title: Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration.
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. 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 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.
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lalatsa
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK; Nanomerics Ltd., 14 Approach Road, St. Albans, Hertfordshire AL1 1SR, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Schätzlein
authors.affiliation: School of Physics, University of Exeter, Stocker Road, Exeter EX4 4QL, UK.
authors.forename: N L
authors.initials: NL
authors.lastname: Garrett
authors.affiliation: School of Physics, University of Exeter, Stocker Road, Exeter EX4 4QL, UK.
authors.forename: J
authors.initials: J
authors.lastname: Moger
authors.affiliation: GlaxoSmithKline, Pharmaceuticals R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Briggs
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Godfrey
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iannitelli
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Jay
authors.initials: J
authors.lastname: Freeman
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK; Nanomerics Ltd., 14 Approach Road, St. Albans, Hertfordshire AL1 1SR, UK. Electronic address: Ijeoma.uchegbu@ucl.ac.uk.
authors.forename: I F
authors.initials: IF
authors.lastname: Uchegbu
mesh_terms: D061605:Administration, Intravenous; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D021461:Animals, Outbred Strains; D001921:Brain / Q000378:metabolism*; D048271:Chitosan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D057139:Nanofibers / Q000008:administration & dosage / Q000737:chemistry*; D010146:Pain / Q000188:drug therapy; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D011355:Prodrugs; C000600924:enkephalin, palmitoyltyrosinyl(1)-leucyl(5)-; D004743:Enkephalin, Leucine; D048271:Chitosan
keywords: Blood brain barrier; N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ); Peptide delivery; Peptide nanofibres; Self assembly; Tyrosinyl(1−)palmitate-leucine(5)-enkephalin (TPLENK)