Antisense phosphorothioate oligodeoxynucleotides (PS-ODNs) are potential neuropharmaceuticals should these agents be made transportable through the blood-brain barrier (BBB) in vivo. The present studies report on attempts to enhance brain uptake of systemically administered 3'-biotinylated PS-ODN (bio-PS-ODN) by conjugation to a complex of streptavidin (SA) and the OX26 monoclonal antibody to the rat transferrin receptor. This antibody undergoes receptor-mediated transcytosis through the BBB and the OX26/SA conjugate mediates BBB transport of biotinylated therapeutics. The brain uptake of unconjugated [3H]-bio-PS-ODN approximated that of [14C]sucrose, a plasma volume marker that is not significantly transported through the BBB. Conjugation of [3H]-bio-PS-ODN 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 microliters/min/g. However, when the bio-PS-ODN/OX26-SA conjugate was injected intravenously in anesthetized rats, the BBB PS product of the conjugate was reduced 23-fold to a value of 0.173 +/- 0.006 microliters/min/g. The marked inhibition of vector-mediated transport of the bio-PS-ODN after intravenous injection was due to avid plasma protein binding of PS-ODNs, as has been demonstrated with protein binding assays and internal carotid artery perfusion studies. In conclusion, although PS-ODNs have the advantage of increased metabolic stability and resistance to endonucleases in vivo, the BBB transport of antisense PS-ODN therapeutics conjugated to the brain drug delivery vector OX26/SA is markedly attenuated due to plasma protein-binding effects.