In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes.
OBJECTIVE
The purpose of this study was to evaluate formulation factors causing improvement in brain delivery of a small peptide after encapsulation into a targeted nanocarrier in vivo.


METHODS
The evaluation was performed in rats using microdialysis, which enabled continuous sampling of the released drug in both the brain (striatum) and blood. Uptake in brain could thereby be studied in terms of therapeutically active, released drug.


RESULTS
We found that encapsulation of the peptide DAMGO in fast-releasing polyethylene glycol (PEG)ylated liposomes, either with or without the specific brain targeting ligand glutathione (GSH), doubled the uptake of DAMGO into the rat brain. The increased brain delivery was observed only when the drug was encapsulated into the liposomes, thus excluding any effects of the liposomes themselves on the blood-brain barrier integrity as a possible mechanism. The addition of a GSH coating on the liposomes did not result in an additional increase in DAMGO concentrations in the brain, in contrast to earlier studies on GSH coating. This may be caused by differences in the characteristics of the encapsulated compounds and the composition of the liposome formulations.


CONCLUSIONS
We were able to show that encapsulation into PEGylated liposomes of a peptide with limited brain delivery could double the drug uptake into the brain without using a specific brain targeting ligand.
Department of Pharmaceutical Biosciences, Translational PKPD Research Group, Associate member of SciLife Lab, Uppsala University, Box 591, Uppsala, SE-75124, Sweden.
Annika
A
Lindqvist
to-BBB technologies BV, J. H. Oortweg 19, 2333 CH, Leiden, The Netherlands.
Jaap
J
Rip
to-BBB technologies BV, J. H. Oortweg 19, 2333 CH, Leiden, The Netherlands.
Joan
J
van Kregten
to-BBB technologies BV, J. H. Oortweg 19, 2333 CH, Leiden, The Netherlands.
Pieter J
PJ
Gaillard
Department of Pharmaceutical Biosciences, Translational PKPD Research Group, Associate member of SciLife Lab, Uppsala University, Box 591, Uppsala, SE-75124, Sweden. mhu@farmbio.uu.se.
Margareta
M
Hammarlund-Udenaes
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004337:Drug Carriers; D004339:Drug Compounding; D016503:Drug Delivery Systems; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005978:Glutathione / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D011092:Polyethylene Glycols; D005978:Glutathione
blood–brain barrier; brain delivery; liposomes; microdialysis; opioid peptide