Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector.
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 microg/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.
Song
Bi-Wei
BW
Department of Pathology, University of California Los Angeles, School of Medicine, Los Angeles, California 90024, USA.
Vinters
Harry V
HV
Wu
Dafang
D
Pardridge
William M
WM
D000818:Animals; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D016222:Fibroblast Growth Factor 2