RADIOPHARMACEUTICALS TARGETED TO TUMOR FOLATE RECEPTORS

描述：（改编自研究者摘要）申请人将 开发针对叶酸结合蛋白（FBP）的放射性药物， 一种在多种肿瘤细胞上过度表达的受体。 先前 数据显示，叶酸（叶酸盐;维生素）以及 与叶酸结合的大分子与该受体结合， 通过受体介导的内吞作用进入细胞。 叶酸将结合 螯合剂，以允许用Ga、In、Cu、Tc的放射性同位素标记 和/或Re。最初，含有宏观量的 将制备非放射性金属用于物理化学表征。 放射性标记的叶酸偶联物将在体外检测其亲和力 对于MDA-231乳腺癌细胞系的肿瘤细胞和KB 鼻咽癌细胞系，两者均表现出FBP。 A-549肺 不展示FBP的癌细胞系将用作 受体阴性对照。 来自相同细胞系的人类肿瘤将 在裸鼠中生长，用于体内测试大多数人的肿瘤摄取。 有前途的放射性标记叶酸缀合物。 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 肿瘤中的定位是可饱和的受体依赖性过程。 第二 将使用动物模型（患有自发性肿瘤的犬）进一步研究 评价最有希望的放射性标记偶联物成像的能力 肿瘤超过背景。

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.