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Metal-based molecules for biomedical applications: investigation of their biological activities in cancer cells

Aikman, Brech 2021. Metal-based molecules for biomedical applications: investigation of their biological activities in cancer cells. PhD Thesis, Cardiff University.
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Abstract

Cisplatin, a platinum(II) based drug exhibiting potent cytotoxic effects in highly dividing and proliferating cells, is widely applied as chemotherapeutic agent against several forms of cancer. However, current drawbacks and limitations such as its severe nephrotoxicity and increased drug resistance are still of great concern. This doctoral research aimed to address these issues by exploring the potential of new families of metal-based molecules for biomedical applications as either anticancer agents or anticancer drug delivery vehicles for the aforementioned Pt(II) drug. Two strategies were then deployed. The first part of the thesis describes the study of small molecule gold(III) complexes with different scaffolds designed as aquaporin (AQP) inhibitors. AQP are membrane proteins enabling permeation of water, but also of small solutes, such as glycerol and hydrogen peroxide, across biomembranes, and their expression has been correlated to several types of cancer, making them attractive as diagnostic and therapeutic targets. Based on preliminary data on AQP modulation (inhibition) by metal-based compounds, two series of gold(III) complexes, either coordination or organometallics, were investigated for their ability to target these membrane proteins using different spectroscopic methods, and the compounds’ cytotoxic effect were also studied in vitro. The second part of this thesis focuses on another strategy to improve cisplatin`s selectivity and targeting without altering its structure/properties via the use of new generation metal-based drug delivery systems, which are able to protect the drug from metabolism (speciation) and to facilitate its uptake in cancer cells. Therefore, supramolecular coordination complexes (SCCs), specifically three dimensional (3D) metallacages, were chosen. These discrete supramolecular entities, formed via selfassembly of ligands and appropriate metal precursors, can not only be exploited for their host-guest properties to achieve drug encapsulation, but they can also be exofunctionalized with targeting moieties to improve their delivery at a tumour site. Our study provides the proof-of-concept that a specific family of metallacages of general formula [Pd2L4] 4+ (L= ligand), bioconjugated to integrin targeting ligands, can encapsulate cisplatin and increase its potency in human cancer cells overexpressing the integrin receptors. Moreover, the metallacages can be functionalized with fluorophores to enable the study of their uptake and intracellular distribution by iv fluorescence microscopy. As such, the mechanism of accumulation of [Pd2L4] 4+ cages labelled with fluorescent BODIPY moieties was investigated in vitro.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Chemistry
Date of First Compliant Deposit: 8 December 2021
Last Modified: 09 Dec 2021 09:55
URI: https://orca.cardiff.ac.uk/id/eprint/146014

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