Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure

Nabeshi, Hiromi; Yoshikawa, Tomoaki; Matsuyama, Kiichi; Nakazato, Yasutaro; Arimori, Akihiro; Isobe, Masaaki; Tochigi, Saeko; Kondoh, Sayuri; Hirai, Toshiro; Akase, Takanori; Yamashita, Takuya; Yamashita, Kohei; Yoshida, Tokuyuki; Nagano, Kazuya; Abe, Yasuhiro; Yoshioka, Yasuo; Kamada, Haruhiko; Imazawa, Takayoshi; Itoh, Norio; Kondoh, Masuo; Yagi, Kiyohito; Mayumi, Tadanori; Tsunoda, Shin-ichi; Tsutsumi, Yasuo

doi:10.1088/0957-4484/23/4/045101

Cited by 70 publications

(72 citation statements)

References 26 publications

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“…32 Further studies should be performed to understand if both conditions, erythrocyte hemolysis and platelet aggregation, may be caused by the administration of SiNPs. SiNPs of 70 nm had been demonstrated to induce coagulopathy as well as fatality in Balb/C mice but not larger sizes, including 100, 300, and 1,000 nm; 45 no such disaster was seen in our mice that received nanoparticle size of 150 nm. 31 or 80% of the injected rod-shaped mesoporous SiNPs.…”

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confidence: 48%

In vivo toxicologic study of larger silica nanoparticles in mice

Chan¹,

Liu²,

Chiau³

et al. 2017

IJN

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Silica nanoparticles (SiNPs) are being studied and used for medical purposes. As nanotechnology grows rapidly, its biosafety and toxicity have frequently raised concerns. However, diverse results have been reported about the safety of SiNPs; several studies reported that smaller particles might exhibit toxic effects to some cell lines, and larger particles of 100 nm were reported to be genotoxic to the cocultured cells. Here, we investigated the in vivo toxicity of SiNPs of 150 nm in various dosages via intravenous administration in mice. The mice were observed for 14 days before blood examination and histopathological assay. All the mice survived and behaved normally after the administration of nanoparticles. No significant weight change was noted. Blood examinations showed no definite systemic dysfunction of organ systems. Histopathological studies of vital organs confirmed no SiNP-related adverse effects. We concluded that 150 nm SiNPs were biocompatible and safe for in vivo use in mice.

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confidence: 48%

In vivo toxicologic study of larger silica nanoparticles in mice

Chan¹,

Liu²,

Chiau³

et al. 2017

IJN

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“…Intravenous injections of nanoparticles have been linked to fatal coagulopathy in mice, 34,35 resulting from phosphatidyl serine-tissue factor complex presentation on the surface of leukocytes (leukocyte PCA). As shown in Figure S5, no effect of SPIONdex on PCA was detectable up to a concentration of 320 µg/mL.…”

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confidence: 99%

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Unterweger

Janko

Schwarz

et al. 2017

IJN

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Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial–monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size <30 nm was achieved, without affecting their hemo- and biocompatibility. Our findings suggest that due to their excellent biocompatibility, safety upon intravenous administration and size-tunability, SPIONdex particles may represent a suitable candidate for a new-generation MRI contrast agent.

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“…However, because of their decreased particle size and associated unique physicochemical properties, nSP are anticipated to exhibit hazards such as acute toxicity and reproductive toxicity. 5,6) The continued use of products containing nSP rests on effectively evaluating their safety.…”

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confidence: 99%

Modifying the Surface of Silica Nanoparticles with Amino or Carboxyl Groups Decreases Their Cytotoxicity to Parenchymal Hepatocytes

Nagano

Nabeshi

et al. 2017

Biological & Pharmaceutical Bulletin

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We previously reported that unmodified silica nanoparticles with diameters of 70 nm (nSP70) induced liver damage in mice, whereas nSP70 modified with carboxyl or amino groups did not. In addition, we have found that both unmodified and modified nSP70s localize in both Kupffer cells and parenchymal hepatocytes. We therefore evaluated the contributions of nSP70 uptake by these cell populations to liver damage. To this end, we pretreated mice with gadolinium (III) chloride hydrate (GdCl 3 ) to prevent nSP70 uptake by Kupffer cells, subsequently injected the mice with either type of nSP70, and then assessed plasma levels of alanine aminotransferase (ALT). In mice given GdCl 3 , unmodified nSP70 increased ALT levels. From these data, we hypothesized that in GdCl 3 -treated mice, the unmodified nSP70 that was prevented from entering Kupffer cells was shunted to parenchymal hepatocytes, where it induced cytotoxicity and increased liver damage. In contrast, GdCl 3 pretreatment had no effect on ALT levels in mice injected with surface-modified nSP70s, suggesting that modified nSP70s spared parenchymal hepatocytes and thus induced negligible liver damage. In cytotoxicity analyses, the viability of a parenchymal hepatocyte line was greater when exposed to surface-modified nSP70s than to unmodified nSP70s. These findings imply that the decreased liver damage associated with surface-modified compared with unmodified nSP70 is attributable to decreased cytotoxicity to parenchymal hepatocytes.

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Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure

Cited by 70 publications

References 26 publications

In vivo toxicologic study of larger silica nanoparticles in mice

In vivo toxicologic study of larger silica nanoparticles in mice

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Modifying the Surface of Silica Nanoparticles with Amino or Carboxyl Groups Decreases Their Cytotoxicity to Parenchymal Hepatocytes

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