Recognition of DNA junctions by Metallo-Supramolecular Complexes and their cellular delivery by spherical Nucleic Acids

Williams, Hugo D. ORCID: https://orcid.org/0000-0002-8833-7913 (2024). Recognition of DNA junctions by Metallo-Supramolecular Complexes and their cellular delivery by spherical Nucleic Acids. University of Birmingham. Ph.D.

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Abstract

The work presented in this thesis investigates the binding of non-canonical DNA structures by a range of metallo-supramolecular structures. The DNA binding properties of a palladium tetra-stranded helicate is investigated and it’s platinum analogue (PtCyl) is synthesised for the first time. Both the platinum and palladium complexes bind and stabilise DNA 3WJ and 4WJ structures. The platinum complex displays more effective binding to DNA structures due to its enhanced stability in buffered solution. The B-DNA and junction binding properties of this PtCyl and two other known junction binding agents (NiP and AuPill) are compared through several biophysical studies. These studies reveal insights into the structural properties of the complexes that favour junction binding and also the surprisingly high selectivity of PtCyl for DNA 3WJ structures. The binding affinity of the PtCyl and a three stranded dinuclear nickel supramolecular complex (NiP) for a DNA 3WJ structure are quantified through the use of isothermal titration calorimetry. Mass spectrometry is investigated as a possible method for studying the interactions of these supramolecular metal complexes with DNA structures. Spherical nucleic acids (SNAs) are studied as a potential vehicle for the delivery of these supramolecular metal complexes. SNAs are successfully synthesised and loaded with the NiP and PtCyl. The gold-SNA nanoparticles are able to release the metal complexes in the presence of their preferred binding target, DNA junctions. Efforts were made to increase the loading of the metal complexes on the nanoparticles, with limited success. Preliminary cell studies indicate very little toxicity of these systems which is likely due to the low loading of the complexes achieved.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Hannon, Michael J. UNSPECIFIED orcid.org/0000-0002-5797-6747 Pikramenou, Zoe UNSPECIFIED UNSPECIFIED Bicknell, Roy UNSPECIFIED UNSPECIFIED Styles, Iain B UNSPECIFIED UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges > College of Engineering & Physical Sciences
School or Department:	School of Chemistry
Funders:	Engineering and Physical Sciences Research Council
Subjects:	Q Science > Q Science (General) Q Science > QD Chemistry
URI:	http://etheses.bham.ac.uk/id/eprint/15400

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