Wells, Connor John Robert; (2023) Probing the Importance of Nanostructure Design for Magnetic Resonance Imaging (MRI) Contrast Agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Magnetic resonance imaging (MRI) is a prominent diagnostic technique owing to its non-invasive nature and highly resolved imaging. Contrast agents enhance this imaging tool by improving the relaxation of protons in different tissues, enabling distinguished contrast. At present, the only clinically available contrast agents are those based on molecular chelated gadolinium (Gd3+) species, requiring high doses for impactful resolution. However, by attaching these chelated Gd3+ units onto nanoparticles, immense improvements on their performance as MRI contrast agents have been found. Taking advantage of their generally high surface areas, nanostructured contrast agents often host large numbers of paramagnetic centres thereby increasing sensitivity through increased local concentration. Relaxometry can provide analysis of a number of parameters that impact MRI performance, including the water diffusion behaviour, local and global tumbling rates, and the hydration number of the Gd3+-chelate, allowing the optimisation of these nanoparticular contrast agents. There is also increasing evidence that nanoscale design features, such as pore size and surface chemistry can influence water mobility and hence affect the ultimate capability of these nanostructures as MRI contrast agents. Surface modifications can not only impact water diffusion, but also directly affect the local tumbling rate of a chelated paramagnetic centre. However, understanding the structure-property relationship of designed nanostructured contrast agents is still relatively poor and therefore a more thorough investigation is required in order to improve their potency. The aim of this thesis is to explore how nearby surface modifications may influence the relaxation of Gd3+-chelates loaded into mesoporous silica nanoparticles (MSNs). MSNs have been functionalised, both internally in the porous network, and externally on the outer surface, with a range of functional groups, including hydrophilic thiols, hydrophobic phenyls, phosphates, and photoswitchable azobenzenes, alongside the MRI-active Gd3+-DOTA moieties. These functionalised MSNs provide valuable information regarding the structure-property relationship of nanostructured contrast agents. Furthermore, attaching photoswitchable azobenzene directly onto DOTA chelates attached to MSNs has been trialled, revealing the importance of ligand design in the context of contrast agent development. Finally, core@shell silica nanoparticles, with Gd3+-DOTA groups attached to a non-porous core, with a mesoporous shell of varying pore size, have been synthesised and characterised to provide detailed analysis on the accessibility of water for the impact on relaxation. A complete physical and structural characterisation of each differently modified MSNs has been obtained, and their resulting influence on relaxometry measured and analysed. This work provides valuable insights into the importance of nanomaterial design features, in particular the location and nature of functional groups, in MRI contrast agent design. An improved understanding of the interplay between these factors should prove useful in the development of such agents for diagnostics.

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