RADIOPHARMACEUTICALS TARGETED TO TUMOR FOLATE RECEPTORS

描述：(改编自调查人员摘要)申请者将 开发靶向叶酸结合蛋白(FBP)的放射性药物 一种在多种肿瘤细胞上过度表达的受体。上一首 数据显示，叶酸(叶酸；一种维生素)以及 与叶酸结合的大分子，结合到这个受体上，并被 通过受体介导的内吞作用进入细胞。叶酸将被偶联 涉及允许用镓、铟、铜、铯的放射性同位素进行标记的螯合剂 和/或Re。最初，含有宏观量的 将准备进行物理化学表征的非放射性金属。 放射性标记的叶酸结合物将在体外测试它们的亲和力 对乳腺癌细胞系MDA-231和KB的肿瘤细胞 鼻咽癌细胞株，两者均表现为FBP。A-549肺 不显示FBP的癌细胞株将被用作 受体阴性对照。来自相同细胞系的人类肿瘤将被 生长于裸鼠体内检测肿瘤摄取最多 前景看好的放射性标记叶酸结合物。竞争性结合研究 将进行未标记的叶酸以证明放射性示踪剂 肿瘤的定位是一个饱和的受体依赖的过程。一秒钟 动物模型(患有自发性肿瘤的狗)将被用于进一步 评估最有希望的放射性标记偶联物的成像能力 肿瘤在背景之上。

DESCRIPTION: (Adapted from investigator's abstract) The applicants will develop radiopharmaceuticals to target Folate Binding Protein (FBP) which is a receptor that is overexpressed on a wide variety of tumor cells. Previous data have shown that folic acid (folate; a vitamin) as well as macromolecules conjugated to folate, bind to this receptor and are taken into the cell by receptor-mediated endocytosis. Folate will be conjugated to chelating agents to allow labeling with radioisotopes of Ga, In, Cu, Tc and/or Re. Initially, conjugates containing macroscopic amounts of the nonradioactive metals will be prepared for physicochemical characterization. Radiolabeled folate conjugates will be tested for their affinity in vitro for tumor cells of the MDA-231 breast cancer cell line and the KB nasopharyngeal cancer cell line, both of which exhibit FBP. The A-549 lung cancer cell line which does not display FBP will be used as a receptor-negative control. Human tumors from the same cell lines will be grown in nude mice for in vivo testing of the tumor uptake of the most promising radiolabeled folate conjugates. Competitive binding studies with unlabeled folate will be performed to demonstrate that radiotracer localization in tumor is a saturable receptor-dependent process. A second animal model (dogs with spontaneous neoplasms) will be used to further evaluate the ability of the most promising radiolabeled conjugates to image tumor over background.