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Tzelepi, Konstantina; Espinosa Garcia, Cristina; Williams, Phil and Golding, Jon
(2019).
DOI: https://doi.org/10.1039/C8NA00270C
Abstract
Ultra-small gold nanoparticles, surface functionalised with a 50:50 ratio of a thiolated α-Galactose derivative and a thiolated hexaethylene glycol amine, are toxic to HSC-3 oral squamous carcinoma cells. Differences in nanoparticle toxicity were found to be related to synthesis duration, with 1 h reaction nanoparticles being less toxic than 5 h reaction nanoparticles. Ligand density decreased with longer reaction time, although size, charge and ligand ratio remained similar. The concentration of sodium borohydride in the reaction decreased logarithmically over 5 h but remained within a concentration range sufficient to desorb weakly-bound ligands, possibly explaining the observed gradual decrease in ligand density. Nanoparticle toxicity was abrogated by inhibition of either caspase 3/7 or caspase 8, but not by inhibition of caspase 9, consistent with extrinsic apoptosis. Electron microscopic analysis of cellular uptake demonstrated predominantly cytoplasmic localization. However, when energy-dependent transport was inhibited, by lowering the temperature to 4ºC, a remarkable adhesion of nanoparticles to filopodia was observed. Inhibition of filopodial assembly with a fascin inhibitor prevented nanoparticle adhesion to HSC-3 cells at 4ºC, while fascin inhibition at 37ºC resulted in less cytoplasmic uptake. More adhesion to HSC-3 filopodia was seen with the higher toxicity 5 h reaction time nanoparticles than with the 1 h nanoparticles. By including a further two cell types (HaCaT keratinocytes and hCMEC/D3 endothelial cells), a pattern of increasing toxicity with filopodial binding of 5 h reaction nanoparticles became apparent.
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CORE (COnnecting REpositories)
