Development of PEGylated Cysteine-Modified Lysine Dendrimers with Multiple Reduced Thiols To Prevent Hepatic Ischemia/Reperfusion Injury

详细信息    查看全文

• 作者：Hidemasa Katsumi ; Makiya Nishikawa ; Rikiya Hirosaki ; Tatsuya Okuda ; Shigeru Kawakami ; Fumiyoshi Yamashita ; Mitsuru Hashida ; Toshiyasu Sakane ; Akira Yamamoto
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：August 1, 2016
• 年：2016
• 卷：13
• 期：8
• 页码：2867-2873
• 全文大小：362K
• 年卷期：0
• ISSN：1543-8392

文摘

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.