A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain

Molecular Pharmaceutics
Aikaterini LalatsaIjeoma Uchegbu

Abstract

The oral use of neuropeptides to treat brain disease is currently not possible because of a combination of poor oral absorption, short plasma half-lives and the blood-brain barrier. Here we demonstrate a strategy for neuropeptide brain delivery via the (a) oral and (b) intravenous routes. The strategy is exemplified by a palmitic ester prodrug of the model drug leucine(5)-enkephalin, encapsulated within chitosan amphiphile nanoparticles. Via the oral route the nanoparticle-prodrug formulation increased the brain drug levels by 67% and significantly increased leucine(5)-enkephalin's antinociceptive activity. The nanoparticles facilitate oral absorption and the prodrug prevents plasma degradation, enabling brain delivery. Via the intravenous route, the nanoparticle-prodrug increases the peptide brain levels by 50% and confers antinociceptive activity on leucine(5)-enkephalin. The nanoparticle-prodrug enables brain delivery by stabilizing the peptide in the plasma although the chitosan amphiphile particles are not transported across the blood-brain barrier per se, and are excreted in the urine.

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Citations

Oct 16, 2013·Peptides·Richard J Bodnar
Apr 6, 2013·Therapeutic Delivery·Dolores Remedios Serrano Lopez, Aikaterini Lalatsa
Mar 8, 2014·Molecular Pharmaceutics·Aikaterini LalatsaIjeoma F Uchegbu
Jan 8, 2013·ACS Nano·Mariarosa MazzaIjeoma F Uchegbu
Nov 24, 2012·Journal of Pharmaceutical Sciences·Ijeoma F Uchegbu, Adeline Siew
Dec 3, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·A LalatsaI F Uchegbu
Apr 16, 2016·Advanced Drug Delivery Reviews·Zhigao NiuMaría J Alonso
Jan 7, 2015·Molecular Pharmaceutics·Dolores R SerranoIjeoma F Uchegbu
Jul 18, 2016·Biochimica Et Biophysica Acta·Nan JiangAntje Willuweit
Oct 12, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Vivek K PawarManish K Chourasia
Feb 16, 2017·Molecular Pharmaceutics·Miriam RolónMaria Auxiliadora Dea-Ayuela
Jun 8, 2017·Drug Development and Industrial Pharmacy·Ožbej ZupančičAndreas Bernkop-Schnürch
Nov 3, 2017·Journal of Drug Targeting·Chun Y WongCrispin R Dass
Jul 20, 2016·Nanoscale Horizons : the Home for Rapid Reports of Exceptional Significance in Nanoscience and Nanotechnolgy·D CrespyK Landfester
Apr 10, 2021·International Journal of Biological Macromolecules·Jixian ZhangHonglei Tian
Jul 30, 2021·Advanced Science·Yuezhou ZhangWei Huang
May 16, 2018·Molecular Pharmaceutics·Lindsay SmithAikaterini Lalatsa

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