Size- and shape-dependent effects of titanium dioxide nanoparticles on the permeabilization of the blood–brain barrier

Abstract

Titanium dioxide nanoparticles (TiO₂-NPs) have been found to translocate into the brain by penetrating the blood-brain barrier (BBB), but it remains largely unknown how their physicochemical characteristics may impact BBB permeabilization. By testing TiO₂ particles of different shapes and various sizes, we found that: (1) small, spherical TiO₂-NPs permeabilized a BBB-like human brain microvasculature endothelial cell monolayer better than rod-like or large particles; (2) TiO₂-NPs stimulated F-actin stress fiber formation, and induced paracellular gaps and ROCK II activation. The TiO₂-NP-mediated BBB permeabilization was associated with intracellular uptake and cytoskeletal re-organization; and (3) in rats, spherical, small TiO₂-NPs significantly increased the BBB permeability and entered the brain. The TiO₂-NPs were accumulated in the brain, but no obvious pathological anomaly was observed in the cerebral cortex and hippocampus. Our study investigated the neurotoxicity of TiO₂-NPs, thereby providing scientific evaluation for the potential biomedical applications of TiO₂-NPs.