内皮抑素的多硫酸化肝素修饰及修饰物的二级结构和抗新生血管生成活性研究.docVIP

内皮抑素的多硫酸化肝素修饰及修饰物的二级结构和抗新生血管生成活性研究 谭海宁?, ?，王凤山?*, ? （?山东大学药学院， ?山东大学国家糖工程技术研究中心，山东 济南 250012 fax: 0086-531 E-mail: fswang@sdu.edu.cn） Covalent Modification of Endostatin with Polysulfated Heparin and Their Secondary Structure and Anti-angiogenesis Activity Study Haining Tan?, ?, Yuhong Liu?, ? and Fengshan Wang ?*, ? (Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Science, Shandong University, Jinan, 250012, China, and National Glycoengineering Research Center, Shandong University, Jinan, 250012, China.) ABSTRACT Endostatin (ES) is a 20 kD C-terminal fragment of collagen XVIII that inhibits endothelial cell proliferation, angiogenesis and the growth of several primary tumors. However, some obstacles limit its clinical use, such as need of high dose to maintain its efficacy, expensive, and poor stability, etc. In order to overcome these shortcomings, we chemically modified ES by poly-sulfated heparin (PSH). We studied the inhibitions on endothelial cell proliferation and angiogenesis of ES and its modified product, respectively. The changes of the secondary structure were also studied by Circular dichroism (CD) spectra to obtain better ES derivatives. Our study demonstrated that the modified product has a better heat tolerance than ES and the inhibitions on endothelial cell proliferation and angiogenesis is better than ES. The result of secondary-structure analysis suggested that the percentage of β-turn in the modified product, an important factor on the activity and stability, had little change compared with that of ES. Collectively, these findings demonstrated that the modified product of ES (PSH-ES), with little secondary structure change, has a better heat stability and anti-angiogenesis activity than ES. Introduction New blood vessels nourishing tumor growth form by angiogenesis, which make inhibition of vessel formation an excellent target for cancer therapy. Endostatin (ES) is a specific inhibito