Systematic study on the influence of particle size on the Cytotoxicity of nanoparticles

The study of size effects on the cytotoxicity of poly(d,l-lactide-co-glycolide acid) (PLGA) and titanium dioxide (TiO2) nanoparticles was reported in this thesis. The main objective of this study is to investigate how particle size can influence the cytotoxicity of PLGA and TiO2 nanoparticles, and to uncover the mechanism behind such toxic effects. We investigated various cytotoxicity parameters, including cell viability, generation of reactive oxygen species (ROS), mitochondrial depolarization, plasma membrane leakage, increased intracellular calcium concentration and inflammation response, to comprehensively understand the toxicity of different sized nanoparticles after cells were incubated with these nanoparticles for 24 h. Our current results show that PLGA and TiO2 nanoparticles could trigger size-dependent cytotoxicity to both RAW264.7 cells and BEAS-2B cells. The increased cytotoxicity observed from smaller nanoparticles with larger specific surface area could be explained from their surface area-dependent interactions with biomolecules. TiO2 nanoparticles could also trigger size- and surface area- dependent phototoxicity. The higher generation of hydroxyl radicals could be the major reason for the higher phototoxicity of TiO2 nanoparticles with smaller particle size and/or larger surface area. Surface coating of TiO2 nanoparticles with poly (ethylene-alt-maleic anhydride) (PEMA) and chitosan could reduce phototoxicity of TiO2 nanoparticles, by hindering adsorption of biomolecules and generation of hydroxyl radical (•OH) during photoactivation. Presence of pre-adsorbed extracellular proteins was also found to decrease toxic effects of TiO2 particles as compared to conditions without extracellular proteins. These results also suggest that surface area, a size related factor, could be a paradigm to predict the cytotoxicity of PLGA and TiO2 nanoparticles. However, this study does not overlook the importance of some other of factors such as surface functional group, which worth further exploration in future work.DOCTOR OF PHILOSOPHY (MSE