title: Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery.
abstract: There is a tremendous need to enhance delivery of therapeutic polypeptides to the brain to treat disorders of the central nervous system (CNS). The brain delivery of many polypeptides is severely restricted by the blood-brain barrier (BBB). The present study demonstrates that point modifications of a BBB-impermeable polypeptide, horseradish peroxidase (HRP), with lipophilic (stearoyl) or amphiphilic (Pluronic block copolymer) moieties considerably enhance the transport of this polypeptide across the BBB and accumulation of the polypeptide in the brain in vitro and in vivo. The enzymatic activity of the HRP was preserved after the transport. The modifications of the HRP with amphiphilic block copolymer moieties through degradable disulfide links resulted in the most effective transport of the HRP across in vitro brain microvessel endothelial cell monolayers and efficient delivery of HRP to the brain. Stearoyl modification of HRP improved its penetration by about 60% but also increased the clearance from blood. Pluronic modification using increased penetration of the BBB and had no significant effect on clearance so that uptake by brain was almost doubled. These results show that point modification can improve delivery of even highly impermeable polypeptides to the brain.
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors: Elena V
authors: EV
authors: Batrakova
authors: Serguei V
authors: SV
authors: Vinogradov
authors: Sandra M
authors: SM
authors: Robinson
authors: Michael L
authors: ML
authors: Niehoff
authors: William A
authors: WA
authors: Banks
authors: Alexander V
authors: AV
authors: Kabanov
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005227:Fatty Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D051379:Mice; D008823:Micelles; D010455:Peptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D005227:Fatty Acids; D008823:Micelles; D010455:Peptides; D011108:Polymers