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In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes



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.


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.


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.


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.

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Blood–brain barrier


Bovine serum albumin


Egg-yolk phosphatidylcholine




Hydrogenated soy phosphatidylcholine


Polydispersity index


Polyethylene glycol

Kp,uu :

Unbound brain-to-plasma concentration ratio at steady state


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Acknowledgments and Disclosures

The authors acknowledge the excellent technical assistance of Britt Jansson and Jessica Dunhall (Department of Pharmaceutical Biosciences, Uppsala University, Sweden) and editorial assistance of Corine Visser (to-BBB technologies BV, Leiden, the Netherlands). The Department of Pharmaceutical Sciences at Uppsala University carried the cost for the animal work and analytics and to-BBB technologies provided the DAMGO infusion solutions. Drs J Rip, J van Kregten and PJ Gaillard were employees of to-BBB technologies BV and Dr. Gaillard held founder shares in to-BBB holding BV.

Compliance with Ethical Standards

All procedures involving animals performed in the study were in accordance with the ethical standards of the institution and approved by the Uppsala Regional Animal Ethics Committee, Uppsala, Sweden (C328/10).

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Correspondence to Margareta Hammarlund-Udenaes.

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Lindqvist, A., Rip, J., van Kregten, J. et al. In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes. Pharm Res 33, 177–185 (2016).

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