Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo.
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.
Pardridge
W M
WM
Department of Medicine, University of California, Los Angeles, School of Medicine 90024, USA.
Boado
R J
RJ
Kang
Y S
YS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry; D001483:Base Sequence; D001812:Blood-Brain Barrier; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers; D015757:Genes, rev; D015497:HIV-1 / Q000235:genetics; D008969:Molecular Sequence Data; D009757:Nylons / Q000737:chemistry / Q000493:pharmacokinetics*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D019809:Streptavidin
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D004337:Drug Carriers; D009757:Nylons; D016376:Oligonucleotides, Antisense; D019809:Streptavidin