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Guanine Quadruplex Targeted Ruthenium(II) Polypyridyl Luminophores for Imaging and Therapeutics

Holden, Lorcan (2024) Guanine Quadruplex Targeted Ruthenium(II) Polypyridyl Luminophores for Imaging and Therapeutics. PhD thesis, Dublin City University.

Abstract
Ru(II) polypyridyl luminophores are often overlooked as candidates towards live cell imaging and sensing. Their promising photophysical attributes include environmentally sensitive 3MLCT states, large Stoke-shifts and photostability, allowing them to overcome some limitations of their organic fluorophore counterparts such as high background noise and photobleaching for applications in imaging. Further, these attributes can facilitate the multi-modal imaging and sensing such as phosphorescence lifetime imaging microscopy, resonance Raman mapping, and super resolution STED microscopy providing exciting opportunities to explore cellular environments and dynamics. Some of the most thoroughly studied Ru(II) complexes contain extended planar dppz ligands promoting DNA intercalation. More recently, derivatives of these complexes have targeted the non-canonical DNA and RNA secondary structure, guanine quadruplexes, though often a barrier to their exploration in a biological environment is poor cellular uptake or endosomal entrapment. Presented in this thesis is the development of Ru(II) complexes designed to target guanine quadruplex nucleic acids while also promoting live cell uptake. Chapter 2 explores designing Ru-PDC3, a [Ru(phen)2(dppz)]2+ derivative, that contains the highly selective G4 targeting ligand, phen-DC3. This chapter examines the DNA binding properties and tests its potential as a multi-modal probe for G4 imaging across a series of cell lines. In Chapter 3 an analogue of Ru-PDC3 is synthesised, containing two TAP ligands with the aim of developing a G4 targeting probe capable of undergoing photoexcited redox chemistry in hypoxia, proving to be an excellent candidate for photodynamic therapy. Further, it was established that the complex was capable of mitochondrial localisation, providing the exciting prospect of targeting mitoG4s present in the mitochondrial genome. Chapter 4 investigated the bioconjugation of a [Ru(bpy)2(Pic-COOH)]2+ complex to a G4 binding peptide derived from the RHAU helicase. Conjugation of RHAU promoted DNA/RNA G4 binding and stability. Importantly, the conjugate was capable of cellular uptake where it was found to induce and localise to stress granules in a concentration and time dependent manner. This is the first reported probe of this type to image the formation of stress granules without the requirement for an external stressor.
Metadata
Item Type:Thesis (PhD)
Date of Award:August 2024
Refereed:No
Supervisor(s):Keyes, Tia
Uncontrolled Keywords:Ruthenium, G-quadruplex, Cell Imaging, DNA
Subjects:Biological Sciences > Cell biology
Humanities > Biological Sciences > Cell biology
Physical Sciences > Chemistry
Physical Sciences > Inorganic chemistry
Physical Sciences > Photochemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Research Institutes and Centres > National Centre for Sensor Research (NCSR)
Research Institutes and Centres > National Biophotonics and Imaging Platform Ireland (NBIPI)
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 License. View License
Funders:Irish Research Council, Science Foundation Ireland
ID Code:30283
Deposited On:26 Nov 2024 09:44 by Tia Keyes . Last Modified 26 Nov 2024 09:44
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Creative Commons: Attribution-Noncommercial 4.0
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