Abstract
This Thesis presents new investigations into designing and testing novel theranostic metallo-thiosemicarbazonato probes for the molecular imaging of prostate cancer (PCa). Following the Introduction, the synthesis and characterisation details of thiosemicarbazonato compounds with different functionalised groups and metal centres, as well as the PCa targeting peptide-based conjugates are given in Chapters 1-5. The cytotoxicity of as-synthesised agents on human PCa cells DU145 and human fibroblasts AG09429 was measured via MTT assays. The comparative cellular uptake and intracellular biodistribution of as-prepared probes on human PCa cells DU145 and PC-3, and human fibroblasts AG09429 were investigated by laser confocal scanning microscopy. The in vitro fluorescence lifetime of a selection of compounds on PC-3 was measured by fluorescence lifetime imaging microscopy (FLIM).Most metal thiosemicarbazonato compounds had significant cytotoxicity on PCa cells and no obvious toxicity on healthy fibroblasts. The corresponding derived thiosemicarbazonato-peptide conjugates can be effectively taken up by PC-3 cells, distributed in the cytoplasm and exhibited fluorescence, which showed promising potential for PCa imaging and therapy.
Chapter 1 is the Introduction, which describes the context of this work, introducing and discussing the limitations of current diagnostic techniques and treatment strategies for PCa. Briefly reviewed the applications of thiosemicarbazonato-based probes and bombesin-based conjugates in PCa imaging and therapy.
Chapter 2 describes the synthesis of bis(substituted) thiosemicarbazone ligands and corresponding metal derivatives by adapted methodologies or novel synthetic routes. As well as their optimised spectroscopic studies, and an unprecedented investigation into the oxidation properties and [18F]F radiolabelling approaches to a range of selected
compounds.
Chapter 3 describes the synthesis and characterisation of mono(substituted) thiosemicarbazone ligands and corresponding metal derivatives. The kinetic stability and optical properties of selected compounds were investigated by UV/Vis spectroscopy and fluorescence spectroscopy. Density functional theory (DFT) calculations were performed to calculate the geometries and energies of selected Zn(III), Ga(III) and Cu(II) complexes. Electron paramagnetic resonance (EPR) spectroscopy was used to explore the metal coordination modes of Cu(II) complexes and to probe the possibility of the co-existence of multiple Cu(II) centres in these compounds.
Chapter 4 describes the synthesis and characterisation of functionalised bis(thiosemicarbazone) ligands, metal complexes, and corresponding peptide-based conjugates. The kinetic stability and optical properties of these compounds were investigated by UV/Vis spectroscopy and fluorescence spectroscopy. The fluorescence lifetime of selected compounds was measured by the two-photon time-correlated single photon counting (TCSPC).
Chapter 5 discusses the results of cellular experiments, including MTT assays, fluorescence imaging, colocalisation studies and fluorescence lifetime imaging.
Chapter 6 summarises the results of this work and discusses the outlook of future studies based on this thesis.
Chapter 7 contains detailed experimental information and characterisation data of compounds synthesised for this work.
The Appendix includes supporting data of mass spectrometry, DFT calculations, Raman spectroscopy and X-ray crystallography, and as-processed data regarding the TCSPC and fluorescence lifetime results as exponential decay traces.
| Date of Award | 13 Nov 2024 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Sofia Pascu (Supervisor) & Charareh Pourzand (Supervisor) |
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