title: The fate of calcium carbonate nanoparticles administered by oral route: absorption and their interaction with biological matrices.
abstract: BACKGROUND
  Orally administered particles rapidly interact with biological fluids containing proteins, enzymes, electrolytes, and other biomolecules to eventually form particles covered by a corona, and this corona potentially affects particle uptake, fate, absorption, distribution, and elimination in vivo. This study explored relationships between the biological interactions of calcium carbonate particles and their biokinetics.
  
  
  METHODS
  We examined the effects of food grade calcium carbonates of different particle size (nano [N-Cal] and bulk [B-Cal]: specific surface areas of 15.8 and 0.83 m(2)/g, respectively) on biological interactions in in vitro simulated physiological fluids, ex vivo biofluids, and in vivo in gastrointestinal fluid. Moreover, absorption and tissue distribution of calcium carbonates were evaluated following a single dose oral administration to rats.
  
  
  RESULTS
  N-Cal interacted more with biomatrices than bulk materials in vitro and ex vivo, as evidenced by high fluorescence quenching ratios, but it did not interact more actively with biomatrices in vivo. Analysis of coronas revealed that immunoglobulin, apolipoprotein, thrombin, and fibrinogen, were the major corona proteins, regardless of particle size. A biokinetic study revealed that orally delivered N-Cal was more rapidly absorbed into the blood stream than B-Cal, but no significant differences were observed between the two in terms of absorption efficiencies or tissue distributions. Both calcium carbonates were primarily present as particulate forms in gastrointestinal fluids but enter the circulatory system in dissolved Ca(2+), although both types showed partial phase transformation to dicalcium phosphate dihydrate. Relatively low dissolution (about 4%), no remarkable protein-particle interaction, and the major particulate fate of calcium carbonate in vivo gastrointestinal fluids can explain its low oral absorption (about 4%) regardless of particle size.
  
  
  CONCLUSIONS
  We conclude that calcium carbonate nanoparticles can act more actively with biological matrices in vitro and ex vivo, but that in vivo, their biological interactions and biokinetics are not affected by particle size.
authors.affiliation: Department of Food Science and Technology, Seoul Women's University, Seoul, Republic of Korea.
authors.forename: Jeong-A
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Department of Food Science and Technology, Seoul Women's University, Seoul, Republic of Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Republic of Korea.
authors.forename: Hyoung-Mi
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Hazard Substances Analysis Division, Gwangju Regional Food and Drug Administration, Ministry of Food and Drug Safety, Gwangju, Republic of Korea.
authors.forename: Jong Kwon
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Department of Food Science and Biotechnology, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Young-Rok
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Republic of Korea.
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Oh
authors.affiliation: Department of Food Science and Technology, Seoul Women's University, Seoul, Republic of Korea.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Choi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001826:Body Fluids; D002119:Calcium Carbonate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D005243:Feces; D005260:Female; D007408:Intestinal Absorption; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage*; D010316:Particle Size; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D011506:Proteins; D002119:Calcium Carbonate
keywords: biokinetics; biological interaction; oral absorption; protein corona; size effect
references.citation: Int J Mol Sci. 2014 Jun 17;15(6):10950-73
references.pmid: 24941255
references.citation: Am J Ther. 1995 Aug;2(8):546-552
references.pmid: 11854825
references.citation: Nanotechnology. 2009 Nov 11;20(45):455101
references.pmid: 19822937
references.citation: Biochem Biophys Res Commun. 2007 Feb 2;353(1):26-32
references.pmid: 17184736
references.citation: Gut. 1993 Mar;34(3):365-70
references.pmid: 8472985
references.citation: J Lipid Res. 1996 Dec;37(12):2473-91
references.pmid: 9017501
references.citation: Nanomedicine (Lond). 2011 Jul;6(5):803-14
references.pmid: 21793673
references.citation: Nat Nanotechnol. 2013 Oct;8(10):772-81
references.pmid: 24056901
references.citation: Clin J Am Soc Nephrol. 2010 Jan;5 Suppl 1:S23-30
references.pmid: 20089499
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14265-70
references.pmid: 18809927
references.citation: Trends Immunol. 2007 Apr;28(4):184-92
references.pmid: 17336159
references.citation: Colloids Surf B Biointerfaces. 2014 Sep 1;121:354-61
references.pmid: 24974013
references.citation: Cancer Epidemiol Biomarkers Prev. 1997 Oct;6(10):769-74
references.pmid: 9332757
references.citation: J Nanobiotechnology. 2004 Apr 30;2(1):3
references.pmid: 15119954
references.citation: J Infect Dis. 1978 Sep;138(3):351-8
references.pmid: 701850
references.citation: J Nutr. 2009 Jul;139(7):1308-14
references.pmid: 19474156
references.citation: Adv Drug Deliv Rev. 2009 Jun 21;61(6):428-37
references.pmid: 19376175
references.citation: Mol Pharm. 2012 Mar 5;9(3):654-63
references.pmid: 22277076
references.citation: Spectrochim Acta A Mol Biomol Spectrosc. 2012 Nov;97:366-76
references.pmid: 22797377
references.citation: Proteomics. 2004 Nov;4(11):3446-55
references.pmid: 15468290
references.citation: N Engl J Med. 1993 Feb 18;328(7):460-4
references.pmid: 8421475
references.citation: Nanotechnology. 2009 Sep 16;20(37):375102
references.pmid: 19706952
references.citation: Langmuir. 2005 Nov 8;21(23):10644-54
references.pmid: 16262332
references.citation: J Mass Spectrom. 1999 Feb;34(2):105-16
references.pmid: 10093212
references.citation: J Food Sci. 2008 Nov;73(9):H246-51
references.pmid: 19021809
references.citation: J Pharmacol Exp Ther. 2005 Jun;313(3):1217-22
references.pmid: 15734899
references.citation: J Clin Invest. 1984 Mar;73(3):640-7
references.pmid: 6707197
references.citation: ACS Nano. 2011 Sep 27;5(9):7155-67
references.pmid: 21866933
references.citation: J Drug Target. 2002 Jun;10(4):317-25
references.pmid: 12164380
references.citation: Biomaterials. 2004 Nov;25(26):5681-703
references.pmid: 15147815
references.citation: ACS Nano. 2010 Jan 26;4(1):365-79
references.pmid: 20020753
references.citation: Annu Rev Biomed Eng. 2012;14:1-16
references.pmid: 22524388
references.citation: Nat Mater. 2009 Jul;8(7):543-57
references.pmid: 19525947
references.citation: J Mater Chem B. 2013 Jul 7;1(25):3175-3184
references.pmid: 32260918