title: Pharmacokinetics and brain uptake of biotinylated basic fibroblast growth factor conjugated to a blood-brain barrier drug delivery system.
abstract: Human basic fibroblast growth factor (bFGF) is a potent neuroprotective agent. The clinical efficacy of this neurotrophin, however, is restricted by poor permeability across the blood-brain barrier (BBB). This study was designed to test the hypotheses that bFGF will retain its biological activity and have an enhanced BBB transport after re-formulation and conjugation to a BBB peptide drug delivery vector. The BBB delivery vector is comprised of a conjugate of streptavidin (SA) and the murine OX26 monoclonal antibody against the rat transferrin receptor, and the conjugate of biotinylated bFGF (bio-bFGF) bound to a vector is designated bio-bFGF/OX26-SA. A radioreceptor binding assay shows that the native bFGF, bio-bFGF, and bio-bFGF/OX26-SA conjugate have IC50 values of 0.12, 0.40, and 0.56 nM, respectively. After an IV bolus injection to the rat, [125I]-bio-bFGF is avidly taken up by peripheral organs, with low brain uptake at 60 min, 0.010+/-0.004% of injected dose (ID)/g brain. By contrast, the brain uptake of the [125I]-bio-bFGF/OX26-SA is increased 5-fold to 0.050+/-0.011%ID/g, although the uptake of the conjugate by peripheral tissues was decreased relative to the unconjugated bio-bFGF. In conclusion, conjugation of bio-bFGF to a BBB drug delivery vector (a) causes only a minor decrease in affinity for the bFGF receptor, (b) decreases the peripheral organ uptake of the bFGF, and (c) increases the brain uptake of the neurotrophin. The re-formulation of bFGF to enable receptor-mediated transcytosis across the BBB may improve the therapeutic index of this neurotrophin as a neuroprotective agent.
authors.affiliation: Department of Pathology, UCLA School of Medicine, CA 90095, USA. dwu@mednet.ucla.edu
authors.forename: Dafang
authors.initials: D
authors.lastname: Wu
authors.forename: Bi-Wei
authors.initials: BW
authors.lastname: Song
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: William M
authors.initials: WM
authors.lastname: Pardridge
mesh_terms: D000465:Algorithms; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D001665:Binding Sites; D019921:Biotinylation / Q000379:methods; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002339:Carotid Arteries; D016503:Drug Delivery Systems / Q000379:methods*; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007261:Infusions, Intra-Arterial; D007457:Iodine Radioisotopes; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000276:immunology; D019809:Streptavidin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes; D009414:Nerve Growth Factors; D011990:Receptors, Transferrin; D016222:Fibroblast Growth Factor 2; D019809:Streptavidin