Covalent linkage of apolipoprotein e to albumin nanoparticles strongly enhances drug transport into the brain.
Drug delivery to the brain is becoming more and more important but is severely restricted by the blood-brain barrier. Nanoparticles coated with polysorbates have previously been shown to enable the transport of several drugs across the blood-brain barrier, which under normal circumstances is impermeable to these compounds. Apolipoprotein E was suggested to mediate this drug transport across the blood-brain barrier. In the present study, apolipoprotein E was coupled by chemical methods to nanoparticles made of human serum albumin (HSA-NP). Loperamide, which does not cross the blood-brain barrier but exerts antinociceptive effects after direct injection into the brain, was used as model drug. Apolipoprotein E was chemically bound via linkers to loperamide-loaded HSA-NP. This preparation induced antinociceptive effects in the tail-flick test in ICR mice after i.v. injection. In contrast, nanoparticles linked to apolipoprotein E variants that do not recognize lipoprotein receptors failed to induce these effects. These results indicate that apolipoprotein E attached to the surface of nanoparticles facilitates transport of drugs across the blood-brain barrier, probably after interaction with lipoprotein receptors on the brain capillary endothelial cell membranes.
Institute for Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany.
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Michaelis
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Hoffmann
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Dreis
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Herbert
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Alyautdin
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Michaelis
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Kreuter
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Langer
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry / Q000493:pharmacokinetics*; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008139:Loperamide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D010146:Pain / Q000188:drug therapy; D012709:Serum Albumin / Q000737:chemistry / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001057:Apolipoproteins E; D004337:Drug Carriers; D012709:Serum Albumin; D008139:Loperamide