VECTOR-MEDIATED DELIVERY OF A POLYAMIDE (PEPTIDE) NUCLEIC-ACID ANALOGTHROUGH THE BLOOD-BRAIN-BARRIER IN-VIVO

Polyamide (''peptide'') nucleic acids (PNAs) are molecules with antige ne and antisense effects that mag prole to be effective neuropharmaceu ticals if these molecules are enabled to undergo transport through the brain capillary endothelial wall, which makes up the blood-brain barr ier in vivo. The model PNA used in the present studies is an 18-mer th at 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 t o a conjugate of streptavidin (SA) and the OX26 murine monoclonal anti body to the rat transferrin receptor, The blood-brain barrier is endow ed 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 admi nistration, 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 gra m 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 ne gligible, delivery of these potential neuropharmaceutical drugs to the brain may be achieved by coupling them to vector-mediated peptide-dru g delivery systems.