Mechanisms of Nanoparticle Toxicity in Cancer and Normal Cells

Tzelepi, Konstantina Nadia (2019). Mechanisms of Nanoparticle Toxicity in Cancer and Normal Cells. PhD thesis The Open University.



Nanotechnology offers vital tools for cancer diagnosis, early detection and novel treatments. Gold nanoparticles (AuNPs) are at the forefront of biological and biomedical research and show an increased promise in targeted cancer therapy due to their unique physicochemical properties. They offer the advantage of biomolecular interaction both at the cell surface level and inside the cell.

In this thesis, 2nm AuNPs surface functionalised with a 50:50 ratio of a thiolated α-Galactose derivative and a thiol-PEGamine were examined for their toxicity and uptake in normal and cancer cell lines in vitro. Using this simple ligand structure, a selective cancer toxicity was observed, which was highly dependent upon the nanoparticles’ synthesis duration. This observation was correlated to ligand density, which decreased with shorter synthesis time, making particles less toxic. Detailed insight into the mechanism of toxicity and uptake was gained by energy-dependent experiments and cell death assays, revealing a significant adhesion of these particles to filopodia. The proposed mechanism of cell death in HSC oral squamous carcinoma cells exposed to AuNPs was identified to be the extrinsic apoptotic pathway, as toxicity was abrogated by inhibition of either caspase 3/7 or caspase 8, but not by inhibition of caspase 9.

Future directions include batch standardisation of the optimum nanoparticle synthesis conditions and elucidation of the mechanisms of cell uptake and toxicity in a variety of cancer and normal cell lines.

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