PEG比率
树枝状大分子
化学
聚乙二醇
半胱氨酸
再灌注损伤
谷胱甘肽
生物化学
赖氨酸
缺血
药理学
氨基酸
酶
内科学
医学
经济
财务
作者
Hidemasa Katsumi,Makiya Nishikawa,Rikiya Hirosaki,Takatoshi Okuda,Shigeru Kawakami,Fumiyoshi Yamashita,Mitsuru Hashida,Toshiyasu Sakane,Akira Yamamoto
标识
DOI:10.1021/acs.molpharmaceut.6b00557
摘要
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 (111In-K4C–PEG) exhibited prolonged retention in the plasma, whereas 111In-K2C–PEG and 111In-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.
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