title: Delivery of proteins to the brain by bolaamphiphilic nano-sized vesicles.
abstract: 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 °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.
authors.affiliation: Department of Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.
authors.forename: George R
authors.initials: GR
authors.lastname: Dakwar
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Abu Hammad
authors.forename: Mary
authors.initials: M
authors.lastname: Popov
authors.forename: Charles
authors.initials: C
authors.lastname: Linder
authors.forename: Sarina
authors.initials: S
authors.lastname: Grinberg
authors.forename: Eliahu
authors.initials: E
authors.lastname: Heldman
authors.forename: David
authors.initials: D
authors.lastname: Stepensky
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002417:Cattle; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D042783:Endothelial Cells / Q000378:metabolism; D005663:Furans / Q000737:chemistry*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000737:chemistry*; D011728:Pyridones / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D005663:Furans; D011728:Pyridones; C543575:bolaamphiphile; D012710:Serum Albumin, Bovine