Journal
JOURNAL OF CONTROLLED RELEASE
Volume 197, Issue -, Pages 87-96Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2014.10.028
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); Tyrosinyl(1)-palmitate-leucine(5)-enkephalin (TPLENK)
Funding
- Engineering and Physical Sciences Research Council (EPSRC) [EPG0483/1, EP/K502340/1]
- GlaxoSmithKline (GSK) [EPG0483/1]
- EPSRC [EP/L024772/1, EP/K502339/1, EP/K502340/1, EP/G061483/1, EP/L024748/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/L024772/1, EP/G061483/1, GR/T20410/02, EP/K502339/1, GR/T20410/01, EP/L024748/1, EP/K502340/1] Funding Source: researchfish
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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. Leucine(5)-enkephalin (LENK) nanofibres formed from the LENK ester prodrug -tyrosinyl(1)palmitate-leucine(5)-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 AUC(0-4) decreased by 54% and brain AUC(0-4) 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. (C) 2014 The Authors. Published by Elsevier B.V.
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