title: In vitro evaluation of 2-hydroxyalkylated β-cyclodextrins as potential therapeutic agents for Niemann-Pick Type C disease.
abstract: This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-β-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥8mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated β-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxybutyl-β-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD≫HPBCD>HEBCD, HBBCD=HPBCD>HEBCD and HBBCD≫HPBCD=HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease.
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tokumaru
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishitsuka
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Taguchi
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Sanin Rosai Hospital, 1-8-1, Kaikeshinden, Yonago 683-8605, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan. Electronic address: tirie@gpo.kumamoto-u.ac.jp.
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002352:Carrier Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol
keywords: Cholesterol; Hydroxypropyl-β-cyclodextrin; Lysosomal storage disease; Niemann-Pick Type C