title: Role of Phosphatidylserine-Derived Negative Surface Charges in the Recognition and Uptake of Intravenously Injected B16BL6-Derived Exosomes by Macrophages.
abstract: Exosomes are cell-derived extracellular vesicles that function as intercellular delivery carriers. Our previous study demonstrated that macrophages in the liver contributed to the rapid clearance of intravenously administered B16BL6-derived exosomes from the systemic circulation in mice. Phosphatidylserine (PS) may be responsible for this clearance because it is exposed on the surface of exosomes and is recognized by macrophages. In this study, the role of PS exposed on the membranes of exosomes in the uptake of B16BL6-derived exosomes by macrophages was investigated. Negatively charged PS- or phosphatidylglycerol-loaded liposomes suppressed the cellular uptake of PKH67-labeled exosomes by macrophages, whereas phosphatidylcholine-containing liposome did not affect uptake. Subsequently, for the in vivo analysis, exosomes were labeled with Gaussia luciferase, a reporter protein, or (3-125I-iodobenzoyl)norbiotinamide using exosome-tropic fusion proteins comprising the exosome-tropic protein lactadherin. The blood clearance of Gaussia luciferase-labeled exosomes after intravenous injection into mice was significantly delayed by the preinjection of PS- or phosphatidylglycerol-containing liposomes. Moreover, the accumulation of (3-125I-iodobenzoyl)norbiotinamide-labeled exosomes in the liver was decreased by the preinjection of PS-containing liposomes. These results indicate that the negative charge of PS in exosomal membranes is involved in the recognition and clearance of intravenously injected exosomes by macrophages.
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: ytakahashi@pharm.kyoto-u.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Makiya
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Morishita
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Chonlada
authors.initials: C
authors.lastname: Charoenviriyakul
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Takakura
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055354:Exosomes / Q000378:metabolism*; D007275:Injections, Intravenous; D008081:Liposomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010718:Phosphatidylserines / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D008081:Liposomes; D010718:Phosphatidylserines
keywords: clearance; lipids; nanoparticles; pharmacokinetics; phospholipids; physicochemical; static charge