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

A. Lalatsa; A. G. Schätzlein; N. L. Garrett; J. Moger; Michael Briggs; Lisa Godfrey; Antonio Iannitelli; Jay Freeman; I. F. Uchegbu

doi:10.1016/j.jconrel.2014.10.028

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

A. Lalatsa, A. G. Schätzlein, N. L. Garrett, J. Moger, Michael Briggs, Lisa Godfrey, Antonio Iannitelli, Jay Freeman, I. F. Uchegbu^*

^*Corresponding author for this work

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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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 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.

Original language	English
Pages (from-to)	87-96
Number of pages	10
Journal	Journal of Controlled Release
Volume	197
DOIs	https://doi.org/10.1016/j.jconrel.2014.10.028
Publication status	Published - 10 Jan 2015

Funding

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.

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
tyrosinylpalmitate-leucine-enkephalin (TPLENK)

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10.1016/j.jconrel.2014.10.028Licence: CC BY 3.0

Lalatsa-etal-JCR2015-Chitosan-amphiphile-coating-peptide-nanofibres-reduces-liver-uptakeFinal published version, 1.29 MBLicence: CC BY 3.0

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@article{f6b1f823c4da416e833d00e1583d3554,

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. 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.",

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, tyrosinylpalmitate-leucine-enkephalin (TPLENK)",

author = "A. Lalatsa and Sch{\"a}tzlein, {A. G.} and Garrett, {N. L.} and J. Moger and Michael Briggs and Lisa Godfrey and Antonio Iannitelli and Jay Freeman and Uchegbu, {I. F.}",

note = "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: {\textcopyright} 2014 The Authors. Published by Elsevier B.V.",

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month = jan,

day = "10",

doi = "10.1016/j.jconrel.2014.10.028",

language = "English",

volume = "197",

pages = "87--96",

journal = "Journal of Controlled Release",

issn = "0168-3659",

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T1 - Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration

AU - Lalatsa, A.

AU - Schätzlein, A. G.

AU - Garrett, N. L.

AU - Moger, J.

AU - Briggs, Michael

AU - Godfrey, Lisa

AU - Iannitelli, Antonio

AU - Freeman, Jay

AU - Uchegbu, I. F.

N1 - 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.

PY - 2015/1/10

Y1 - 2015/1/10

N2 - 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.

AB - 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.

KW - blood brain barrier

KW - N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ)

KW - peptide delivery

KW - peptide nanofibres

KW - self assembly

KW - tyrosinylpalmitate-leucine-enkephalin (TPLENK)

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DO - 10.1016/j.jconrel.2014.10.028

M3 - Article

C2 - 25449808

AN - SCOPUS:84911489194

SN - 0168-3659

VL - 197

SP - 87

EP - 96

JO - Journal of Controlled Release

JF - Journal of Controlled Release

ER -

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

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