title: Molecular complex composed of β-cyclodextrin-grafted Chitosan and pH-sensitive amphipathic peptide for enhancing cellular cholesterol efflux under acidic pH.
abstract: Excess of cholesterol in peripheral cells is known to lead to atherosclerosis. In this study, a molecular complex composed of β-cyclodextrin-grafted chitosan (BCC) and cellular cholesterol efflux enhancing peptide (CEEP), synthesized by modifying pH sensitive amphipathic GALA peptide, is introduced with the eventual aim of treating atherosclerosis. BCC has a markedly enhanced ability to induce cholesterol efflux from cell membranes compared to β-cyclodextrin, and the BCC-CEEP complex exhibited a 2-fold increase in cellular cholesterol efflux compared to BCC alone under weakly acidic conditions. Isothermal titration calorimetry and fluorescence spectroscopy measurements demonstrated that the random coil structure of CEEP at neutral pH converted to the α-helical structure at acidic pH, resulting in a three-order larger binding constant to BCC (K = 3.7 × 10(7) at pH 5.5) compared to that at pH 7.4 (K = 7.9 × 10(4)). Such high-affinity binding of CEEP to BCC at acidic pH leads to the formation of 100-nm-sized aggregate with positive surface charge, which would efficiently interact with cell membranes and induce cholesterol efflux. Since the cholesterol efflux ability of HDL is thought to be impaired under acidic environments in advanced atherosclerotic lesions, the BCC-CEEP complex might serve as a novel nanomaterial for treating atherosclerosis.
authors.affiliation: †Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.|‡International Center for Materials Nanoarchitectonics, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takechi-Haraya
authors.affiliation: †Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: †Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tsuji
authors.affiliation: §TA Instruments Japan, Inc., 5-2-4 Nishi-Gotanda, Shinagawa-ku, Tokyo, 141-0031 Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Asami
authors.affiliation: ‡International Center for Materials Nanoarchitectonics, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.|∥Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-Minami, Tottori 680-8552, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Izawa
authors.affiliation: †Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shigenaga
authors.affiliation: †Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.affiliation: †Institute of Health Biosciences, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Shoumachi, Tokushima 770-8505, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saito
authors.affiliation: ‡International Center for Materials Nanoarchitectonics, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
authors.forename: Kohsaku
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000595:Amino Acid Sequence; D048271:Chitosan / Q000737:chemistry* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D047392:beta-Cyclodextrins; C571277:chitosan-beta-cyclodextrin; D048271:Chitosan; D002784:Cholesterol; C031215:betadex