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

Lalatsa, A. and Schätzlein, A. G. and Garrett, N. L. and Moger, J. and Briggs, Michael and Godfrey, Lisa and Iannitelli, Antonio and Freeman, Jay and Uchegbu, I. F. (2015) Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration. Journal of Controlled Release, 197. pp. 87-96. ISSN 0168-3659 (https://doi.org/10.1016/j.jconrel.2014.10.028)

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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.

ORCID iDs

Lalatsa, A. ORCID logoORCID: https://orcid.org/0000-0003-4791-7468, Schätzlein, A. G., Garrett, N. L., Moger, J., Briggs, Michael, Godfrey, Lisa, Iannitelli, Antonio, Freeman, Jay and Uchegbu, I. F.;
  • Item type:Article
    ID code:80804
    Dates:
    Date
    Event
    10 January 2015
    Published
    Notes:Funding Information: This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) ( EPG0483/1, EP/K502340/1 ) and GlaxoSmithKline (GSK) ( EPG0483/1 ). Raffaele Longhi (Aptuit, Inc.) is acknowledged for extraction and mass spectroscopy quantification of biological samples. Mr. David McCarthy (UCL School of Pharmacy) is thanked for providing transmission electron microscopy expertise. Publisher Copyright: © 2014 The Authors. Published by Elsevier B.V.
    Subjects:Medicine > Pharmacy and materia medica
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:19 May 2022 08:24
    Last modified:11 Nov 2024 13:29
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/80804
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