Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes

Autor: Anh D. Lê, Alexandrine L. Martel, Leila Mousavifar, Jordan D. Lewicky, Hoang-Thanh Le, Thi M.-D. Nguyen, René Roy, Douglas Funk, Nya L. Fraleigh, Peter W. Schiller
Jazyk: angličtina
Rok vydání: 2021
Předmět:
kappa opioid receptor antagonist
QH301-705.5
dynantin
Dynorphin
Pharmacology
Blood–brain barrier
blood–brain barrier
Dynorphins
κ-opioid receptor
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
0302 clinical medicine
In vivo
glycoliposome
Humans
Medicine
Distribution (pharmacology)
Biology (General)
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
Spectroscopy
030304 developmental biology
0303 health sciences
business.industry
Receptors
Opioid
kappa
Organic Chemistry
Antagonist
targeted delivery
General Medicine
Corpus Striatum
peptide
3. Good health
Computer Science Applications
Chemistry
medicine.anatomical_structure
Targeted drug delivery
CNS therapeutic
Liposomes
Nasal administration
addiction
dopamine
Peptides
business
030217 neurology & neurosurgery
neurotransmitter
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 15
International Journal of Molecular Sciences, Vol 22, Iss 7996, p 7996 (2021)
ISSN: 1422-0067
DOI: 10.3390/ijms22157996
Popis: 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.
Databáze: OpenAIRE
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