小肝癌靶向树枝状大分子造影剂的合成与成像研究

Early diagnosis is critical for successful treatment of hepatic cancer. Magnetic resonance imaging (MRI) are primary means of locating and diagnosing hepatic cancer in recent years. However, it is difficult to identify small hepatocellular carcinoma whose diameter is less than 1 cm since current contrast agents are inclined to accumulate in normal hepatic cells. In this project, we plan to synthesize a dendritic contrast agent targeting hypoxic tumor lesions to make MRI have greater sensitivity for diagnosis of small hepatocellular carcinoma. A bifunctional dendimer will be synthesized to conjugate MRI contrast agent inside and zwitterion along with tumor-hypoxia-targeting moiety on its surface. The introduction of zwitterion which is able to avoid protein adhesion and opsonization can produce less accumulation in normal hepatic cells. In addition, and the introduction of tumor-hypoxia-targeting moiety can increase their accumulation in hepatic cancer cells, which leads to sharp contrast between small hepatocellular carcinoma and normal tissues. This project will provide a method to fabricate targeting MRI contrast agents for small hepatocellular carcinoma diagnosis, and find the relationship of structure and performance between surface zwitterionic modification and accumulation in normal hepatic tissue as well as the performance of different tumor-hypoxia-targeting moieties.

肝癌的早期诊断是提高其治疗成功率的关键。磁共振成像（MRI）是目前肝癌定位和诊断的主要手段之一，但由于目前的MRI造影剂无法有效地靶向小肝癌，导致其对于直径小于1 cm 的小肝癌难以诊断。对此，项目针对小肝癌血管生成不明显、缺氧的特性，设计合成肿瘤厌氧靶向的树枝状大分子造影剂，增加造影剂的小肝癌靶向性，提高MRI诊断小肝癌的灵敏度。项目提出利用一种内外双官能团的树枝状大分子，在其内部键合小分子MRI造影剂，并在表面修饰两性离子，避免因蛋白粘附产生的调理作用被肝内巨噬细胞吞噬，减少造影剂在正常肝组织中的蓄积，同时引入厌氧靶向基团增加造影剂在小肝癌中的蓄积，大幅增加小肝癌与正常肝组织的对比度，从而大幅提高MRI检测小肝癌的灵敏度。项目将建立起构建小肝癌靶向MRI造影剂的方法，探明树枝状大分子造影剂表面两性离子结构与避免肝脏蓄积性能之间的关系，以及肿瘤厌氧靶向基团结构与小肝癌靶向性能之间的关系。

肝癌的早期诊断是提高其治疗成功率的关键。磁共振成像（MRI）是目前肝癌定位和诊断的主要手段之一，但由于目前MRI造影剂无法有效地靶向小肝癌，导致其对于直径小于1cm的小肝癌难以诊断。对此，项目针对小肝癌血管生成不明显、缺氧的特性，设计合成了肿瘤厌氧靶向的树枝状大分子造影剂，增加造影剂的小肝癌靶向性，提高MRI诊断小肝癌的灵敏度。项目建立了以环糊精为核半胱胺和烯丙基缩水甘油醚为单体，通过交替点击化学反应，高效合成内外双官能团树枝状大分子的方法，并构建了能够避免肝内巨噬细胞吞噬的方法和材料体系，研究了不同结构树枝状大分子造影剂的结构与性能关系，获得能有效规避正常肝细胞和巨噬细胞吞噬的树枝状大分子造影剂，制备的小肝癌靶向树枝状大分子造影剂，注射后30min后肝内转移灶的信噪比可达65，显著增强MRI检测肝癌的灵敏度。同时，项目还制备了一种谷胱甘肽（GSH）响应性的铁基纳米造影剂，其能在减弱正常肝脏信号的同时提高肿瘤内的信号，大幅增加肿瘤与正常组织的对比度，显著提高了MRI检测肝转移癌的灵敏度。项目发表SCI收录论文12篇，获发明专利授权6项，培养博士研究生4名，硕士研究生2名，博士后2名，圆满完成了项目的研究任务。