Brain microvascular endothelial cell association and distribution of a 5 nm ceria engineered nanomaterial.
OBJECTIVE
Ceria engineered nanomaterials (ENMs) have current commercial applications and both neuroprotective and toxic effects. Our hypothesis is that ceria ENMs can associate with brain capillary cells and/or cross the blood-brain barrier.


METHODS
An aqueous dispersion of ∼5 nm ceria ENM was synthesized and characterized in house. Its uptake space in the Sprague Dawley rat brain was determined using the in situ brain perfusion technique at 15 and 20 mL/minute flow rates; 30, 100, and 500 μg/mL ceria perfused for 120 seconds at 20 mL/minute; and 30 μg/mL perfused for 20, 60, and 120 seconds at 20 mL/minute. The capillary depletion method and light and electron microscopy were used to determine its capillary cell and brain parenchymal association and localization.


RESULTS
The vascular space was not significantly affected by brain perfusion flow rate or ENM, demonstrating that this ceria ENM did not influence blood-brain barrier integrity. Cerium concentrations, determined by inductively coupled plasma mass spectrometry, were significantly higher in the choroid plexus than in eight brain regions in the 100 and 500 μg/mL ceria perfusion groups. Ceria uptake into the eight brain regions was similar after 120-second perfusion of 30, 100, and 500 μg ceria/mL. Ceria uptake space significantly increased in the eight brain regions and choroid plexus after 60 versus 20 seconds, and it was similar after 60 and 120 seconds. The capillary depletion method showed 99.4% ± 1.1% of the ceria ENM associated with the capillary fraction. Electron microscopy showed the ceria ENM located on the endothelial cell luminal surface.


CONCLUSIONS
Ceria ENM association with brain capillary endothelial cells saturated between 20 and 60 seconds and ceria ENM brain uptake was not diffusion-mediated. During the 120-second ceria ENM perfusion, ceria ENM predominately associated with the surface of the brain capillary cells, providing the opportunity for its cell uptake or redistribution back into circulating blood.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky Academic Medical Center, Lexington, KY 40536-0596, USA. mo.dan@uky.edu
Mo
M
Dan
Michael T
MT
Tseng
Peng
P
Wu
Jason M
JM
Unrine
Eric A
EA
Grulke
Robert A
RA
Yokel
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D001923:Brain Chemistry; D002196:Capillaries / Q000737:chemistry / Q000378:metabolism; D002560:Cerebrovascular Circulation; D002563:Cerium / Q000737:chemistry / Q000493:pharmacokinetics*; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008853:Microscopy; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D002563:Cerium