title: Transcytosis-Targeting Peptide: A Conductor of Liposomal Nanoparticles through the Endothelial Cell Barrier.
abstract: The ultimate goal in the area of drug-delivery systems is the development of a nanoparticle that can penetrate the endothelial cell monolayer for the targeting of tissue parenchyma. In the present study, we identify a transcytosis-targeting peptide (TTP) that permits polyethyleneglycol (PEG)-modified liposomes (PEG-LPs) to penetrate through monolayers of brain-derived endothelial cells. These endothelial cells were layered on a gelatin nanofiber sheet, a nanofiber meshwork that allows the evaluation of transcellular transport of nanosized particles (ca. 100 nm). Systematic modification of the sequences results in the identification of the consensus sequence of TTP as L(R/K)QZZZL, where Z denotes hydrophilic amino acids (R/K/S and partially D). The TTP-modified liposomes are bound on the heparin sulfate proteoglycan, and are then taken up via lipid raft-mediated endocytosis. Subsequent intracellular imaging of the particles reveals a unique intracellular sorting of TTP-modified PEG liposomes (TTP-PEG-LPs); namely the TTP-LPs are not localized with the lysosomes, whereas this co-localization is dominant in the unmodified PEG liposomes (PEG-LPs). The in vivo endothelial penetration of liposomes in adipose tissue is conferred by the dual modification of the particles with TTP and tissue-targeting ligands. This technology promises innovations in intravenously available delivery system to tissue parenchyma.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita12 Nishi6, Kita-ku, Sapporo City, Hokkaido, 060-0812, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita12 Nishi6, Kita-ku, Sapporo City, Hokkaido, 060-0812, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita12 Nishi6, Kita-ku, Sapporo City, Hokkaido, 060-0812, Japan.
authors.forename: Sarochin
authors.initials: S
authors.lastname: Santiwarangkool
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita12 Nishi6, Kita-ku, Sapporo City, Hokkaido, 060-0812, Japan.
authors.forename: Nazir
authors.initials: N
authors.lastname: Hossen
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita12 Nishi6, Kita-ku, Sapporo City, Hokkaido, 060-0812, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kajimoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita12 Nishi6, Kita-ku, Sapporo City, Hokkaido, 060-0812, Japan.
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Sayed
authors.affiliation: Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita12 Nishi6, Kita-ku, Sapporo City, Hokkaido, 060-0812, Japan.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D057139:Nanofibers / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D054457:Tissue Scaffolds / Q000737:chemistry; D057900:Transcytosis / Q000187:drug effects*
chemical_list: D008024:Ligands; D008081:Liposomes; D010455:Peptides; D011092:Polyethylene Glycols
keywords: biofunctional materials; biosystems; liposomes; nanoparticles; peptides