title: The buccal mucosa as a route for TiO2 nanoparticle uptake.
abstract: The oral cavity, although part of the aero-digestive tract, is still neglected in terms of risk assessment with respect to nanoparticle uptake. If nanoparticles enter the oral cavity, either via oral products or inhaled materials, it is not clear whether they rapidly interact with the mucosae or are swallowed. In this study, interactions of three distinct titanium dioxide (TiO2) particles (i.e. NM 100, NM 101 and NM 105) with oral tissues are presented. Physicochemical properties were addressed in relevant media, and particle penetration was investigated with an ex vivo model using porcine mucosa. To avoid modification of the particle surfaces via labeling, multiphoton microscopy was introduced as an accurate method to detect TiO2 particles within the tissue. The spatiotemporal aspects of nanoparticle uptake, as well as the intracellular localization in human epithelial cells, were studied and potential toxic effects were evaluated. Although TiO2 particles formed large aggregates once dispersed in media, 10-50% remained in the nanoscale range, rapidly interacting with the mucus layer and infecting the epithelium. However, differences in the penetration depth were observed depending on the particle characteristics. NM 100 and NM 105 were found in both the upper part and the lower part of the buccal mucosa, while NM 101 (smallest particle sizes) only penetrated the upper parts. Transport studies revealed that TiO2 nanoparticles were found in vesicles, as well as freely distributed in the cytoplasm. Cell viability/integrity was not affected negatively; however, NM 105 triggered the production of reactive oxygen species. These data clearly suggest that the oral cavity should be considered in further risk assessment studies.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmaceutical Sciences, Karl-Franzens University , Graz , Austria .
authors.forename: Birgit Johanna
authors.initials: BJ
authors.lastname: Teubl
authors.forename: Gerd
authors.initials: G
authors.lastname: Leitinger
authors.forename: Marc
authors.initials: M
authors.lastname: Schneider
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Eva
authors.initials: E
authors.lastname: Roblegg
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D066298:In Vitro Techniques; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure*; D009061:Mouth Mucosa / Q000737:chemistry*; D010316:Particle Size; D010539:Permeability; D013552:Swine; D014018:Tissue Distribution; D014025:Titanium / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; C009495:titanium dioxide; D014025:Titanium
keywords: Energy filtered transmission electron microscopy; multiphoton microscopy; particle characterization; penetration/permeation; titanium dioxide