title: Development of PEGylated Cysteine-Modified Lysine Dendrimers with Multiple Reduced Thiols To Prevent Hepatic Ischemia/Reperfusion Injury.
abstract: To inhibit hepatic ischemia/reperfusion injury, we developed polyethylene glycol (PEG) conjugated (PEGylated) cysteine-modified lysine dendrimers with multiple reduced thiols, which function as scavengers of reactive oxygen species (ROS). Second, third, and fourth generation (K2, K3, and K4) highly branched amino acid spherical lysine dendrimers were synthesized, and cysteine (C) was conjugated to the outer layer of these lysine dendrimers to obtain K2C, K3C, and K4C dendrimers. Subsequently, PEG was reacted with the C residues of the dendrimers to obtain PEGylated dendrimers with multiple reduced thiols (K2C-PEG, K3C-PEG, and K4C-PEG). Radiolabeled K4C-PEG ((111)In-K4C-PEG) exhibited prolonged retention in the plasma, whereas (111)In-K2C-PEG and (111)In-K3C-PEG rapidly disappeared from the plasma. K4C-PEG significantly prevented the elevation of plasma alanine aminotransferase (ALT) activity, an index of hepatocyte injury, in a mouse model of hepatic ischemia/reperfusion injury. In contrast, K2C-PEG, K3C-PEG, l-cysteine, and glutathione, the latter two of which are classical reduced thiols, hardly affected the plasma ALT activity. These findings indicate that K4C-PEG with prolonged circulation time is a promising compound to inhibit hepatic ischemia/reperfusion injury.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Makiya
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Rikiya
authors.initials: R
authors.lastname: Hirosaki
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.|Department of Chemistry, Dokkyo Medical University , Shimotsuga-gun, Tochigi 321-0293, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.|Department of Pharmaceutical Informatics, Graduate School of Biomedical Sciences, Nagasaki University , Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D003545:Cysteine / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry* / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000737:chemistry*; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D050091:Dendrimers; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D011092:Polyethylene Glycols; D008239:Lysine; D003545:Cysteine
keywords: PEGylation; cysteine; dendrimer; drug delivery; hepatic ischemia/reperfusion injury; reactive oxygen species; thiol