Blood-brain barrier drug targeting enables neuroprotection in brain ischemia following delayed intravenous administration of neurotrophins.
The blood-brain barrier (BBB) is the rate-limiting step in the translation of neurotrophin neuroscience into clinically effective neurotherapeutics. Since neurotrophins do not cross the BBB, these proteins cannot be used for neuroprotection following intravenous administration, and it is not feasible to administer these molecules by intra-cerebral injection in human stroke. The present studies describe the development of the chimeric peptide brain drug targeting technology and the use of brain-derived neurotrophic factor (BDNF) chimeric peptides in either global or regional brain ischemia. The BDNF chimeric peptide is formed by conjugation of BDNF to a monoclonal antibody (MAb) to the BBB transferrin receptor, and the MAb acts as a molecular Trojan Horse to ferry the BDNF across the BBB via transport on the endogenous BBB transferrin receptor. High degrees of neuroprotection in transient forebrain ischemia, permanent middle cerebral artery occlusion, or reversible middle cerebral artery occlusion are achieved with the delayed intravenous administration of BDNF chimeric peptides. In contrast, no neuroprotection is observed following the intravenous administration of unconjugated BDNF, because the neurotrophin does not cross the BBB in vivo.
Pardridge
William M
WM
Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1682, USA.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010455:Peptides / Q000378:metabolism / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D010455:Peptides; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D011092:Polyethylene Glycols