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Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their...

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Autores principales: Lewicky, Jordan D., Fraleigh, Nya L., Martel, Alexandrine L., Nguyen, Thi M.-D., Schiller, Peter W., Mousavifar, Leila, Roy, René, Le, Anh Dzung, Funk, Douglas, Le, Hoang-Thanh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348236/
https://www.ncbi.nlm.nih.gov/pubmed/34360762
http://dx.doi.org/10.3390/ijms22157996
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author Lewicky, Jordan D.
Fraleigh, Nya L.
Martel, Alexandrine L.
Nguyen, Thi M.-D.
Schiller, Peter W.
Mousavifar, Leila
Roy, René
Le, Anh Dzung
Funk, Douglas
Le, Hoang-Thanh
author_facet Lewicky, Jordan D.
Fraleigh, Nya L.
Martel, Alexandrine L.
Nguyen, Thi M.-D.
Schiller, Peter W.
Mousavifar, Leila
Roy, René
Le, Anh Dzung
Funk, Douglas
Le, Hoang-Thanh
author_sort Lewicky, Jordan D.
collection PubMed
description Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.
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spelling pubmed-83482362021-08-08 Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes Lewicky, Jordan D. Fraleigh, Nya L. Martel, Alexandrine L. Nguyen, Thi M.-D. Schiller, Peter W. Mousavifar, Leila Roy, René Le, Anh Dzung Funk, Douglas Le, Hoang-Thanh Int J Mol Sci Article Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS. MDPI 2021-07-27 /pmc/articles/PMC8348236/ /pubmed/34360762 http://dx.doi.org/10.3390/ijms22157996 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lewicky, Jordan D.
Fraleigh, Nya L.
Martel, Alexandrine L.
Nguyen, Thi M.-D.
Schiller, Peter W.
Mousavifar, Leila
Roy, René
Le, Anh Dzung
Funk, Douglas
Le, Hoang-Thanh
Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
title Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
title_full Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
title_fullStr Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
title_full_unstemmed Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
title_short Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
title_sort improving the utility of a dynorphin peptide analogue using mannosylated glycoliposomes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348236/
https://www.ncbi.nlm.nih.gov/pubmed/34360762
http://dx.doi.org/10.3390/ijms22157996
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