Interaction of poly(butylcyanoacrylate) nanoparticles with the blood-brainbarrier in vivo and in vitro

Poly(butylcyanoacrylate) nanoparticles were produced by emulsion polymerisa tion and used either uncoated or overcoated with polysorbate 80 (Tween (R) 80). [H-3]-dalargin bound to nanoparticles overcoated with polysorbate 80 o r in the form of saline solution was injected into mice and the brain conce ntrations of radioactivity determined. Statistically significant, three-fol d higher brain concentrations with the nanoparticle preparations were obtai ned after 45 minutes, the time of greatest pharmacological response assesse d as analgesia in previous experiments. In addition the brain inulin spaces in rats and the uptake of fluoresceine isothio-cyanate labelled nanopartic les in immortalised rat cerebral endothelial cells, (RBE4) were measured. T he inulin spaces after i.v. injection of polysorbate 80-coated nanoparticle s were significantly increased by 1% compared to controls. This is interpre ted as indicating that there is no large scale opening of the tight junctio ns of the brain endothelium by the polysorbate 80-coated nanoparticles. In in vitro experiments endocytic uptake of fluorescent nanoparticles by RBE4 cells was only observed after polysorbate 80-overcoating, not with uncoated particles. These results further support the hypothesis that the mechanism of blood-brain barrier transport of drugs by polysorbate 80-coated nanopar ticles is one of endocytosis followed by possible transcytosis. The experim ents were conducted in several laboratories as part of an EEC/INTAS collabo rative program. For various procedural and regulatory reasons this necessit ated the use of both rats and mice as experimental animals. The brain endot helial cell line used for the in vitro studies is the rat RBE4.