Multimetallic nanoscale systems for magnetic resonance imaging

Gadolinium-based contrast agents are widely used in clinical magnetic resonance imaging (MRI) to improve the visibility of important features in the body. However, the low sensitivity of these agents means that they must be administered in very large quantities, often several grams. There is, therefore, an indisputable need to improve the performance of gadolinium-based MRI contrast agents as this would enable them to be administered at a reduced dose. It is known that incorporating multiple gadolinium chelates into a single structure improves the ability of the chelates to enhance the contrast in MRI. These macromolecular structures are large in size, which means that they exhibit a reduced rotational speed and hence an improved relaxivity. Additionally, confining multiple gadolinium chelates into a small region of space means that they can benefit from the multimeric effect, which results in a greater contrast enhancement in the MR image. This thesis explores two different approaches to improving the relaxivity of gadolinium chelates: tethering them to the surface of gold nanoparticles and incorporating them into multimetallic complexes. For each approach, two different gadolinium chelates have been employed, both of which feature a cyclic, octadentate chelator for robust, irreversible encapsulation of the Gd3+ ion and a dithiocarbamate moiety for attachment to the gold nanoparticle surface/ metal ion core. The work described in this thesis aims to contribute to the ongoing research into the development of MRI contrast agents by exploring different multi-gadolinium systems, from functionalised gold nanoparticles to multimetallic complexes. The first chapter describes the assessment of a number of functionalised gold nanoparticles, which benefit from impressive relaxivities and high gadolinium loading. The second chapter focuses on multimetallic complexes, which were investigated in terms of their relaxivity, stability, cellular toxicity and cellular uptake. The final chapter describes the journey of a novel, targeted MRI contrast agent from testing in the laboratory through to application in vivo. It is hoped that this work will provide a platform for further research in this area.