PHARMACOKINETICS AND BLOOD-BRAIN-BARRIER TRANSPORT OF [H-3] BIOTINYLATED PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE CONJUGATED TO A VECTOR-MEDIATED DRUG-DELIVERY SYSTEM

Antisense phosphorothioate oIigodeoxynucleotides (PS-ODNs) are potenti al neuropharmaceuticals should these agents be made transportable thro ugh the blood-brain barrier (BBB) in vivo. The present studies report on attempts to enhance brain uptake of systemically administered 3'-bi otinylated PS-ODN (bio-PS-ODN) by conjugation to a complex of streptav idin (SA) and the OX28 monoclonal antibody to the rat transferrin rece ptor. This antibody undergoes receptor-mediated transcytosis through t he BBB and the OX26/SA conjugate mediates BBB transport of biotinylate d therapeutics. The brain uptake of unconjugated [H-3]-bio-PS-ODN appr oximated that of [C-14]sucrose, a plasma volume marker that is not sig nificantly transported through the BBB. Conjugation of [H-3]-bio-PS-OD N to the OX26/SA vector resulted in a marked increase in BBB transport and the permeability-surface area (PS) product of the conjugate was 4 .0 mu l/min/g. However, when the bio-PS-ODN/OX26-SA conjugate was inje cted intravenously in anesthetized rats, the BBB PS product of the con jugate was reduced 23-fold to a value of 0.173 +/- 0.006 mu l/min/g. T he marked inhibition of vector-mediated transport of the bio-PS-ODN af ter intravenous injection was due to avid plasma protein binding of PS -ODNs, as has been demonstrated with protein binding assays and intern al carotid artery perfusion studies. In conclusion, although PS-ODNs h ave the advantage of increased metabolic stability and resistance to e ndonucleases in vivo, the BBB transport of antisense PS-ODN therapeuti cs conjugated to the brain drug delivery vector OX26/SA is markedly at tenuated due to plasma protein-binding effects.