Transport of glucose-coated gold nanoparticles across brain endothelium in vitro
Treatment of CNS disease is severly restricted because of the structure called the blood-brain barrier which prevents >95 % of potentially useful drugs from entering the brain. The blood-brain barrier is formed by the brain microvascular endothelium, which has continuous tight junctions and an array of ABC-transporters that actively efflux many xenobiotics. Brain endothelium also has set of metabolite transporters, including the glucose transporter, GLUT-1, which have been exploited in different ways.
The aim of this study was to investigate whether 4 nm glucose-coated gold nanoparticles would selectively cross human brain endothelium. The rate of transport was compared in vitro, in primary brain endothelium, the brain endothelikal line hCMEC/D3 and 2 non-brain endothelial cell lines. Transport was measured by transmission electron microscopy (TEM), counting nanoparticles localizes between the basal plasma membrane of the endothelium and the basal lamina over 0 to 8 hrs. The rate of movement of movement the nanoparticles across brain endothelium was 20 - 50x paster than across non-brain endothelium. The nanoparticles crossed the endothelium by moving through cytosol, they were not seen in inter-cellular junctions or in vesicles or in nuclei of the endothelium. Nor did antibiotics that block different vesicular pathways inhibit movement. The results indicate that these nanoparticlesselectively cross brain endothelium by a biophysical process that involves movement across the apical and basal plasma membranes of the endothelium.
To demonstrate that these nanoparticles could be use as a potential carrier to glial cells, we have used a newly developed 3-dimensional tissue culture system. This system includes human astrocytes in a 3D gel matrix overlaid with a brain endothelial cell monolayer (hCMEC/D3). Transmission electron microscopy demonstrates that the nanoparticles cross the brain endothelium and migrate through the gel matrix, to become selectively localised in astrocytes (in their nuclei and cytoplasm).
