Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system.
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.
Wu
D
D
Department of Medicine, UCLA School of Medicine, USA.
Boado
R J
RJ
Pardridge
W M
WM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D001483:Base Sequence; D001692:Biological Transport; D001710:Biotin / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier; D002343:Carotid Artery, Internal / Q000502:physiology; D016503:Drug Delivery Systems; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010477:Perfusion; D011422:Propionates / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D019809:Streptavidin; D013873:Thionucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014316:Tritium
D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D001798:Blood Proteins; D018796:Immunoconjugates; D016376:Oligonucleotides, Antisense; D011422:Propionates; D013873:Thionucleotides; D014316:Tritium; C021749:N-succinimidyl propionate; D001710:Biotin; D019809:Streptavidin