title: Delivery of serotonin to the brain by monocytes following phagocytosis of liposomes.
abstract: Many drugs are not able to enter the brain due to the presence of the blood-brain barrier (BBB) and therefore cannot be used in the treatment of diseases of the brain. Since it is now known that the brain is under immunological surveillance, we hypothesized that phagocytic cells of the innate immune system, mainly neutrophils and monocytes, can be exploited as transporters of drugs to the brain. To target circulating mononuclear phagocytic cells, negatively-charged nano-sized liposomes were formulated encapsulating serotonin, a BBB impermeable neurological drug. Brain uptake, biodistribution, and the mechanism of brain transport were examined in vitro and in rats and rabbits by utilizing double-radiolabeled (3)H (in the membrane) and (14)C-serotonin (in the core), and liposomes with fluorescent markers (membrane and core). The brain uptake of liposomal serotonin was significantly higher (0.138%+/-0.034 and 0.097%+/-0.011, vs. 0.068%+/-0.02 and 0.057%+/-0.01, 4 h and 24 h after IV administration in rats, serotonin liposomes and in solution, respectively). The same brain uptake of both empty and serotonin liposomes, the co-localization in the brain of both markers, and the unchanged ratio of (3)H:(14)C suggest that intact liposomes entered the brain. Since treatment of animals by liposomal alendronate resulted with inhibition of monocytes but not of neutrophils, and with no brain delivery, it is suggested that monocytes are the main transporters of liposomes to the brain.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Afergan
authors.forename: Hila
authors.initials: H
authors.lastname: Epstein
authors.forename: Rachel
authors.initials: R
authors.lastname: Dahan
authors.forename: Nickolay
authors.initials: N
authors.lastname: Koroukhov
authors.forename: Keren
authors.initials: K
authors.lastname: Rohekar
authors.forename: Haim D
authors.initials: HD
authors.lastname: Danenberg
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002465:Cell Movement / Q000502:physiology; D002784:Cholesterol / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology*; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000008:administration & dosage* / Q000378:metabolism; D018490:Serotonin Agents / Q000008:administration & dosage / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D008081:Liposomes; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D018490:Serotonin Agents; D012701:Serotonin; C084352:distearoyl phosphatidylglycerol; D002784:Cholesterol; C010942:1,2-distearoyllecithin