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Title: Advancing a methodology for implant-triggered cancer treatment with Bioorthogonal Palladium-Labile prodrugs
Author: Bray, Thomas Llewelyn
ISNI:       0000 0004 7229 3981
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2018
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Chemotherapeutics are potent molecules capable of systematically treating cancer. As healthy tissues contain features also inherent to cancer cells, treatment often results in unwanted sideeffect. As chemotherapeutic side-effect produces significant harm and often limits optimal drug dosing, new strategies must be developed to improve treatment selectivity. A prodrug strategy provides one option to improve the selectivity of an established chemotherapeutic. By modifying a pharmaceutically active drug, interaction with biology may be functionally masked. Subsequent ‘un-masking’ the prodrug exclusively at the intended treatment site may direct treatment only to where the anticancer effect is required. This thesis progresses the novel approach of bioorthogonal organometallic (BOOM) prodrug activation. A metal catalyst and masked chemotherapeutic constitute reaction partners to provide a new strategy for intratumoural prodrug activation. Whereby the prodrug and metal catalyst are independently non-cytotoxic, in combination the prodrug undergoes catalytic activation to deliver an anticancer affect. By positioning the metal catalyst within a tumour (i.e. by microsurgery), an administered masked prodrug sensitive to catalyst-mediated activation could allow for ‘targeted’ chemotherapy localised to the tumour site. The design, synthesis and study of new BOOM prodrug candidates are reported herein. Novel protecting groups are developed to enhance drug masking to biology and subsequent catalyst-mediated activation. Prodrug screening studies are carried out in cancer cell culture models, with zebrafish and in ex vivo rodent model tumour explants. The catalyst, a palladium (Pd0) functionalised bead system, is optimised for enhanced activation, drug release and in vivo implantation. The potentially infinite generation of active chemotherapeutics exclusively in tumour would increase the efficacy of treatment whilst reducing harmful effect on healthy tissue.
Supervisor: Unciti-Broceta, Asier ; Hastie, Nick Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: chemotherapeutics ; bioorthogonal organometallic reactions ; BOOM ; palladium functionalised bead system