| Summary: | Radiotherapy is currently used in around 50% of cancer treatments. Although highly effective it is also damaging to surrounding healthy tissues and needs to be improved by better targeting of cancer cells. Improved radiotherapy outcomes can be achieved by using nanoparticles, especially those with high atomic number (Z), that interact with ionising radiation to generate secondary electrons and reactive species that increase cellular damage. One of the most promising elements to use is gold, in the form of gold nanoparticles (AuNPs) because of its biocompatibility and amenability to surface modification. For example, surface modification of AuNPs with simple sugars can improve their solubility and cellular uptake. Furthermore, positively charged AuNPs are thought to have an improved cellular uptake because of their interactions with negatively charged cell membranes. This thesis is focussed on two research areas: (1) the development of dual action chemo-radiosensitising AuNPs and (2) the development of oligonucleotide-AuNPs for radiosensitisation. (1) It is shown that sugar-PEGamine coated AuNPs demonstrate selective uptake and toxicity toward skin cancer cells with an IC50 of 1 μg/ml [Au], without damaging normal skin cells at this concentration. Oxidative stress and caspase-dependent apoptosis both play a key role in the toxicity of these AuNPs. Moreover, AuNPs coated with sugar and PEGamine show a strong radiosensitisation effect in combination with kilovoltage X-rays and a smaller effect with megavoltage X-rays. (2) Oligonucleotide-phosphine-coated AuNPs are shown to demonstrate a limited uptake in the cellular cytoplasm compared to the previous AuNPs but increase AuNPs uptake into the cell nucleus. The limited uptake into the cells, as well as the DNA triplex forming oligonucleotides (TFOs) attached to the AuNPs, is still responsible for a radiosensitisation effect, although smaller than with sugar:PEGamine AuNPs. In the future, the uptake of the oligonucleotides AuNPs may possibly be improved by varying their size (from 3.5 to 2 nm) and/or adding a spacer between the NP and the TFO.
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