肿瘤淋巴转移监测用三重靶向近红外荧光造影研究

遍布全身的淋巴系统是肿瘤转移的主要通道。淋巴结肿瘤转移是最常见的早期转移方式，也是临床上肿瘤分期、治疗、预后判断的重要指标。早期癌症治愈率可达80-90%，对肿瘤及其淋巴转移进行早期检测和诊断，是当今肿瘤学和外科学研究热点。吲哚菁绿(ICG)是美国FDA批准的唯一临床用荧光造影剂，对肿瘤转移灶负显影，没有靶向性，半衰期2至4分钟，注入后迅速被机体排出。本申请拟保留ICG发色团骨架，将其与癌细胞靶向基团叶酸连接，再与线粒体定位基团三苯基膦连接，合成靶向肿瘤细胞且定位其线粒体亚细胞器的ICG造影剂衍生物；再将其包裹到带有叶酸标签的脂质体中，借助脂质体对淋巴系统的靶向性，实现对淋巴结肿瘤转移灶的三重靶向近红外荧光造影。利用细胞、小动物活体荧光成像验证上述设想，获得具有自主知识产权的造影剂及其脂质体，实现对淋巴结肿瘤的选择性正染、成像，为监测肿瘤经淋巴转移、癌症的早期诊断及"荧光手术"创造条件。

According to the literature, the lymphatic system throughout the body provides the main channels for tumor metastasis. It is noted that lymph node is one of the most common transfer route for early stage tumor metastasis, and the cure rate can reach as high as 80-90% for early-stage cancer. Whether there is a tumor metastasis on the lymph node can be utilized as important indicator during tumor staging, treatment and prognosis of clinical judgment. In recent years, near-infrared (NIR) fluorescence imaging of tumor and lymph node metastasis has been employed for early detection and diagnosis, and has developed into a research focus of oncology and surgery. Being the only clinical employed NIR imaging agent approved by FDA (Food and Drug Administration), Indocyanine Green (ICG) is lack of targeting group on tumor metastasis, and all the lymphatic system is imaged, tumor metastasis is deduced based on anomaly lymphatic structure. Furthermre, its half-life in the body is around 2-4 minutes, and the body remaining time is too short to meet the clinical need. To solve these problems, in the proposal, the main chromophore structure of ICG was retained to keep its basic property, a cancer targeted group folic acid and a mitochondria localization group triphenylphosphine were introduced into the structure to get ICG derivatives. And then it was further packaged into liposome bearing the folic acid label. After injection,the folic acid labeled liposome can target the lymphatic system first, and then target tumor cells; meanwhile,the ICG derivative can target tumor cells and locate in the mitochondria of tumor cell organelles after released by the liposome. Finally, the lymphatic tumour cells can be triple targeted with high selectivity and NIR fluorescence image can be acquired. After both in vitro and in vivo measurements, its potential clinical application will be further studied. All these can lay a foundation for detecting tumor metastasis through lymphatic node, early-stage cancer diagnosis and "fluorescent surgery".