Magnetic resonance imaging (MRI) is a non-invasive imaging technique that has emerged as one of the most powerful diagnostic tools in clinical medicine. Paramagnetic contrast agents (CAs), usually Gd-chelates, are often employed during an MRI scan to achieve better image contrast between a diseased and normal tissue. They work by modulating the longitudinal and transverse relaxation times of water protons within the tissues. Most of the current commercially available CAs, which can be broadly classified as low molecular weight CAs, are small, fast reorientating molecules with restricted specificity and targeting ability and relatively moderate efficiency (called relaxivity in the case of MRI CAs). Also, there have been reports linking their use with nephrogenic systemic fibrosis, a serious disorder that occurs in patients with chronic kidney disease and acute renal failure. The suspected cause is the dissociation of the Gd-ligand complex due to their slow clearance as a result of renal failure, suggesting the need for more stable CAs. This has spurred interest in developing stable high molecular weight CAs. Such CAs possess slow molecular reorientation, resulting in much better contrast activities compared to their low molecular weight counterparts. They are also passively targeted towards tumours due to enhanced permeation and retention. A useful approach for increasing the molecular weight (or size) of MRI CAs is to impart amphiphilic character to them and let them self-assemble to form supramolecular nanoparticles (hereafter called nanoassemblies) upon dispersion in an aqueous solution. Supramolecular MRI CAs have all the benefits of high molecular weight CAs and can also provide high payloads of Gd(III) ions at the target site. In this thesis, highly ordered supramolecular nanoassemblies, made of paramagnetic amphiphilic chelates, were developed and investigated as advanced MRI CAs. To begin with, relaxation theory based on the dipolar and scalar relaxation mechanisms in the two spin system was pedagogically (re)derived to understand the theoretical framework of a paramagnetic MRI CA. Based on this, novel paramagnetic amphiphilic chelates were designed and synthesised with the ability to form lamellar or inverse bicontinuous cubic nanoassemblies by themselves. Selected paramagnetic amphiphiles were also incorporated, at various concentrations, within non-ionic external lipid matrices to assist the formation of highly ordered mesophases. Differential scanning calorimetry, thermogravimetric analysis, polarised optical microscopy and synchrotron small angle X-ray scattering (SAXS) were employed to characterise the neat amphiphiles and examine the self-assembly structures of their bulk phases. Upon dispersion in an aqueous solution, cryogenic transmission electron microscopy, variable temperature SAXS, and dynamic light scattering were used to investigate the morphology, structure and size of the dispersed nanoassemblies. To assess their potential as MRI CAs, the in-vitro relaxivities of the nanoassemblies were measured at various magnetic field strengths (ranging from 0.47 – 11.74 T) and in some cases, contrast enhancement was directly observed by performing in-vitro MRI experiments. For nanoassemblies made solely from the paramagnetic amphiphiles, molecular parameters such as reorientational correlation time and water exchange rate were determined by comparing the theoretical models to the variable temperature 17O transverse relaxation time measurements, and the variable magnetic field 1H longitudinal relaxation time measurements (also known as nuclear magnetic relaxation dispersions profiles). It was found that paramagnetic amphiphilic chelates containing branched hydrophobic chains can be incorporated at a higher concentration within the inverse bicontinuous cubic phases of an external lipid compared to paramagnetic amphiphilic chelates with unsaturated unbranched chains. In general, the in-vitro relaxivities (and in some cases image contrast) of the nanoassemblies were found to be higher than Magnevist, a commercially available CA, at both low and high magnetic field strengths. The nanoassemblies made of mixed amphiphiles (paramagnetic amphiphilic chelates and non-ionic external lipids) showed better relaxivities than those made solely from paramagnetic amphiphiles at high magnetic field strength. Liposomal nanoassemblies made from sole paramagnetic amphiphiles with branched chains and monoamide conjugates as the chelating head groups showed faster water exchange than the previously reported paramagnetic liposomes (with unbranched chains and bisamide conjugates as head groups). Nevertheless, their relaxation enhancement was still found to be limited by water exchange. Improved relaxivities were largely due to the slow molecular reorientation. Finally, a novel and efficient method of determining relaxivities was also developed. According to this method, relaxivity of a paramagnetic MRI CA can be determined by relating the two NMR observables: induced chemical shifts and enhanced relaxation rates, both of which are dependent on the concentration of the paramagnetic MRI CA
