dissertationAdvances in the synthesis and characterization of engineered silica nanoparticles (SNPs) are not matched by careful assessment of their effects on biological systems, environmental health, and safety. Better understanding of how silica nanoparticles interact with biological fluids and cells is required to predict safety, mechanism of action, dissolution, clearance, and possible adverse effects. In this dissertation the impact of physicochemical properties of SNPs such as size, porosity, density, and surface functionality on cellular toxicity and genomic response was explored on RAW 264.7 macrophages. Size-dependent cytotoxicity was observed. Mesoporous SNPs showed higher LC50 of 223.6±15.6 compared to the similar size nonporous SNPs with LC50 of 33.7±0.6. The observed lower cell association and toxicity of mesoporous particles is probably related to the lower density of silanol groups per square nm on surface. In addition, decreased sedimentation, cell uptake, and toxicity for lower density particles with rattle structure and under flow conditions was observe compared to nonporous particles. The influence of size, porosity, and surface functionality of SNPs on early response of RAW 264.7 macrophages at sub-toxic doses revealed no significant gene expression alteration for nonporous SNPs at 4 h incubation time, however, mesoporous SNPs induced genomic response associated with lysosomal activity. The global gene expression analysis of mesoporous and nonporous nanoparticles with similar diameters of approximately 500 nm showed time- and dose-dependent gene expression response of macrophages as a function of porosity of SNPs
