RADIOPHARMACEUTICALS TARGETED TO TUMOR FOLATE RECEPTORS

描述(改编自申请者摘要)：该项目将继续 验证放射性标记的叶酸结合物可以作为载体的假设 用于选择性地将放射性核素输送到肿瘤，如卵巢癌， 过量表达叶酸的细胞膜受体。《公约》的具体目标 该项目包括合成用于标记的叶酸偶联物 In、Cu和Y的放射性同位素，以及它们的能力表征 在体外和体内选择性靶向肿瘤细胞。新型叶酸螯合物和 将合成叶酸-多肽结合物，其中放射性标记的螯合物 或多肽共价连接到叶酸的伽玛-羧酸盐或 叶酸-类似物。通过叶酸对细胞摄取的结合物的亲和力 受体将通过竞争结合分析在体外确定 培养的人类肿瘤细胞。展示叶酸受体介导的细胞的药物 体外摄取将进一步筛选，以评估其靶向能力。 体内的肿瘤组织。这些筛查研究的主要动物模型 将是携带叶酸受体阳性的人类肿瘤异种移植的无瘤小鼠。 放射性标记叶酸结合物的生物分布和药代动力学 将在静脉注射后直接在小鼠肿瘤模型中进行评估 放射性药物的管理。展示的放射性药物 重要的肿瘤摄取和肿瘤选择性将被更详细地研究 以：(Ii)确认叶酸受体的参与；(Ii)评估 靶细胞对放射性示踪剂的内化；以及(Iii)探测代谢 放射性示踪剂的命运。这些结果将为决策提供依据 一种特定药物的更密集的临床前开发 这是正当的。通过对靶向部分的独立操作， 放射性标记的片段和相关的连接物化学，这些是靶标 分子也被设计成直接探测结构-活性关系 这将有助于合理设计以叶酸受体为靶标的改良药物 探员们。如果能够实现适当的肿瘤特异性示踪剂摄取，例如 放射性药物可以在非侵入性疾病中得到广泛的临床应用 诊断和/或治疗各种原发和转移性肿瘤。

DESCRIPTION (Adapted from applicant's abstract): This project will continue to test the hypothesis that radiolabeled folate conjugates can serve as vehicles for selective radionuclide delivery to tumors, such as ovarian carcinoma, that overexpress a cell membrane receptor for folic acid. The specific aims of the project involve the synthesis of folate-conjugates designed for labeling with radioisotopes of In, Cu and Y, followed by characterization of their ability to selectively target tumor cells in vitro and in vivo. Novel folate-chelate and folate-peptide conjugates will be synthesized in which the radiolabeled chelate or peptide is covalently linked to the gamma-carboxylate of folic acid or a folate-analog. The affinity of the conjugate for cell uptake via the folate receptor will be determined in vitro through competitive binding assays with cultured human tumor cells. Agents exhibiting folate-receptor-mediated cell uptake in vitro will be further screened to assess their ability to target neoplastic tissue in vivo. The primary animal model for these screening studies will be athymic mice bearing folate-receptor-positive human tumor xenografts. The biodistribution and pharmacokinetics of the radiolabeled folate-conjugates will be directly evaluated in the mouse tumor model following intravenous administration of the radiopharmaceutical. Radiopharmaceuticals that exhibit significant tumor uptake and tumor selectivity will be examined in more detail to: (ii) confirm involvement of the folate-receptor; (ii) evaluate the rate of radiotracer internalization by targeted cells; and (iii) probe the metabolic fate of the radiotracer. These results will provide the basis for deciding whether more intensive pre-clinical development of a specific agent is warranted. Through independent manipulations of the targeting moiety, the radiolabeled fragment, and associated linker chemistry, these the target molecules are also designed to directly probe structure-activity relationships that should assist in rational design of improved folate-receptor-targeted agents. If suitable tumor-specific tracer uptake can be achieved, such radiopharmaceuticals could find widespread clinical use in the non-invasive diagnosis and/or treatment of a variety of primary and metastatic tumors.