This dissertation explores the two main approaches to enhance the relaxivity for the DO3A- or DOTAGA-based gadolinium chelates (Gd-DO3A-NH2 or Gd-DOTAGA-NH2) (Chapters 2, 3 and 4) as well as to allow a deep knowledge of the interactions between a thiol-based surface unit and a gold assembly (Chapters 5 and 6).
Following an introduction to the area (Chapter 1), Chapter 2 describes the incorporation of multiple gadolinium chelates into a single structure. Using both d- and f- block metals (gold, nickel, cobalt, and ruthenium cations), multimetallic assemblies were constructed through a rigid DEDTC moiety as the linker. Relaxivity, stability tests and in vitro toxicity studies are reported for the assemblies.
In Chapter 3, DO3A-based multiple gadolinium chelates targeting atherosclerotic plaque were established by the confinement of the chelates into a narrow region of space using a rigid piperazine linker and the attachment of the N3-Peptide (Lys(N3)-Val-Val-Gly-Ser-Pro-Ser-Ala-Gln-Asp-Glu-Ala-Ser-Pro-Leu-Ser) to the established system using an inflexible aryl-based linker (Gd4-TESMA). Similarly to the relaxivities for the multimetallic assemblies, its relaxivity was also enhanced more than 2-fold. Furthermore, Gd4-TESMA produced high contrast images between healthy and diseased tissue in atherosclerosis in a clinical MRI scanner. Stability and in vitro and in vivo toxicity studies were performed, which indicated that Gd4-TESMA should be a very promising MRI contrast agent for the clinical diagnosis of heart disease. Of benefit to future commercial use, the most effective and economical synthetic protocol for the tetra-Gd unit was identified, allowing high-purity multigram scale synthesis to be successfully achieved (> 10 g).
For multipurpose imaging and theranostic applications, Chapter 4 describes how biocompatible nanogels were investigated as platforms for the aforementioned three different gadolinium chelates (Gd-DO3A-NH2, Gd-DOTAGA-NH2, and Gd4-NH2) and they were classified into two groups depending on their morphology (‘Type I nanogels’ and ‘Type II nanogels’). The gadolinium chelates were combined with the external and internal Type I nanogels, whilst they were embedded in the Type II nanogels, such as a drug delivery system. Due to the decrease in the molecular tumbling motion of the gadolinium chelates caused by the increase in their molecular weight, the overall relaxivities at pH 7 were enhanced up to two times. Both nanogel systems possessing the gadolinium chelate(s) were constructed using the radical vinyl polymerisation of the monomeric building blocks bearing ester groups. The gadolinium chelates were released from their mother nanogels by the cleavage of the ester groups under acidic and basic conditions and this led to an increase in the observed relaxivity as they came into contact with the bulk water. It is expected that these nanogel systems can be also used for therapeutics by the functionalisation of the monomer(s) or the incorporation with a functional protein.
Due to the enhanced permeability and retention (EPR) effect, functionalised gold nanomaterials have been studied in various ways for the treatment of disease. In order to functionalise gold nanomaterials, a thiol-based linker is generally adopted because of the strong affinity between gold and sulfur atoms. However, more evidence is needed to support this relationship, particularly for sulfur units beyond thiol(ate)s, so Au-S was explored using an Au200 nanocluster (Td) as a model for real gold nanoparticles, allowing different sizes and shapes of thiolate surface units to be explored in Chapter 5. This provided the knowledge of the fundamental interactions present through a combined theoretical and experimental investigation. This effort revealed the key information that the thiolate surface unit(s) interact with a gold assembly through both covalent and non-covalent interactions and that the covalent Au-S linkage is based on chemisorption. After a deeper understanding of the relationship between gold and sulfur has been uncovered, a theoretical and experimental study on DEDTC capped gold assemblies was performed to explain the stronger Au-S interaction for dithiocarbamate surface units in Chapter 6. These investigations revealed that the two sulfur atoms in a dithiocarbamate unit have different functions in a gold assembly, which contribute to the observed properties.