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Photoactivatable iridium(III) anticancer complexes
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Carter, Oliver W. L. (2023) Photoactivatable iridium(III) anticancer complexes. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3944129
Abstract
Platinum chemotherapeutics like cisplatin are pivotal in the treatment of cancer. However, platinum drug resistance and undesirable side effects require the development of anticancer agents with different mechanisms of action and better cancer selectivity. Photodynamic therapy and photoactivated chemotherapy use light to activate prodrugs with high spatial resolution, reducing off target effects. Furthermore, since cancer cells overexpress a wide array of membrane proteins, conjugating active complexes to targeting vectors can increase cancer cell selectivity.
In this thesis, glycoconjugated photosensitizers were designed to target the GLUT1 receptor which is typically overexpressed in cancer cells. A series of fourteen photo-stable Ir(III) and Ru(II) glycoconjugates were synthesised. Ir(III) complexes 1-10 exhibited phosphorescence from 475-500 nm, with good singlet oxygen quantum yields, whilst Ru(II) complexes 11-14 failed to exhibit notable phosphorescence or singlet oxygen production.
The Ir(III) complexes demonstrated low micromolar photoactivity and in-cell singlet oxygen generation. Accumulation in lung cancer cells was unaffected by the sugar bound directly to Ir(III) complexes. However, a dependence on the linker length between glucose and the Ir(III) complex was observed. Co-treatment of cells with a GLUT1 inhibitor reduced the cellular accumulation of glycoconjugate 9 but not of 4, which differ by a nine-atom linker between the Ir(III) complex and glucose. Complexes were selective for cancer cells and non-toxic towards non-cancerous lung cells at 100 μM.
This thesis also details the in-cell stability and localisation of a novel Pt-Ir complex using synchrotron X-ray techniques. This complex is comprised of an Ir(III) PDT agent conjugated to a Pt(IV) PACT agent, utilising two mechanisms of action upon blue light irradiation. X-ray fluorescence experiments of lung cancer cells treated with Pt-Ir determined the complex photo-decomposed in cells, with the resulting Pt complex localising predominantly in cell nuclei. Intracellular Pt content increased upon irradiation, with ~60% of platinum reduced to Pt(II).
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RS Pharmacy and materia medica |
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Library of Congress Subject Headings (LCSH): | Cancer -- Chemotherapy, Platinum compounds -- Therapeutic use, Metals -- Therapeutic use, Photosensitizing compounds, Cisplatin -- Therapeutic use, Drug resistance in cancer cells, Antineoplastic agents, Cancer -- Treatment -- Research | ||||
Official Date: | February 2023 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Sadler, P. J. | ||||
Sponsors: | Engineering and Physical Sciences Research Council ; GoldenKeys High-tech Materials Co., Ltd | ||||
Format of File: | |||||
Extent: | xiv unnumbered pages, ix, 265 pages : illustrations | ||||
Language: | eng |
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