PEGylation of Protein Drugs utilizing the Complexation with Cyclodextrin

本研究的目的是通过环糊精（CyD）和客体分子修饰聚乙二醇（PEG）的相互作用设计蛋白质的可逆聚乙二醇化。首先，我们制备了葡萄糖醛基葡萄糖基- - cyd （GUG- - cyd）胰岛素偶联物。与单独使用胰岛素相比，该缀合物的热稳定性和酶稳定性得到了改善。然而，胰岛素的降糖作用由于与GUG- - cyd结合而丧失。接下来，我们制备了胰岛素与客体分子（金刚烷）的偶联物，与完整的胰岛素相比，该偶联物保持了活性。此外，超分子聚乙二醇化胰岛素，包括胰岛素/金刚烷缀合物和聚乙二醇化-CyD，与单独胰岛素和胰岛素/金刚烷缀合物相比，显示出持久的降糖作用。结果表明，超分子聚乙二醇化增加了蛋白质药物的循环半衰期而不丧失活性。

The purpose of this study is to design the reversible PEGylation of proteins throughthe interaction of cyclodextrin (CyD) and guest-molecule modified polyethylene glycol(PEG). First, we prepared the insulin conjugate with glucuronylglucosyl- -CyD (GUG- -CyD). Thermostability and enzymatic stability of the conjugate were improved compared toinsulin alone. However, the hypoglycemic effect of the insulin was lost by theconjugation with GUG- -CyD.Next, we prepared insulin conjugate with guest-molecule (adamantane), and thisconjugate retained the activity compared to intact insulin. In addition, supramolecularPEGylated insulin, consisting insulin/adamantine conjugate and PEGylated -CyD showedprolonged hypoglycemic effect compared to insulin alone and insulin/adamantineconjugate.The results suggest that supramolecular PEGylation increases circulating half-life ofprotein drugs without loss of the activity.