Zhao Hong, Greenwald Richard B, Reddy Prasanna, Xia Jing, Peng Ping
Enzon Pharmaceuticals Inc., 20 Kingsbridge Road, Piscataway, New Jersey 08854, USA.
Bioconjug Chem. 2005 Jul-Aug;16(4):758-66. doi: 10.1021/bc049804k.
The oligonucleotide (oligo, ODN), Genasense (GS), an ODN currently waiting for FDA approval, was chosen as a model and modified with a 5' or 3' aminohexyl functionality (1 and 4, respectively) using solid-state synthesis. These amino derivatives were reacted with different releasable PEGs (rPEGs). The in vitro results of the PEG-modified oligos (Table 1) clearly show a substantial increase in rat plasma half-life and enhanced stability against a variety of nucleases, especially the predominant nuclease (PEII) in mammals, which is the main source of oligo degradation in cells. The advantage of using a PEG prodrug approach was further demonstrated by the pharmacokinetic (PK) results, which exhibited much greater C(max), plasma half-life, and area under the curve (AUC) for 3 compared to unmodified GS. A key step in the synthesis of ODN prodrug conjugates with a dye label was also accomplished successfully by employing dihydropyran derivatives of alcohols and acids as orthogonal protecting groups during the synthesis.
寡核苷酸（oligo，ODN）Genasense（GS）是一种目前正在等待美国食品药品监督管理局（FDA）批准的ODN，被选作模型，并使用固相合成法分别在5'或3'端引入氨基己基官能团（分别为1和4）进行修饰。这些氨基衍生物与不同的可释放聚乙二醇（rPEGs）反应。聚乙二醇修饰寡核苷酸的体外实验结果（表1）清楚地表明，大鼠血浆半衰期显著延长，并且对多种核酸酶，尤其是哺乳动物中主要的核酸酶（PEII，细胞中寡核苷酸降解的主要来源）的稳定性增强。药代动力学（PK）结果进一步证明了使用聚乙二醇前药方法的优势，与未修饰的GS相比，化合物3的C(max)、血浆半衰期和曲线下面积（AUC）都要大得多。在合成带有染料标记的ODN前药缀合物时，通过在合成过程中使用醇和酸的二氢吡喃衍生物作为正交保护基团，也成功完成了一个关键步骤。
