peg为载灯盏乙素前药的合成及生物活性的研究.pdfVIP

摘 要 灯盏乙素(Breviscapin)是菊科植物灯盏细辛(Erigeron breviscapus)的提取 物, 主要有效成分为灯盏乙素(Scutellarin), 即4’，5, 6-三羟基黄酮-7-葡糖醛酸 苷。灯盏乙素具有扩张血管、增加心脏冠脉流量、增加脑血流量、降低脑血管阻力、 提高血脑屏障通透性以及对抗由二磷酸腺苷引起的血小板凝集作用，已用于临床多 年。但灯盏乙素难溶于水，口服生物半衰期短，绝对生物利用度低，临床应用需大 剂量多次给药才能达到治疗目的，不能维持有效血药浓度而发挥持久治疗功效。 前药的设计已应用于众多的治疗领域以改善药物的药理特性。这项技术已被延 伸应用到小分子药物的平台领域。目前采用聚乙二醇与灯盏花相连来改善药物的特 性引起较大的关注。聚乙二醇是线性分子，具有不宜降解、无毒、非免疫原性等特 点被广泛应用于蛋白质和小分子药物的修饰。前药的设计可有效地解决某些药物的 水溶性和稳定性问题,提高生物利用度和降低毒副作用。 聚乙二醇以良好的水溶性、无毒、良好的生物相容性和无免疫原性等其他高分 子无法比拟的优点,在前药的合成和制备中占有重要地位。由于PEG的无毒特性及良 好的生物相容性，PEG是被FDA批准的极少数能作为体内注射药用的合成聚合物之一。 为此，我们采用的研究方法是用聚乙二醇来修饰灯盏乙素，来增加水溶性和延 长半衰期等特性来改善它自身的缺陷，为此我们合成了一系列不同分子量的灯盏花 前药，并对这些化合物进行了结构表征，这些前药的理化性质及生物活性正在测试 中。 关键词：聚乙二醇化；灯盏乙素；前药；生物活性 I Abstract Scutellarin is an active ingredient extracted from Erigeron breviscapus, a traditional Chinese medicine. Pharmacological study showed that scutellarin could significantly reduce the blood viscosity, improve the blood flow, decrease the vascular resistance, inhibit the platelet aggregation and the thrombosis induced by cerebrovascular accidents, Although commonly used as an oral agent, the low solubility of scutellarin in water leads to its poor bioavailability. The use of prodrug design has been applied to numerous therapeutic areas with the goal to improving the pharmacologic properties of drugs. This technology has also been extenged into small molecule prodrug platforms. One methodology that has received only sparse consideration is the conjugation of scrtellarin toPEG. It is a linear amphiphilic polymer that is nonbiodegradable, nontoxic, and nonimmunogenic and has been widely studied for both protein and small molecule modification. PEG has been extensively utilized due to its ability to increase th