title: Preparation of hydrophilic C60(OH)10/2-hydroxypropyl-β-cyclodextrin nanoparticles for the treatment of a liver injury induced by an overdose of acetaminophen.
abstract: Stable hydrophilic C60(OH)10 nanoparticles were prepared from 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and applied to the treatment of an acetaminophen overdose induced liver Injury. C60(OH)10 nanoparticles were produced by cogrinding α-CD, β-CD, γ-CD and HP-β-CD and characterized in terms of solubility, mean particle diameter, ζ-potential and long term dispersibility in water. Hydrophilic C60(OH)10 nanoparticles with particle sizes less than 50 nm were effectively produced by cogrinding HP-β-CD with C60(OH)10 at a molar ratio of 1:3 (C60(OH)10:CD). The resulting C60(OH)10/HP-β-CD nanoparticles were stable in water and showed no aggregation over a 1 month period. The C60(OH)10/CDs nanoparticles scavenged not only free radicals (DPPH and ABTS radicals) but also reactive oxygen species (O2(•-) and •OH). When C60(OH)10/HP-β-CD nanoparticles were intraperitoneally administered to mice with a liver injury induced by an overdose of acetaminophen (APAP), the ALT and AST levels were markedly reduced to almost the same level as that for normal mice. Furthermore, the administration of the nanoparticles prolonged the survival rate of liver injured mice, while all of the mice that were treated with APAP died within 40 h. To reveal the mechanism responsible for liver protection by C60(OH)10 nanoparticles, GSH level, CYP2E1 expression and peroxynitrite formation in the liver were assessed. C60(OH)10/HP-β-CD nanoparticles had no effect on CYP2E1 expression and GSH depletion, but suppressed the generation of peroxynitrite in the liver. The findings indicate that the protective effect of C60(OH)10/HP-β-CD nanoparticles was due to the suppression of oxidative stress in mitochondria, as the result of scavenging ROS such as O2(•-), NO and peroxynitrite, which act as critical mediators in the liver injuries.
authors: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
authors: Yoshitaka
authors: Y
authors: Umezaki
authors: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
authors: Daisuke
authors: D
authors: Iohara
authors: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
authors: Makoto
authors: M
authors: Anraku
authors: Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Yoichi
authors: Y
authors: Ishitsuka
authors: Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Tetsumi
authors: T
authors: Irie
authors: DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
authors: Kaneto
authors: K
authors: Uekama
authors: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan. Electronic address: fhira@ph.sojo-u.ac.jp.
authors: Fumitoshi
authors: F
authors: Hirayama
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000082:Acetaminophen; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry; D001713:Biphenyl Compounds / Q000737:chemistry; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D062787:Drug Overdose; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000737:chemistry; D037741:Fullerenes / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000627:therapeutic use* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D030421:Peroxynitrous Acid / Q000378:metabolism; D010851:Picrates / Q000737:chemistry; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D012995:Solubility; D055672:Static Electricity; D013451:Sulfonic Acids / Q000737:chemistry; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D052160:Benzothiazoles; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D037741:Fullerenes; D010851:Picrates; D020011:Protective Agents; D013451:Sulfonic Acids; D047392:beta-Cyclodextrins; D030421:Peroxynitrous Acid; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D000082:Acetaminophen; D014443:Tyrosine; C004931:1,1-diphenyl-2-picrylhydrazyl; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione
keywords: Acetaminophen; Antioxidant; Cyclodextrin; Liver; Nanoparticle; Polyhydroxylated fullerene