title: Bioavailability, distribution and clearance of tracheally-instilled and gavaged uncoated or silica-coated zinc oxide nanoparticles.
abstract: BACKGROUND
  Nanoparticle pharmacokinetics and biological effects are influenced by several factors. We assessed the effects of amorphous SiO2 coating on the pharmacokinetics of zinc oxide nanoparticles (ZnO NPs) following intratracheal (IT) instillation and gavage in rats.
  
  
  METHODS
  Uncoated and SiO2-coated ZnO NPs were neutron-activated and IT-instilled at 1 mg/kg or gavaged at 5 mg/kg. Rats were followed over 28 days post-IT, and over 7 days post-gavage. Tissue samples were analyzed for 65Zn radioactivity. Pulmonary responses to instilled NPs were also evaluated at 24 hours.
  
  
  RESULTS
  SiO2-coated ZnO elicited significantly higher inflammatory responses than uncoated NPs. Pulmonary clearance of both 65ZnO NPs was biphasic with a rapid initial t1/2 (0.2 - 0.3 hours), and a slower terminal t1/2 of 1.2 days (SiO2-coated ZnO) and 1.7 days (ZnO). Both NPs were almost completely cleared by day 7 (>98%). With IT-instilled 65ZnO NPs, significantly more 65Zn was found in skeletal muscle, liver, skin, kidneys, cecum and blood on day 2 in uncoated than SiO2-coated NPs. By 28 days, extrapulmonary levels of 65Zn from both NPs significantly decreased. However, 65Zn levels in skeletal muscle, skin and blood remained higher from uncoated NPs. Interestingly, 65Zn levels in bone marrow and thoracic lymph nodes were higher from coated 65ZnO NPs. More 65Zn was excreted in the urine from rats instilled with SiO2-coated 65ZnO NPs. After 7 days post-gavage, only 7.4% (uncoated) and 6.7% (coated) of 65Zn dose were measured in all tissues combined. As with instilled NPs, after gavage significantly more 65Zn was measured in skeletal muscle from uncoated NPs and less in thoracic lymph nodes. More 65Zn was excreted in the urine and feces with coated than uncoated 65ZnO NPs. However, over 95% of the total dose of both NPs was eliminated in the feces by day 7.
  
  
  CONCLUSIONS
  Although SiO2-coated ZnO NPs were more inflammogenic, the overall lung clearance rate was not affected. However, SiO2 coating altered the tissue distribution of 65Zn in some extrapulmonary tissues. For both IT instillation and gavage administration, SiO2 coating enhanced transport of 65Zn to thoracic lymph nodes and decreased transport to the skeletal muscle.
authors.forename: Nagarjun V
authors.initials: NV
authors.lastname: Konduru
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Murdaugh
authors.forename: Georgios A
authors.initials: GA
authors.lastname: Sotiriou
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Donaghey
authors.forename: Philip
authors.initials: P
authors.lastname: Demokritou
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Brain
authors.affiliation: Center for Nanotechnology and Nanotoxicology, Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, School of Public Health, Harvard University, 665 Huntington Avenue, Boston 02115, MA, USA. rmolina@hsph.harvard.edu.
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Molina
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006207:Half-Life; D019570:Inhalation Exposure / Q000009:adverse effects; D008168:Lung / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D018482:Muscle, Skeletal / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D011014:Pneumonia / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D012822:Silicon Dioxide / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution; D015034:Zinc Oxide / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D012822:Silicon Dioxide; D015034:Zinc Oxide