Tissue Biodistribution Revealed Blood-Brain Barrier Clearance of Intravenously Administrated Titanium Dioxide Nanoparticles and Brain Inflammation in Rat.

Notwithstanding the reported advances in the translocation of titanium dioxide nanoparticles (TiO2 NPs) through biological barriers, the biodistribution of TiO2 NPs to the central nervous system as well as the functional consequences of their biokinetic on the blood-brain barrier (BBB) physiology remain poorly characterized. Here we report time-related responses from a single dose of 1mg/kg TiO2 NPs intravenous (IV) administration to rats with particular emphasis on the titanium (Ti) quantification in the brain. Biokinetic analysis revealed Ti bioaccumulation in liver, lungs and spleen up to one year after TiO2 NPs administration to rats. A significant increase of Ti in the brain was observed at early end point followed by a subsequent decrease in the Ti’s rat brain content. An in depth analysis of Ti in the brain demonstrated quantitative Ti uptake and clearance by brain endothelial microvessels with a minimal translocation in the brain parenchyma compartment after TiO2 NPs administration at low dose of 1mg/kg. The presence of Ti in the brain microvessels does not affect the BBB integrity despite a rapid reversible modulation of Breast Cancer Resistance Protein activity. We demonstrated that long term Ti bioaccumulation in organs such as liver, spleen and lungs is associated with a significant increase of tight junction proteins, (claudin-5 and occludin), interleukin 1â (IL-1â), chemokine ligand 1 (CXCL1) and ã inducible protein-10 (IP-10/CXCL10) in the rat brain microvessels and also increased levels of IL-1â in brain parenchyma despite the lack of Ti evidence in the brain. Exposure of in vitro BBB model to serum from TiO2 NPs-treated animals confirmed the tightness of the BBB and astrocyte inflammatory responses. Overall, these findings suggest the clearance of TiO2 NPs at the BBB level and pointed out the role of Ti bioaccumulation in organs in maintaining persistent brain inflammation.