title: Delivery of analgesic peptides to the brain by nano-sized bolaamphiphilic vesicles made of monolayer membranes.
abstract: Inefficient drug delivery to the brain is a major obstacle for pharmacological management of brain diseases. We investigated the ability of bolavesicles - monolayer membrane vesicles self-assembled from synthetic bolaamphiphiles that contain two hydrophilic head groups at each end of a hydrophobic alkyl chain - to permeate the blood-brain barrier and to deliver the encapsulated materials into the brain. Cationic vesicles with encapsulated kyotorphin and leu-enkephalin (analgesic peptides) were prepared from the bolalipids GLH-19 and GLH-20 and studied for their analgesic effects in vivo in experimental mice. The objectives were to determine: (a) whether bolavesicles can efficiently encapsulate analgesic peptides, (b) whether bolavesicles can deliver these peptides to the brain in quantities sufficient for substantial analgesic effect, and to identify the bolavesicle formulation/s that provides the highest analgetic efficiency. The results indicate that the investigated bolavesicles can deliver analgesic peptides across the blood-brain barrier and release them in the brain in quantities sufficient to elicit efficient and prolonged analgesic activity. The analgesic effect is enhanced by using bolavesicles made from a mixture the bolas GLH-19 (that contains non-hydrolyzable acetylcholine head group) and GLH-20 (that contains hydrolysable acetylcholine head group) and by incorporating chitosan pendants into the formulation. The release of the encapsulated materials (the analgesic peptides kyotorphin and leu-enkephalin) appears to be dependent on the choline esterase (ChE) activity in the brain vs. other organs and tissues. Pretreatment of experimental animals with pyridostigmine (the BBB-impermeable ChE inhibitor) enhances the analgesic effects of the studied formulations. The developed formulations and the approach for their controlled decapsulation can serve as a useful modality for brain delivery of therapeutically-active compounds.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Mary
authors.initials: M
authors.lastname: Popov
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Abu Hammad
authors.forename: Tzach
authors.initials: T
authors.lastname: Bachar
authors.forename: Sarina
authors.initials: S
authors.lastname: Grinberg
authors.forename: Charles
authors.initials: C
authors.lastname: Linder
authors.forename: David
authors.initials: D
authors.lastname: Stepensky
authors.forename: Eliahu
authors.initials: E
authors.lastname: Heldman
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002412:Cations; D048271:Chitosan / Q000737:chemistry; D002802:Cholinesterases / Q000378:metabolism; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004723:Endorphins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D005663:Furans / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles; D010146:Pain / Q000188:drug therapy; D010455:Peptides / Q000737:chemistry; D011728:Pyridones / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000700:Analgesics; D002412:Cations; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004723:Endorphins; D005663:Furans; D010455:Peptides; D011728:Pyridones; C543575:bolaamphiphile; C019448:kyotorphin; D004743:Enkephalin, Leucine; D048271:Chitosan; D002802:Cholinesterases
keywords: ACh; Analgesic peptides; BBB; Bolavesicles; Brain delivery of drugs; CF; CS; ChE; DDS; Drug delivery systems; Liposomes; acetylcholine; blood–brain barrier; carboxyfluorescein; chitosan; choline esterase; drug delivery system