基于乳粘素类似物的PS靶向性探针18F- (cLac2-C)2的合成及肿瘤凋亡分子成像研究

项目名称： 基于乳粘素类似物的PS靶向性探针18F- (cLac2-C)2的合成及肿瘤凋亡分子成像研究

项目编号： No.81201125

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 影像医学与生物医学工程

项目作者： 卜丽红

作者单位： 哈尔滨医科大学

项目金额： 23万元

中文摘要： 诱导细胞发生凋亡是肿瘤治疗，尤其是分子靶向治疗的重要分子机制，所以活体检测细胞凋亡意义重大。目前临床尝试应用的99mTc-膜联蛋白V检测方法存在诸多缺欠：①钙离子依赖；②生物学分布特性不佳；③可与磷脂酰乙醇胺结合而出现假阳性等等 ，故寻找一种理想的临床精确检测肿瘤细胞凋亡的新方法已成为重大科研命题。前期研究表明：乳粘素与凋亡蛋白磷脂酰丝氨酸（PS）结合的特性明显优于膜联蛋白V。预实验合成了乳粘素类似物cLac2-C，并构建了PS靶向的小分子探针Cy5.5-cLac2-C和64Cu-cLac2-C，结果表明其靶向性和特异性很高，体内显像效果非常好。本项目拟通过"二聚化"技术进一步优化并合成18F-（cLac2-C）2，建立一种非钙离子依赖、生物学分布特性更佳，更准确的PET凋亡成像方法。这将为深入研究肿瘤发生发展机制、早期检测肿瘤治疗疗效提供新的方法，并将在凋亡成像临床转化方面实现重大突破。

中文关键词： 乳粘素；磷脂酰丝氨酸；细胞凋亡；正电子发射断层成像；分子成像

英文摘要： Induction of apoptosis is the primary mechnasim through which most anti-tumor therapies ,especially molecular targeting therapy, cause tumor cell death, so assessment of apoptosis in vivo is very important and meaningful. 99mTc-Annexin V is the most intensively studied apoptosis detection probe in clinical trial. It is limited for further clinical use because of its suboptimal pharmacokinetics ,micro molar concentration Ca2+ dependent and enhanced binding to membranes containing phosphatidylethanolamine，which result in false positive detection. However, to date, the goal of imaging the apoptosis process in vivo as part of routine clinical practice has not been achieved. It has been widely proven that Bovine lactadherin holds better phosphatidylserine (PS) binding characterizations than Annexin V. In preliminary study, we synthesized a cyclic peptide cLac2-C according to the key residues of the PS-targeting C2 domain of lactadherin and labeled with Cy5.5 and Cu64. We further showed that Cy5.5 and Cu64 labeled cLac2-C are specific PS targeting, with better selectivity, sensitivity ,accuracy for apoptotic cells binding and reasonable biodistribution characterization.The novel probes can detect early apoptosis e?ectively in vivo. The principal objective of the present study is to further optimize and modify the str

英文关键词： Lactadherin；phosphatidylserine；apoptosis；PET；molecular imaging