Nanomaterials for Drug Delivery and Multi-Modal Imaging

Abstract

Molecular imaging uses techniques to visualise, characterise and measure biological processes at the cellular and molecular level. These techniques can be incredibly sensitive, allowing the detection of small abnormalities at the tissue or cellular level based on molecular differences, and thus providing accurate diagnosis and monitoring of disease, especially in the field of oncology. Image acquisition relies on the use of molecular imaging agents which target and accumulate at biomarker sites, allowing visualisation of the target in comparison to background tissue. Nanomedicine is a field which refers to the use of nanomaterials in a therapeutic or diagnostic setting. Nanomaterials often display unique characteristics, offer structural versatility and act as scaffolds; providing platforms that have the potential to be truly multi-functional. In this thesis, we take advantage of these properties by synthesising and developing tumour-targeted nanomaterial constructs for multi-modal imaging and therapy. Iron oxide nanoparticles provide MRI contrast, therefore, following radiolabelling with a diagnostic radionuclide, the nanoparticles can be used as multi-modal imaging agents in techniques such as PET/MRI. Chapter 2 in this thesis focuses on the synthesis, characterisation and development of iron oxide nanoparticles for further experiments and applications. Preliminary radiolabelling methods explore classical radiolabeling techniques, where chelates are deployed to bind radionuclides. Subsequent radiolabelling techniques focus on non-classical, chelate-free methods which offer fast and efficient synthesis, superior yields, and have minimal impact to the nanoparticle structure. We explore the versatility of chelate-free radiolabelling on different nanoparticles and also perform kinetic studies to gain an insight into the mechanism by which this process occurs. Using chemistries established in Chapter 2, Chapter 3 focuses on developing the nanoparticle systems for PET/MR imaging. Nanoparticle constructs are targeted toward an established cancer biomarker, and tested in vitro and in vivo by using small-animal PET imaging. Chapters 4 and 5 use graphene nanomaterials as scaffolds to create multi-modal agents. Graphene nanoflakes (GNFs) consist of a graphene sheet approximately 30 nm in diameter with a pristine aromatic system and an edge terminated with carboxylic acid groups. Their high water solubility and relative ease of functionalization by using carboxylate chemistry means that GNFs are potential scaffolds for the design of multi-modality nanomedicines. Chapter 4 establishes the chemistry and provides a first indication on the flexibility of GNFs as potential theranostic agents. GNFs are multi-functionalised with drug molecules, chelates to bind PET active radionuclides, small-molecule biological targeting vectors and pharmacokinetic modifying groups. Further experiments in vitro and in vivo were used to evaluate the performance of GNFs in theranostic drug design. Building from our experience with GNFs functionalised with small-molecule targeting agents, Chapter 5 further utilises GNFs to create targeted constructs for application in PET/MRI. GNFs are multi-functionalised with, chelates to bind PET radionuclides as well as gadolinium complexes for MRI contrast, they are then functionalised with an antibody that is known to bind a specific cancer biomarker. Again, constructs are evaluated in vitro and in vivo to evaluated their pharmacokinetics and tumour-targeting and to test their potential as PET/MRI agents.