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Engineered amorphous silica nanoparticles (SiO 2 -NPs) are widely used in dyes, varnishes, plastics and glue, as well as in pharmaceuticals, cosmetics and food. Novel composite SiO 2 -NPs are promising multifunctional devices and combine labels for subsequent tracking and are functionalized e.g. to specifically target cells to deliver their cargo. However, biological and potential toxic effects of SiO 2 -NPs are insufficiently understood. The aim of this study was to determine the uptake and fate of SiO 2 -NPs in mammalian cells. Also, silica submicron particles (SiO 2 -SMPs) were included in the studies in order to identify effects, which are only observed for nano-sized SiO 2 particles. Fluorescently labelled SiO 2 -NPs (nominal size 70 nm) and SiO 2 -SMPs (nominal size 200 and 500 nm) were used to examine cytotoxicity, cellular uptake and localization in human cervical carcinoma cells (HeLa). Particle uptake and intracellular localization in mitochondria, endosomes, lysosomes and nuclei were studied by wide field and confocal laser scanning fluorescence microscopy. Physicochemical characterization of SiO 2 -NPs by transmission electron microscopy and dynamic light scattering revealed a spherical morphology and a monodisperse size distribution. In the presence of serum, all SiO 2 particles are non-toxic. However, in the absence of serum SiO 2 -NPs but not SiO 2 -SMPs are highly toxic. SiO 2 particles, irrespective of size, were detected in the cytosol and accumulated in endosomal compartments of HeLa cells. No accumulation of SiO 2 particles in nuclei or mitochondria of HeLa cells could be observed. In contrast to SiO 2 -SMPs, SiO 2 -NPs are preferentially localized in lysosomes.

Several in vitro studies have suggested that silica nanoparticles (NPs) might induce adverse effects in gut cells. Here, we used the human colon cancer epithelial cell line HCT116 to study the potential cytotoxic effects of ingested silica NPs in the presence or absence of serum. Furthermore, we evaluated different physico-chemical parameters important for the assessment of nanoparticle safety, including primary particle size (12, 70, 200, and 500 nm) and surface modification (–NH2 and –COOH). Silica NPs triggered cytotoxicity, as evidenced by reduced metabolism and enhanced membrane leakage. Automated microscopy revealed that the silica NPs promoted apoptosis and necrosis proportional to the administered specific surface area dose. Cytotoxicity of silica NPs was suppressed by increasing amount of serum and surface modification. Furthermore, inhibition of caspases partially prevented silica NP-induced cytotoxicity. In order to investigate the role of specific cell death pathways in more detail, we used isogenic derivatives of HCT116 cells which lack the pro-apoptotic proteins p53 or BAX. In contrast to the anticancer drug cisplatin, silica NPs induced cell death independent of the p53–BAX axis. In conclusion, silica NPs initiated cell death in colon cancer cells dependent on the specific surface area and presence of serum. Further studies in vivo are warranted to address potential cytotoxic actions in the gut epithelium. The unintended toxicity of silica NPs as observed here could also be beneficial. As loss of p53 in colon cancer cells contributes to resistance against anticancer drugs, and thus to reoccurrence of colon cancer, targeted delivery of silica NPs could be envisioned to also deplete p53 deficient tumor cells.

Nanostructured silica particles are commonly used in biomedical and biotechnical fields, as well as, in cosmetics and food industry. Thus, their environmental and health impacts are of great interest and effects after oral uptake are only rarely investigated. In the present study, the toxicological effects of commercially available nano-scaled silica with a nominal primary diameter of 12 nm were investigated on the human gastric carcinoma cell line GXF251L. Besides the analysis of cytotoxic and proliferative effects and the comparison with effects of particles with a nominal primary diameter of 200 nm, emphasis was also given to their influence on the cellular epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (MAPK) signaling pathways—both of them deeply involved in the regulation of cellular processes like cell cycle progression, differentiation or proliferation. The investigated silica nanoparticles (NPs) were found to stimulate cell proliferation as measured by microscopy and the sulforhodamine B assay. In accordance, the nuclear level of the proliferation marker Ki-67 was enhanced in a concentration-dependent manner. At high particle concentrations also necrosis was induced. Finally, silica NPs affected the EGFR and MAPK pathways at various levels dependent on concentration and time. However, classical activation of the EGFR, to be reflected by enhanced levels of phosphorylation, could be excluded as major trigger of the proliferative stimulus. After 45 min of incubation the level of phosphorylated EGFR did not increase, whereas enhanced levels of total EGFR protein were observed. These results indicate interference with the complex homeostasis of the EGFR protein, whereby up to 24 h no impact on the transcription level was detected. In addition, downstream on the level of the MAP kinases ERK1/2 short term incubation appeared to affect total protein levels without clear increase in phosphorylation. Depending on the concentration range, enhanced levels of ERK1/2 phosphorylation were only observed after 24 h of incubation. Taken together, the present study demonstrates the potential of the tested silica particles to enhance the growth of gastric carcinoma cells. Although interference with the EGFR/MAPK cascade is observed, additional mechanisms are likely to be involved in the onset of the proliferative stimulus.

Engineered amorphous silicananoparticles (SiO sub(2)-NPs) are widely used in dyes, varnishes, plastics and glue, as well as in pharmaceuticals, cosmetics and food. Novel composite SiO sub(2)-NPs are promising multifunctional devices and combine labels for subsequent tracking and are functionalized e.g. to specifically target cells to deliver their cargo. However, biological and potential toxic effects of SiO sub(2)-NPs are insufficiently understood. The aim of this study was to determine the uptake and fate of SiO sub(2)-NPs in mammalian cells. Also, silica submicron particles (SiO sub(2)-SMPs) were included in the studies in order to identify effects, which are only observed for nano-sized SiO sub(2) particles. Fluorescently labelled SiO sub(2)-NPs (nominal size 70nm) and SiO sub(2)-SMPs (nominal size 200 and 500nm) were used to examine cytotoxicity, cellular uptake and localization in human cervical carcinoma cells (HeLa). Particle uptake and intracellular localization in mitochondria, endosomes, lysosomes and nuclei were studied by wide field and confocal laser scanning fluorescence microscopy. Physicochemical characterization of SiO sub(2)-NPs by transmission electron microscopy and dynamic light scattering revealed a spherical morphology and a monodisperse size distribution. In the presence of serum, all SiO sub(2) particles are non-toxic. However, in the absence of serum SiO sub(2)-NPs but not SiO sub(2)-SMPs are highly toxic. SiO sub(2) particles, irrespective of size, were detected in the cytosol and accumulated in endosomal compartments of HeLa cells. No accumulation of SiO sub(2) particles in nuclei or mitochondria of HeLa cells could be observed. In contrast to SiO sub(2)-SMPs, SiO sub(2)-NPs are preferentially localized in lysosomes.