title: Enhanced gene transfection in macrophages by histidine-conjugated mannosylated cationic liposomes.
abstract: Targeted gene delivery to macrophages is important for the treatments of various immune diseases. Since macrophages express mannose receptors, development of efficient mannosylated non-viral carriers is an effective approach to macrophages-selective in vivo gene transfection. In this study, a pH-sensitive mannosylated cholesterol derivative, Man-His-C4-Chol, which possesses histidine (His) residues, containing lipoplexes (Man-His-lipoplexes) was characterized for transfection both in vitro and in vivo. In primary cultured macrophages, both Man-His-lipoplexes and mannosylated (Man)-lipoplexes showed significantly higher cellular uptake than bare-lipoplexes and there was no significant difference between Man-His-lipoplexes and Man-lipoplexes at 37 degrees C but the cellular uptake of these three lipoplexes was reduced at 4 degrees C. Similarly, the transfection efficacy of Man-His-lipoplexes showed significantly higher gene expression than bare-lipoplexes and Man-lipoplexes. After intraperitoneal administration to mice, Man-His-lipoplexes showed higher gene expression in peritoneally exuded cells (PECs) which contained macrophages than Man-lipoplexes and bare-lipoplexes at 3, 6, and 24 h. In addition, Man-His-lipoplexes showed higher gene expression than Gal-His-lipoplexes in PECs, suggesting that Man-His-lipoplexes are taken up by macrophages via mannose receptor-mediated endocytosis. These results suggest that Man-His-lipoplexes have superior transfection activity to Man-lipoplexes in macrophages.
authors.affiliation: Department of Drug Delivery Research, Kyoto University, Yoshida, Sakyo-ku, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kuramoto
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Mukai
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000818:Animals; D002412:Cations; D002478:Cells, Cultured; D018014:Gene Transfer Techniques / Q000639:trends; D006639:Histidine / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008358:Mannose / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008813:Mice, Inbred ICR; D014162:Transfection / Q000379:methods*
chemical_list: D002412:Cations; D008081:Liposomes; D006639:Histidine; D008358:Mannose