Cytotoxicity of silica nanoparticles through exocytosis of von Willebrand factor and necrotic cell death in primary human endothelial cells

Bauer, Alexander; Stróżyk, Elwira; Gorzelanny, Christian; Westerhausen, Christoph; Desch, Anna; Schneider, Mat­thias; Schneider, Stefan W.

doi:10.1016/j.biomaterials.2011.07.078

Cited by 86 publications

(56 citation statements)

References 49 publications

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“…All these significant increases happen to be after 2 h of incubation at concentrations of 800, 1600 and 3400 µg·mL −1 for SiNP-7, SiNP-12 and SiNP-22, respectively. As already proposed by Bauer et al, surface area may also play a crucial role in cytotoxicity of SiNPs [41]. When scaling the concentration to the particle size one might use the total area of NPs applied to the cells.…”

Section: Discussionmentioning

confidence: 99%

On the pathway of cellular uptake: new insight into the interaction between the cell membrane and very small nanoparticles

Messerschmidt¹,

Hofmann²,

Kroeger³

et al. 2016

Beilstein J. Nanotechnol.

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SummaryFor any living cell the exchange with its environment is vital. Therefore, many different kinds of cargo are able to enter cells via energy-dependent or -independent routes. Nanoparticles are no exemption. It is known that small silica nanoparticles with a diameter below 50 nm are taken up by cells and that their uptake exerts pronounced toxic effects beyond a certain concentration threshold. However, neither the exact uptake mechanism of these particles nor the actual reason for their toxicity has yet been elucidated. In this study we examined the uptake of silica nanoparticles with a diameter of 7, 12 and 22 nm by means of transmission electron microscopy, accompanied by toxicological assays. We show that for every particle diameter tested a different membrane morphology during uptake can be observed and that the amount of particles entering in one event is different for the three sizes. Silica particles with a diameter of 22 nm show single-particle internalization with a membrane wrapped around the particles in the cytosol, whereas 12 nm particles display row-like multi-particle uptake into elongated membrane structures and those with a diameter of 7 nm or less end up in tubular endocytic structures containing many particles. These membrane morphologies proved to be highly reproducible as we found them in five different cell lines. Additionally, we performed ATP and LDH assays to determine particle toxicity. Exceeding a certain concentration threshold the nanoparticles showed a high toxic potential both in the biochemical assay measurements and from morphological findings. We could not find any hint at the induction of apoptosis, neither morphologically nor biochemically. In this regard we discuss membrane damage and consumption as one possible mechanism of toxicity, linking morphological observations to toxicological findings to bridge the gap in understanding the mechanism of toxicity of small nanoparticles.

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Section: Discussionmentioning

confidence: 99%

On the pathway of cellular uptake: new insight into the interaction between the cell membrane and very small nanoparticles

Messerschmidt¹,

Hofmann²,

Kroeger³

et al. 2016

Beilstein J. Nanotechnol.

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“…17 There is evidence that SiNPs can induce reactive oxygen species (ROS), impairment of proliferative activity, inflammation, and cell death on vascular endothelial cells. [18][19][20] Our previous study confirmed that SiNPs caused deoxyribonucleic acid (DNA) damage via the Chk1-dependent G 2 /M-checkpoint signaling pathway on endothelial cells. 21 However, understanding of the molecular mechanisms involved in the cytotoxicity of SiNPs on endothelium is still limited.…”

Section: Guo Et Almentioning

confidence: 97%

Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling

Guo¹,

Xia²,

Niu³

et al. 2015

IJN

211

126

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Despite the widespread application of silica nanoparticles (SiNPs) in industrial, commercial, and biomedical fields, their response to human cells has not been fully elucidated. Overall, little is known about the toxicological effects of SiNPs on the cardiovascular system. In this study, SiNPs with a 58 nm diameter were used to study their interaction with human umbilical vein endothelial cells (HUVECs). Dose- and time-dependent decrease in cell viability and damage on cell plasma-membrane integrity showed the cytotoxic potential of the SiNPs. SiNPs were found to induce oxidative stress, as evidenced by the significant elevation of reactive oxygen species generation and malondialdehyde production and downregulated activity in glutathione peroxidase. SiNPs also stimulated release of cytoprotective nitric oxide (NO) and upregulated inducible nitric oxide synthase (NOS) messenger ribonucleic acid, while downregulating endothelial NOS and ET-1 messenger ribonucleic acid, suggesting that SiNPs disturbed the NO/NOS system. SiNP-induced oxidative stress and NO/NOS imbalance resulted in endothelial dysfunction. SiNPs induced inflammation characterized by the upregulation of key inflammatory mediators, including IL-1β, IL-6, IL-8, TNFα, ICAM-1, VCAM-1, and MCP-1. In addition, SiNPs triggered the activation of the Nrf2-mediated antioxidant system, as evidenced by the induction of nuclear factor-κB and MAPK pathway activation. Our findings demonstrated that SiNPs could induce oxidative stress, inflammation, and NO/NOS system imbalance, and eventually lead to endothelial dysfunction via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling. This study indicated a potential deleterious effect of SiNPs on the vascular endothelium, which warrants more careful assessment of SiNPs before their application.

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“…Toxicological effects related to cell internalization have been already identified and depend on several parameters, such as cell type and applied doses. [5][6][7] The presence of nanoparticles induces oxidative stress and inflammation and affects degradation pathways with an appearance of autophagosomes and lysosomal dysfunctions, leading to autophagy and apoptosis. [8][9][10] At biocompatible doses, their ability to easily enter the cell has been proposed as an asset for drug delivery, [11][12][13] cell tracking, and cell therapy, 14,15 with a particular focus on the delivery of anticancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of a beneficial effect on myoblast fusion

Poussard¹,

Décossas²,

Bihan³

et al. 2015

IJN

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The use of silica nanoparticles for their cellular uptake capability opens up new fields in biomedical research. Among the toxicological effects associated with their internalization, silica nanoparticles induce apoptosis that has been recently reported as a biochemical cue required for muscle regeneration. To assess whether silica nanoparticles could affect muscle regeneration, we used the C2C12 muscle cell line to study the uptake of fluorescently labeled NPs and their cellular trafficking over a long period. Using inhibitors of endocytosis, we determined that the NP uptake was an energy-dependent process mainly involving macropinocytosis and clathrin-mediated pathway. NPs were eventually clustered in lysosomal structures. Myoblasts containing NPs were capable of differentiation into myotubes, and after 7 days, electron microscopy revealed that the NPs remained primarily within lysosomes. The presence of NPs stimulated the formation of myotubes in a dose-dependent manner. NP internalization induced an increase of apoptotic myoblasts required for myoblast fusion. At noncytotoxic doses, the NP uptake by skeletal muscle cells did not prevent their differentiation into myotubes but, instead, enhanced the cell fusion.

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Cytotoxicity of silica nanoparticles through exocytosis of von Willebrand factor and necrotic cell death in primary human endothelial cells

Cited by 86 publications

References 49 publications

On the pathway of cellular uptake: new insight into the interaction between the cell membrane and very small nanoparticles

On the pathway of cellular uptake: new insight into the interaction between the cell membrane and very small nanoparticles

Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling

Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of a beneficial effect on myoblast fusion

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Cytotoxicity of silica nanoparticles through exocytosis of von Willebrand factor and necrotic cell death in primary human endothelial cells

Cited by 86 publications

References 49 publications

On the pathway of cellular uptake: new insight into the interaction between the cell membrane and very small nanoparticles

On the pathway of cellular uptake: new insight into the interaction between the cell membrane and very small nanoparticles

Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-&kappa;B signaling

Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of&nbsp;a&nbsp;beneficial effect on myoblast fusion

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Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling

Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of a beneficial effect on myoblast fusion