Prodrugs activated by implantable microsystems
Norman, Daniel James
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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.