Advancing a methodology for implant-triggered cancer treatment with Bioorthogonal Palladium-Labile prodrugs
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Date
30/06/2018Author
Bray, Thomas Llewelyn
Metadata
Abstract
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.