RADIOPHARMACEUTICALS TARGETED TO TUMOR FOLATE RECEPTORS

描述（改编自申请人的摘要）：该项目将继续 检验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，例如卵巢癌， 过表达叶酸的细胞膜受体。的具体目标 该项目涉及叶酸缀合物的合成，用于标记 In、Cu和Y的放射性同位素，然后表征它们的能力， 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-肽缀合物，其中放射性标记的螯合物 或肽共价连接至叶酸的γ-羧酸酯或叶酸的 叶酸类似物。缀合物通过叶酸对细胞摄取的亲和力 受体将通过竞争性结合试验在体外确定， 培养的人类肿瘤细胞。表现出叶酸受体介导的细胞毒性的药剂 将进一步筛选体外摄取，以评估其靶向 体内肿瘤组织。这些筛选研究的主要动物模型 将是携带叶酸受体阳性人肿瘤异种移植物的无胸腺小鼠。 放射性标记叶酸偶联物的生物分布和药代动力学 将在静脉内给药后的小鼠肿瘤模型中直接评价 放射性药物的施用。放射性药物表现出 将更详细地检查显著的肿瘤摄取和肿瘤选择性 目的：（ii）确认叶酸受体的参与;（ii）评估 通过靶细胞的放射性示踪剂内化;和（iii）探测代谢的 放射性示踪剂的命运这些结果将为决定 是否对特定药物进行更深入的临床前开发， 有正当理由通过靶向部分的独立操作， 放射性标记的片段和相关的连接体化学，这些靶向 分子也被设计成直接探测结构-活性关系 这应该有助于合理设计改进的叶酸受体靶向 剂.如果可以实现合适的肿瘤特异性示踪剂摄取，则这样的 放射性药物可以在非侵入性 诊断和/或治疗多种原发性和转移性肿瘤。

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.