title: Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles.
abstract: OBJECTIVE
  [corrected] It has recently been suggested that the poly(butylcyanoacrylate) (PBCA) nanoparticle drug delivery system has a generalized toxic effect on the blood-brain barrier (BBB) (8) and that this effect forms the basis of an apparent enhanced drug delivery to the brain. The purpose of this study is to explore more fully the mechanism by which PBCA nanoparticles can deliver drugs to the brain.
  
  
  METHODS
  Both in vivo and in vitro methods have been applied to examine the possible toxic effects of PBCA nanoparticles and polysorbate-80 on cerebral endothelial cells. Human, bovine, and rat models have been used in this study.
  
  
  RESULTS
  In bovine primary cerebral endothelial cells, nontoxic levels of PBCA particles and polysorbate-80 did not increase paracellular transport of sucrose and inulin in the monolayers. Electron microscopic studies confirm cell viability. In vivo studies using the antinociceptive opioid peptide dalargin showed that both empty PBCA nanoparticles and polysorbate-80 did not allow dalargin to enter the brain in quantities sufficient to cause antinociception. Only dalargin preadsorbed to PBCA nanoparticles was able to induce an antinociceptive effect in the animals.
  
  
  CONCLUSIONS
  At concentrations of PBCA nanoparticles and polysorbate-80 that achieve significant drug delivery to the brain, there is little in vivo or in vitro evidence to suggest that a generalized toxic effect on the BBB is the primary mechanism for drug delivery to the brain. The fact that dalargin has to be preadsorbed onto nanoparticles before it is effective in inducing antinociception suggests specific mechanisms of delivery to the CNS rather than a simple disruption of the BBB allowing a diffusional drug entry.
authors.affiliation: Institut für Pharmazeutische Technologie, Biozentrum, J.W. Goethe-Universität, Frankfurt, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
authors.forename: Peter
authors.initials: P
authors.lastname: Ramge
authors.forename: Valery
authors.initials: V
authors.lastname: Petrov
authors.forename: Stefan
authors.initials: S
authors.lastname: Hamm
authors.forename: Svetlana E
authors.initials: SE
authors.lastname: Gelperina
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Renad
authors.initials: R
authors.lastname: Alyautdin
authors.forename: Hagen
authors.initials: H
authors.lastname: von Briesen
authors.forename: David J
authors.initials: DJ
authors.lastname: Begley
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002196:Capillaries; D002417:Cattle; D002478:Cells, Cultured; D004337:Drug Carriers; D004659:Enbucrilate; D004730:Endothelium, Vascular / Q000378:metabolism*; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008854:Microscopy, Electron; D008954:Models, Biological; D036103:Nanotechnology; D010316:Particle Size; D011136:Polysorbates / Q000737:chemistry*; D051381:Rats
chemical_list: D000701:Analgesics, Opioid; D004337:Drug Carriers; D011136:Polysorbates; D016308:Enkephalin, Leucine-2-Alanine; D004659:Enbucrilate; C040996:enkephalin-Leu, Ala(2)-Arg(6)-