title: Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier.
abstract: Recent studies have shown that drugs that are normally unable to cross the blood-brain barrier (BBB) following intravenous injection can be transported across this barrier by binding to poly(butyl cyanoacrylate) nanoparticles and coating with polysorbate 80. However, the mechanism of this transport so far was not known. In the present paper, the possible involvement of apolipoproteins in the transport of nanoparticle-bound drugs into the brain is investigated. Poly(butyl cyanoacrylate) nanoparticles loaded with the hexapeptide dalargin were coated with the apolipoproteins AII, B, CII, E, or J without or after precoating with polysorbate 80. In addition, loperamide-loaded nanoparticles were coated with apolipoprotein E alone or again after precoating with polysorbate 80. After intravenous injection to ICR mice the antinociceptive threshold was measured by the tail flick test. Furthermore, the antinociceptive threshold of polysorbate 80-coated dalargin-loaded nanoparticles was determined in ApoEtm1Unc and C57BL/6J mice. The results show that only dalargin or loperamide-loaded nanoparticles coated with polysorbate 80 and/or with apolipoprotein B or E were able to achieve an antinociceptive effect. This effect was significantly higher after polysorbate-precoating and apolipoprotein B or E-overcoating. With the apolipoprotein E-deficient ApoEtm1Unc mice the antinociceptive effect was considerably reduced in comparison to the C57BL/6J mice. These results suggest that apolipoproteins B and E are involved in the mediation of the transport of drugs bound to poly(butyl cyanoacrylate) nanoparticles across the BBB. Polysorbate 80-coated nanoparticles adsorb these apolipoproteins from the blood after injection and thus seem to mimic lipoprotein particles that could be taken up by the brain capillary endothelial cells via receptor-mediated endocytosis. Bound drugs then may be further transported into the brain by diffusion following release within the endothelial cells or, alternatively, by transcytosis.
authors.affiliation: Institut für Pharmazeutische Technologie, Biozentrum, J.W. Goethe-Universität, Frankfurt, Germany. kreuter@em.uni-frankfurt.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shamenkov
authors.forename: Valery
authors.initials: V
authors.lastname: Petrov
authors.forename: Peter
authors.initials: P
authors.lastname: Ramge
authors.forename: Klaus
authors.initials: K
authors.lastname: Cychutek
authors.forename: Claudia
authors.initials: C
authors.lastname: Koch-Brandt
authors.forename: Renad
authors.initials: R
authors.lastname: Alyautdin
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D001057:Apolipoproteins E / Q000008:administration & dosage* / Q000172:deficiency / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D036103:Nanotechnology / Q000379:methods*; D010147:Pain Measurement / Q000187:drug effects; D011136:Polysorbates / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D001053:Apolipoproteins; D001057:Apolipoproteins E; D011136:Polysorbates