Abstract
Cancer is among the leading causes of death worldwide and, despite substantial effort and resources targeted towards the development of effective therapies, there are still no treatments available that are selectively cytotoxic to cancer cells. Research into the development of novel methods to target cancer cells directly is ongoing in order to increase survival rates and to reduce the unpleasant side effects associated with chemotherapy. This project has investigated functionalised fluorescent nanoparticles for cancer cell targeting. Two main nanoparticle systems have been developed and studied, including naphthalene diimide (NDI) ligand functionalised carbon dots, and carbohydrate-functionalised quantum dots.The overexpression of G-quadruplex (G4) forming motifs at chromosome telomeres and oncogene promoter regions has led to them being highlighted as potential targets for cancer therapeutics. Unfortunately, there has been a lack of success in the development of drugs based on G-quadruplex stabilising ligands due to their lack of ‘drug-like character’ leading to low bioavailability. In this work, carbon dots (C-Dots) have been functionalised with G4 binding NDI ligands. These multivalent NDI-C-Dot probes were found to stabilise human telomeric G4 DNA more than the free NDI ligand, as determined by numerous biophysical methods including a FRET melting assay, and circular dichroism (CD) titrations. The cytotoxicity of the G4 binding probes was studied in both cancerous and healthy cell lines and showed a lower toxicity than the free NDI ligand. Finally, colocalisation studies with the probes showed internalisation in the mitochondria of HeLa cells.
Cancer cells display an altered glycosylation pattern compared to that of healthy cells, and this difference could potentially be exploited for the selective delivery of cytotoxic drugs to cancer cells. Nanoparticles are useful tools for the study of carbohydrate-protein interactions, as the multivalent display of glycans on the surface of nanoparticles mimics glycan presentation on the cell surface. A library of carbohydrate functionalised CdSe/ZnS quantum dots (QDs) was prepared, and the cellular uptake of these glycan-nanoparticles in cancer cell lines has been investigated. Aggregation of the glycan-QDs caused issues with cellular uptake, but some uptake was observed for lactose-QDs and GlcNAc QDs. This preliminary work indicates that further development is necessary in order for these glyco-nanoparticles to be used for selective cancer cell targeting.
| Date of Award | 24 Jan 2023 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | M C Galan (Supervisor) |