Prodrugs activated by implantable microsystems
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Date
28/11/2019Author
Norman, Daniel James
Metadata
Abstract
The need to improve selectivity in cancer therapies has driven much research
into the design and methods of activation of prodrugs. These are primarily reliant
on biological processes that are present ubiquitously in tissues (healthy and
cancerous) but with elevated levels in and around cancers. As such many
therapies still suffer from dose-limiting toxicities from off-target effects.
Herein are described novel methods of prodrug activation that are reliant on
physical stimuli — namely electrical and photochemical triggers — to generate
the active drug species. These methods allow exogenous control over where,
when and how much prodrug is converted facilitating minimisation of off-target
effects by increasing the selectivity of the therapy. In conjunction with the
Implantable Microsystems for Personalised Anti-Cancer Therapies project, it is
envisioned that these activation systems will be translatable into a device
implantable and activatable within a tumour.
In my thesis, prodrug activation systems were developed for Pt(IV) prodrugs that
use either electrochemical or photochemical approaches to convert bio-inert
prodrugs into the cytotoxic Pt(II) counterparts. This was accomplished utilising
a redox mediator or photocatalyst to limit biological interferences and improve
selectivity towards the Pt species.
In summary, these prodrug activation systems were brought from the stage of
discovery to biological evaluation and validation, with significant optimisation of
their activation capabilities. The application of these novel prodrug activation
strategies forms the basis for future research in to the improvement of cancer
therapies for the benefit of the patient and demonstrates for the first time cancer
prodrug activation using an electrochemical approach.