淋巴结转移性肿瘤靶向多糖类高分子正电子发射计算机断层扫描(PET)示踪剂的研究

At present, the clinically used positron emission computed tomography (PET) tracers are small ionic molecules that can diffuse freely through the extracellular space and excreted rapidly. Then their biodistribution are nonspecific and possess no tumor-targeting property. Therefore, these tracers can not be used as the lymph node metastases-targeting PET tracers for the biological imaging analysis and the early diagnostics of cancer metastasis. The purpose of this project is to undertake research into means to generate a unique range of the lymph node metastases-targeting polysaccharide positron emission computed tomography (PET) tracers. The innovative approach taken will involve, for instance, the synthesis of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and a pentapeptide compound YIGSR (Tyrosine-isoleucine-glycin-serine-arginine) and their attachment to polysaccharide. The water-soluble polymeric ligands will be synthesized by the incorporation of NOTA and YIGSR as a tumor-targeting group into the hydroxyl groups of the polysaccharide carriers such as dextran and hyaluronic acid. Subsequently, these ligands will react with K18F to make the 18F-labelled lymph node metastases-targeting positron emission computed tomography (PET) tracers. These compounds obtained will be further characterized and their properties in regards to cell cytotoxicity assay, PET imaging, biodistribution, biological activity, and tumor selectivity in vitro and in vivo, will be also evaluated. Our intention is to identify the relationships between the structure of these PET tracers, their tumor selectivity and PET imaging, and then explore the mechanism of uptake by tumor tissue and the application to the tumor-targeting PET imaging mediated diagnosis. The outcomes of this research will be expected to enhance the contrast of PET images of the forepart tumors and then improve the early diagnostics of cancer metastasis and the distinguishing capability between the benign tumors and malignant tumors.

拟研制淋巴结转移性肿瘤靶向多糖类高分子正电子发射计算机断层扫描(PET)示踪剂，研究其PET显像性能与肿瘤靶向机理，以及对癌症转移病灶的早期诊断规律。具体内容为：针对目前临床使用的示踪剂都是小分子化合物，在体内不具有肿瘤选择性或靶向性，对肿瘤的显像效果较差等问题，将肿瘤靶向性五肽化合物（酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸，YIGSR）与1,4,7-三氮杂环九烷-1,4,7-三乙酸（NOTA）通过化学反应分别偶联在水溶性葡聚糖、透明质酸等多糖类高分子载体上，制备高分子配体化合物；然后将配体与18F-氟化钾反应制备淋巴结转移性肿瘤靶向18F-氟标记高分子PET示踪剂。并研究示踪剂对淋巴结转移性肿瘤的靶向性能与靶向机理，测试动物体内PET靶向显像、药物毒性和药物分布等性能。研究示踪剂与肿瘤细胞的作用，探讨示踪剂对良、恶性肿瘤与癌症转移病灶的早期鉴别，提高PET成像技术对肿瘤的早期诊断水平。

目前临床的正电子发射计算机断层扫描成像（PET）示踪剂，如18F-FDG等，都是小分子化合物，根据各部位代谢的不同需要而在体内进行分布，不具有组织、器官选择性或靶向性，尤其对肿瘤成像效果较差，代谢速度快，利用率低。而且目前还没有肿瘤靶向PET示踪剂进入临床应用。因此研制具有我国自主知识产权的淋巴结转移性肿瘤靶向PET示踪剂，提高我国PET对肿瘤的临床早期诊断与对癌症转移病灶的早期鉴别水平，具有十分重要的理论意义与深远的影响。.针对我国癌症发病率高的特点，本项目成功研制一系列新型稳定、低毒的肿瘤靶向PET示踪剂，探讨其肿瘤靶向性、毒性、体内药物分布与PET成像性能。主要研究内容为：将肿瘤靶向性五肽化合物（酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸，YIGSR）与1,4,7-三氮杂环九烷-1,4,7-三乙酸（NOTA）通过化学反应分别偶联在聚天冬酰胺、葡聚糖与透明质酸等高分子载体上，制备水溶性高分子配体化合物；然后将配体与18F-氟化钠反应制备淋巴结转移性肿瘤靶向高分子PET示踪剂。并研究示踪剂对肿瘤的靶向性能与靶向机理，测试动物体内PET靶向显像、药物毒性和药物分布等性能。研究示踪剂与肿瘤细胞的作用，探讨示踪剂对良、恶性肿瘤与癌症转移病灶的早期鉴别，提高PET成像对肿瘤的早期诊断水平，得出对肿瘤靶向示踪剂的设计与合成具有指导性的规律。.实验结果表明，与18F-FDG相比，这类18F-氟标记PET示踪剂具有较好的体外细胞毒性、良好的肿瘤靶向性与PET成像性能，成像分辨率与灵敏度高。在体内主要通过肝脏、肾脏代谢，有望可用作肿瘤靶向PET示踪剂。.现已发表学术论文49篇，其中SCI论文14篇，其它期刊论文12篇，会议论文23篇。获授权发明专利7项，申请发明专利4项。项目负责人被评为全国优秀教师、武汉市高新技术产业科技创新团队负责人，荣获湖北省技术发明二等奖、京博杯.第二届中国大学生高分子材料创新创业大赛三等奖（优秀指导老师）、湖北省优秀硕士毕业论文优秀奖（指导老师）、湖北省优秀学士毕业论文优秀奖（3项，指导老师）。