Vol. 301, Issue 2, 605-610, May 2002

Enhanced Neuroprotective Effects of Basic Fibroblast Growth Factor in Regional Brain Ischemia after Conjugation to a Blood-Brain Barrier Delivery Vector

Bi-Wei Song, Harry V. Vinters, Dafang Wu and William M. Pardridge

Departments of Pathology (B.-W. S., H.V.V., D.W.) and Medicine (W.M.P), University of California Los Angeles, School of Medicine, Los Angeles, California

Basic fibroblast growth factor (bFGF) has minimal pharmacological effects in the central nervous system in the absence of blood-brain barrier (BBB) disruption. BBB transport of bFGF occurs via an absorptive-mediated transcytosis mechanism, which is relatively inefficient. To enhance the BBB transport of bFGF, this neurotrophin was reformulated to enable receptor-mediated transport across the BBB via the transferrin receptor. bFGF was monobiotinylated and coupled to a BBB drug-delivery vector comprised of streptavidin (SA) and the OX26 monoclonal antibody to the rat transferrin receptor. The entire conjugate of biotinylated bFGF bound to the OX26-SA is designated bio-bFGF/OX26-SA. The bFGF retains receptor-binding affinity and has increased brain uptake following conjugation to OX26-SA. The bio-bFGF/OX26-SA conjugate protects cortical cell cultures against hypoxia/reoxygenation insult in a dose-dependent manner in vitro. A single intravenous injection of bio-bFGF/OX26-SA, equivalent to a dose of 25 µg/kg bFGF, produces an 80% reduction in infarct volume in the brain of rats subjected to permanent occlusion of the middle cerebral artery in parallel with a significant improvement of neurologic deficit. The neuroprotection is time-dependent, and there is a 67% reduction in stroke volume if the conjugate is administered at 60 min after arterial occlusion, whereas no significant reduction in stroke volume is observed if treatment is delayed 2 h. In conclusion, neuroprotection in regional brain ischemia is possible following the delayed intravenous injection of low doses of bFGF providing the neurotrophin is conjugated to a BBB drug-targeting system.