Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783735291679342592 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8348236 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT lewickyjordand improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT fraleighnyal improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT martelalexandrinel improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT nguyenthimd improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT schillerpeterw improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT mousavifarleila improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT royrene improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT leanhdzung improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT funkdouglas improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes AT lehoangthanh improvingtheutilityofadynorphinpeptideanalogueusingmannosylatedglycoliposomes |