title: Effect of mannose density on mannose receptor-mediated cellular uptake of mannosylated O/W emulsions by macrophages.
abstract: Carbohydrate grafted emulsions are one of the most promising cell-specific targeting systems for lipophilic drugs. We have previously reported that mannosylated (Man-) emulsions composed of soybean oil, EggPC and cholesten-5-yloxy-N-(4-((1-imino-2-d-thiomannosylethyl)amino)alkyl)formamide (Man-C4-Chol) with a ratio of 70:25:5 were significantly delivered to liver non-parenchymal cells (NPC) via mannose receptor-mediated mechanism after intravenous administration in mice. Since the efficient targeting through a receptor-mediated mechanism is largely controlled by ligand-receptor interaction, the effect of mannose density on Man-emulsions was studied with regard to both the disposition in vivo in mice and the uptake in vitro, using elicited macrophages which express a number of mannose receptors. After intravenous injection, Man-emulsions with 5.0% (Man-5.0-emulsions) and 7.5% (Man-7.5-emulsions) of Man-C4-Chol were rapidly eliminated from the blood circulation and preferentially accumulated in the liver-NPC compared with Man-emulsions with 2.5% of Man-C4-Chol (Man-2.5-emulsions) and bare emulsions (Bare-emulsions). The in vitro study showed increased internalization of Man-5.0- and Man-7.5-emulsions and significant inhibition of uptake in the presence of mannan. The enhanced uptake of Man-emulsions was related to the increasing of Man-C4-Chol content that corresponded to confocal microscopy study. These results suggest that the mannose density of Man-emulsions plays an important role in both cellular recognition and internalization via a mannose receptor-mediated mechanism.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Wassana
authors.initials: W
authors.lastname: Yeeprae
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000818:Animals; D019540:Area Under Curve; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D004655:Emulsions; D007275:Injections, Intravenous; D037181:Lectins, C-Type / Q000737:chemistry*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008358:Mannose / Q000737:chemistry* / Q000493:pharmacokinetics*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000737:chemistry*; D051379:Mice; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D011956:Receptors, Cell Surface / Q000737:chemistry*
chemical_list: D004655:Emulsions; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D008358:Mannose