title: Intranasal exposure to amorphous nanosilica particles could activate intrinsic coagulation cascade and platelets in mice.
abstract: BACKGROUND
  Nanomaterials with particle sizes <100 nm have been already applied in various applications such as cosmetics, medicines, and foods. Therefore, ensuring the safety of nanomaterials is becoming increasingly important. Here we examined the localization and biological responses of intranasally administered amorphous nanosilica particles in mice, focusing on the coagulation system.
  
  
  METHODS
  We used nanosilica particles with diameters of 30, 70, or 100 nm (nSP30, nSP70, or nSP100 respectively), and conventional microscale silica particles with diameters of 300 or 1000 nm (mSP300 or mSP1000, respectively). BALB/c mice were intranasally exposed to nSP30, nSP70, nSP100, mSP300, or mSP1000 at concentrations of 500 μg/mouse for 7 days. After 24 hours of last administration, we performed the in vivo transmission electron microscopy analysis, hematological examination and coagulation tests.
  
  
  RESULTS
  In vivo transmission electron microscopy analysis showed that nanosilica particles with a diameter <100 nm were absorbed through the nasal cavity and were distributed into liver and brain. Hematological examination and coagulation tests showed that platelet counts decreased and that the activated partial thromboplastin time was prolonged in nSP30 or nSP70-treated groups of mice, indicating that nanosilica particles might have activated a coagulation cascade. In addition, in in vitro activation tests of human plasma, nanosilica particles had greater potential than did conventional microscale silica particles to activate coagulation factor XII. In nanosilica-particle-treated groups, the levels of soluble CD40 ligand, and von Willebrand factor which are involved in stimulating platelets tended to slightly increase with decreasing particle size.
  
  
  CONCLUSIONS
  These results suggest that intranasally administered nanosilica particles with diameters of 30 and 70 nm could induce abnormal activation of the coagulation system through the activation of an intrinsic coagulation cascade. This study provides information to advance the development of safe and effective nanosilica particles.
authors: Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. yasuo@phs.osaka-u.ac.jp
authors: Tokuyuki
authors: T
authors: Yoshida
authors: Yasuo
authors: Y
authors: Yoshioka
authors: Saeko
authors: S
authors: Tochigi
authors: Toshiro
authors: T
authors: Hirai
authors: Miyuki
authors: M
authors: Uji
authors: Ko-ichi
authors: K
authors: Ichihashi
authors: Kazuya
authors: K
authors: Nagano
authors: Yasuhiro
authors: Y
authors: Abe
authors: Haruhiko
authors: H
authors: Kamada
authors: Shin-Ichi
authors: S
authors: Tsunoda
authors: Hiromi
authors: H
authors: Nabeshi
authors: Kazuma
authors: K
authors: Higashisaka
authors: Tomoaki
authors: T
authors: Yoshikawa
authors: Yasuo
authors: Y
authors: Tsutsumi
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood; D015956:Factor XIIa / Q000378:metabolism; D005260:Female; D006801:Humans; D019570:Inhalation Exposure; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D009296:Nasal Cavity / Q000378:metabolism; D010314:Partial Thromboplastin Time; D010316:Particle Size; D015539:Platelet Activation / Q000187:drug effects*; D010976:Platelet Count; D012822:Silicon Dioxide / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors; D014018:Tissue Distribution; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; D023201:CD40 Ligand; D012822:Silicon Dioxide; D015956:Factor XIIa
references: J Biomed Mater Res B Appl Biomater. 2012 Jul;100(5):1397-403
references: 22566482
references: Fundam Appl Toxicol. 1992 Oct;19(3):399-410
references: 1334015
references: Parasitol Res. 2008 Jul;103(2):253-8
references: 18438740
references: Biomaterials. 2011 Sep;32(26):5970-8
references: 21663954
references: Part Fibre Toxicol. 2011 Jul 27;8:22
references: 21794132
references: Toxicology. 2008 Dec 5;254(1-2):82-90
references: 18929619
references: Arch Toxicol. 2002 Jan;75(11-12):625-34
references: 11876495
references: Exp Biol Med (Maywood). 2008 May;233(5):610-9
references: 18375825
references: Methods Mol Biol. 2011;697:3-8
references: 21116949
references: Blood. 1997 Nov 15;90(10):3819-43
references: 9354649
references: Part Fibre Toxicol. 2012 Feb 02;9:3
references: 22296706
references: Med Welt. 1976 Nov 19;27(47):2302-4
references: 1004182
references: Nat Nanotechnol. 2011 May;6(5):321-8
references: 21460826
references: Nature. 2006 Nov 16;444(7117):267-9
references: 17108940
references: J Clin Invest. 1984 May;73(5):1249-53
references: 6371055
references: Part Fibre Toxicol. 2010 Jun 14;7:16
references: 20546558
references: Scand J Clin Lab Invest. 2011 Apr;71(2):82-6
references: 21385010
references: Nat Nanotechnol. 2008 Jul;3(7):423-8
references: 18654567
references: Adv Drug Deliv Rev. 2008 Aug 17;60(11):1278-88
references: 18514969
references: Fundam Appl Toxicol. 1991 Apr;16(3):590-601
references: 1649779
references: Ann Med. 2011 Aug;43(5):331-40
references: 21244217
references: Recent Pat Food Nutr Agric. 2012 Apr 1;4(1):8-18
references: 22316269
references: PLoS One. 2012;7(7):e38995
references: 22808023
references: Biomaterials. 2011 Nov;32(33):8712-21
references: 21862121
references: Toxicology. 2010 Mar 10;269(2-3):148-54
references: 19698757
references: Nanomedicine (Lond). 2010 Aug;5(6):881-96
references: 20735224
references: J Nanosci Nanotechnol. 2009 Nov;9(11):6335-43
references: 19908531
references: Biochem Biophys Res Commun. 2010 Feb 5;392(2):160-5
references: 20059972
references: Arch Toxicol. 2012 Aug;86(8):1297-307
references: 22418595
references: Toxicol Lett. 2008 Dec 15;183(1-3):72-80
references: 18992307
references: Thromb Haemost. 2006 Jan;95(1):49-55
references: 16543961
references: Biomaterials. 2011 Apr;32(11):2713-24
references: 21262533
references: Nanoscale Res Lett. 2011 Mar 04;6(1):195
references: 21711705
references: FASEB J. 2005 Mar;19(3):311-30
references: 15746175
references: Anal Chim Acta. 2009 Aug 4;647(1):14-30
references: 19576381
references: Nanotechnology. 2012 Feb 3;23(4):045101
references: 22214761
references: Int J Pharm. 2010 Nov 15;400(1-2):183-93
references: 20727955
references: Trends Biotechnol. 2009 Feb;27(2):82-9
references: 19135747
references: Best Pract Res Clin Obstet Gynaecol. 2003 Jun;17(3):369-83
references: 12787532
references: Biomaterials. 2005 Jun;26(16):2965-73
references: 15603791
references: Swiss Med Wkly. 2012 Jun 19;142:w13547
references: 22714122