Document 0445
 DOCN  M9590445
 TI    Vector-mediated delivery of a polyamide (peptide) nucleic acid analogue
       through the blood-brain barrier in vivo.
 DT    9509
 AU    Pardridge WM; Boado RJ; Kang YS; Department of Medicine, University of
       California, Los Angeles,; School of Medicine 90024, USA.
 SO    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5592-6. Unique Identifier :
       AIDSLINE MED/95296357
 AB    Polyamide (peptide) nucleic acids (PNAs) are molecules with antigene and
       antisense effects that may prove to be effective neuropharmaceuticals if
       these molecules are enabled to undergo transport through the brain
       capillary endothelial wall, which makes up the blood-brain barrier in
       vivo. The model PNA used in the present studies is an 18-mer that is
       antisense to the rev gene of human immunodeficiency virus type 1 and is
       biotinylated at the amino terminus and iodinated at a tyrosine residue
       near the carboxyl terminus. The biotinylated PNA was linked to a
       conjugate of streptavidin (SA) and the OX26 murine monoclonal antibody
       to the rat transferrin receptor. The blood-brain barrier is endowed with
       high transferrin receptor concentrations, enabling the OX26-SA conjugate
       to deliver the biotinylated PNA to the brain. Although the brain uptake
       of the free PNA was negligible following intravenous administration, the
       brain uptake of the PNA was increased at least 28-fold when the PNA was
       bound to the OX26-SA vector. The brain uptake of the PNA bound to the
       OX26-SA vector was 0.1% of the injected dose per gram of brain at 60 min
       after an intravenous injection, approximating the brain uptake of
       intravenously injected morphine. The PNA bound to the OX26-SA vector
       retained the ability to bind to synthetic rev mRNA as shown by RNase
       protection assays. In summary, the present studies show that while the
       transport of PNAs across the blood-brain barrier is negligible, delivery
       of these potential neuropharmaceutical drugs to the brain may be
       achieved by coupling them to vector-mediated peptide-drug delivery
       systems.
 DE    Animal  Antibodies, Monoclonal/CHEMISTRY  Bacterial Proteins/CHEMISTRY
       Base Sequence  Blood-Brain Barrier  Chromatography, Gel  Chromatography,
       High Pressure Liquid  Drug Carriers  Genes, rev  HIV-1/GENETICS
       Molecular Sequence Data  Nylons/CHEMISTRY/*PHARMACOKINETICS
       Oligonucleotides, Antisense/ADMINISTRATION & DOSAGE/CHEMISTRY/
       *PHARMACOKINETICS  Rats  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

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