Enhanced Brain Delivery of the Opioid Peptide DAMGO in Glutathione PEGylated Liposomes: A Microdialysis Study
2013 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 10, no 5, 1533-1541 p.Article in journal (Refereed) Published
Glutathione PEGylated (GSH-PEG) liposomes were evaluated for their ability to enhance and prolong blood-to-brain drug delivery of the opioid peptide DAMGO (H-Tyr-d-Ala-Gly-MePhe-Gly-ol). An intravenous loading dose of DAMGO followed by a 2 h constant rate infusion was administered to rats, and after a washout period of 1 h, GSH-PEG liposomal DAMGO was administered using a similar dosing regimen. DAMGO and GSH-PEG liposomal DAMGO were also administered as a 10 min infusion to compare the disposition of the two formulations. Microdialysis made it possible to determine free DAMGO in brain and plasma, while the GSH-PEG liposomal encapsulated DAMGO was measured with regular plasma sampling. The antinociceptive effect of DAMGO was determined with the tail-flick method. All samples were analyzed using liquid chromatography–tandem mass spectrometry. The short infusion of DAMGO resulted in a fast decline of the peptide concentration in plasma with a half-life of 9.2 ± 2.1 min. Encapsulation in GSH-PEG liposomes prolonged the half-life to 6.9 ± 2.3 h. Free DAMGO entered the brain to a limited extent with a steady state ratio between unbound drug concentrations in brain interstitial fluid and in blood (Kp,uu) of 0.09 ± 0.04. GSH-PEG liposomes significantly increased the brain exposure of DAMGO to a Kp,uu of 0.21 ± 0.17 (p < 0.05). By monitoring the released, active substance in both blood and brain interstitial fluid over time, we were able to demonstrate that GSH-PEG liposomes offer a promising platform for enhancing and prolonging the delivery of drugs to the brain.
Place, publisher, year, edition, pages
2013. Vol. 10, no 5, 1533-1541 p.
drug delivery, nanocarrier, liposomes, blood-brain barrier, microdialysis, pharmacokinetics, antinociception, opioid peptide
Research subject Pharmacokinetics and Drug Therapy
IdentifiersURN: urn:nbn:se:uu:diva-191593DOI: 10.1021/mp300272aISI: 000318669600007PubMedID: 22934681OAI: oai:DiVA.org:uu-191593DiVA: diva2:585904