation of conjugates was performed with different Pdloading and spacers trialled. These Pd-antibodies represent a huge step forward and could be used to ultimately image cancer cells in vitro and in vivo. In the future, these biologically targeted Pd-catalyst conjugates could highlight tumour margins by activating a range of florescent probes or activate prodrugs to help kill the tumour at the same time, representing a versatile platform technology to combat lung cancer.
Supervisor: Bradley, Mark ; Dhaliwal, Kanwaldeep ; Frame, Margaret Sponsor: Engineering and Physical Sciences Research Council (EPSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: lung cancer ; palladium ; antibody directed enzyme prodrug therapy ; antibody-catalyst conjugates ; palladium-N-heterocyclic carbene complex ; Pd-catalysts ; Pd-antibody conjugates