Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery

Elena V. Batrakova, Serguei V. Vinogradov, Sandra M. Robinson, Michael L. Niehoff, William A. Banks, Alexander V. Kabanov

Research output: Contribution to journalArticle

75 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)793-802
Number of pages10
JournalBioconjugate Chemistry
Volume16
Issue number4
DOIs
StatePublished - Jul 1 2005

Fingerprint

Polypeptides
Fatty acids
Block copolymers
Horseradish Peroxidase
Brain
Fatty Acids
Peptides
Blood-Brain Barrier
Poloxamer
Central Nervous System Diseases
Endothelial cells
Neurology
Microvessels
Disulfides
Monolayers
Blood
Endothelial Cells

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Batrakova, E. V., Vinogradov, S. V., Robinson, S. M., Niehoff, M. L., Banks, W. A., & Kabanov, A. V. (2005). Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery. Bioconjugate Chemistry, 16(4), 793-802. https://doi.org/10.1021/bc049730c

Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery. / Batrakova, Elena V.; Vinogradov, Serguei V.; Robinson, Sandra M.; Niehoff, Michael L.; Banks, William A.; Kabanov, Alexander V.

In: Bioconjugate Chemistry, Vol. 16, No. 4, 01.07.2005, p. 793-802.

Research output: Contribution to journalArticle

Batrakova, EV, Vinogradov, SV, Robinson, SM, Niehoff, ML, Banks, WA & Kabanov, AV 2005, 'Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery', Bioconjugate Chemistry, vol. 16, no. 4, pp. 793-802. https://doi.org/10.1021/bc049730c
Batrakova, Elena V. ; Vinogradov, Serguei V. ; Robinson, Sandra M. ; Niehoff, Michael L. ; Banks, William A. ; Kabanov, Alexander V. / Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery. In: Bioconjugate Chemistry. 2005 ; Vol. 16, No. 4. pp. 793-802.
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