Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration

Katerina Lalatsa, Andreas Schatzlein, Natalie Laura Garrett, Mojer Julian, Michael Briggs, Lisa Godfrey, Antonio Iannitelli, Jay Freeman, Ijeoma F. Uchegbu

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    Abstract

    The clinical development of neuropeptides has been limited by a combination of the short plasma half-life of these drugs and their ultimate failure to permeate the blood brain barrier. Peptide nanofibres have been used to deliver peptides across the blood brain barrier and in this work we demonstrate that the polymer coating of peptide nanofibres further enhances peptide delivery to the brain via the intravenous route. Leucine5-enkephalin (LENK) nanofibres formed from the LENK ester prodrug - tyrosinyl1palmitate-leucine5-enkephalin (TPLENK) were coated with the polymer - N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) and injected intravenously. Peptide brain delivery was enhanced because the GCPQ coating on the peptide prodrug nanofibres, specifically enables the peptide prodrug to escape liver uptake, avoid enzymatic degradation to non-active sequences and thus enjoy a longer plasma half life. Plasma half-life is increased 520%, liver AUC0-4 decreased by 54% and brain AUC0-4 increased by 47% as a result of the GCPQ coating. The increased brain levels of the GCPQ coated peptide prodrug nanofibres result in the pharmacological activity of the parent drug (LENK) being significantly increased. LENK itself is inactive on intravenous injection.
    Original languageEnglish
    Pages (from-to)87-96
    Number of pages10
    JournalJournal of Controlled Release: Official Journal of the Controlled Release Society
    Volume197
    Early online date5 Nov 2014
    DOIs
    Publication statusPublished - 10 Jan 2015

    Keywords

    • peptide delivery
    • blood brain barrier
    • self assembly
    • peptide nanofibres
    • N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ)
    • Tyrosinyl1 −palmitate-leucine5-enkephalin (TPLENK)

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