Fluorescence-based diagnostics for understanding platinum-based therapy

Thesis

This thesis explores the design of a series of platinum(IV) fluorescent probes as imaging tools to study the intracellular reduction of Pt(IV) prodrugs in real-time via fluorescence microscopy.

Chapter 1 outlines the fundamental properties of platinum. The mode of action of Pt(II) drugs within cells, the development and reduction mechanisms of Pt(IV) prodrugs is discussed. The final sections review prior work on Pt fluorescent sensors, Pt-tagged complexes, and Pt theranostics.

Chapter 2 details the synthetic procedures and characterisation of two novel fluorescent diazido platinum(IV) conjugates for potential PACT-PDT application. The photophysical properties and stability of the complexes are examined.

Chapter 3 presents a set of fluorescence responsive oxaliplatin(IV) carbamate complexes, of which the photophysical and photochemical characteristics in the presence of reductants are studied in detail. The reduction and cytotoxic properties of the OxPt(IV) prodrugs in cancer cells are also investigated.

Chapter 4 extends the work presented in Chapter 3 to prepare the cisplatin-based and carboplatin-based platinum(IV) analogues. The stability, reduction, and cytotoxic profiles of the fluorescent CisPt(IV) and CarboPt(IV) compounds are compared to the OxPt(IV) analogues.

Chapter 5 evaluates the combinatory effect of copper metal ions and ascorbate in an attempt to promote the reduction of less reactive platinum compounds.

Chapter 6 describes the development and characterisation of fluorescent platinum therapeutics as potential dual-action anticancer agents.

Chapter 7 provides an overview of the conclusions met in this work and the consecutive research strands that could be investigated in the future.

Chapter 8 contains the experimental procedures and synthetic methods.

Authors: Boulet, M

• DOI: 10.5287/ora-jbzgyz0mg
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Imaging; Platinum compounds; Fluorescence; Chemistry