Journal
JOURNAL OF CONTROLLED RELEASE
Volume 160, Issue 2, Pages 315-321Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2011.12.042
Keywords
Bolaamphiphiles; Vesicles; Drug delivery systems; Protein delivery; Blood-brain barrier; Brain
Funding
- Israel Science Foundation [973/11]
- Goldman Faculty Fund for Medical Research in Community Health (from the Faculty of Health Sciences, Ben-Gurion University of the Negev)
- US-Israel Binational Science Foundation [2003153]
- Ben-Gurion University of the Negev
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Bolaamphiphilic cationic vesicles with acetylcholine (ACh) surface groups were investigated for their ability to deliver a model protein-bovine serum albumin conjugated to fluorescein isothiocyanate (BSA-FITC) across biological barriers in vitro and in vivo. BSA-FITC-loaded vesicles were internalized into cells in culture, including brain endothelial b.End3 cells, at 37 C, but not at 4 degrees C, indicating an active uptake process. To examine if BSA-FITC-loaded vesicles were stable enough for in vivo delivery, we tested vesicle stability in whole serum. The half-life of cationic BSA-FITC-loaded vesicles with ACh surface groups that are hydrolyzed by choline esterase (ChE) was about 2 h, whereas the half-life of vesicles with similar surface groups, but which are not hydrolyzed by choline esterase (ChE), was over 5 h. Pyridostigmine, a choline esterase inhibitor that does not penetrate the blood-brain barrier (BBB), increased the stability of the ChE-sensitive vesicles to 6 h but did not affect the stability of vesicles with ACh surface groups that are not hydrolyzed by ChE. Following intravenous administration to pyridostigmine-pretreated mice, BSA-FITC encapsulated in ChE-sensitive vesicles was distributed into various tissues with marked accumulation in the brain, whereas non-encapsulated (free) BSA-FITC was detected only in peripheral tissues, but not in the brain. These results show that cationic bolaamphiphilic vesicles with ACh head groups are capable of delivering proteins across biological barriers, such as the cell membrane and the blood-brain barrier (BBB). Brain ChE activity destabilizes the vesicles and releases the encapsulated protein, enabling its accumulation in the brain. (C) 2012 Elsevier B. V. All rights reserved.
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