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BEHAVIORAL PHARMACOLOGY

Covalent Linkage of Apolipoprotein E to Albumin Nanoparticles Strongly Enhances Drug Transport into the Brain

Institute for Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Frankfurt, Germany (K.M., S.D., E.H., J.K., K.L.); Institute for Medical Virology, University Hospital Medical School, Johann Wolfgang Goethe-Universität, Frankfurt, Germany (M.M.); Division of Clinical Chemistry, Department of Medicine, Albert-Ludwigs-University, Freiburg, Germany (M.M.H.); and Department of Pharmacology, Sechenov Medical Academy, Moscow, Russia (R.N.A.)

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.

Address correspondence to: Klaus Langer, Institute for Pharmaceutical Technology, Biocenter of Johann Wolfgang Goethe-University, Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany. E-mail: k.langer{at}em.uni-frankfurt.de