Colon Cancer Specific Radiodiagnostic/Therapeutic Agents

结肠癌特异性放射诊断/治疗剂

• 批准号: 6622852
• 负责人: Wynn A Volkert
• 金额: $ 25.81万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622852
• 关键词: Escherichia coli; SCID mouse; antineoplastics; athymic mouse; bacterial proteins; cell line; colorectal neoplasms; drug design /synthesis /production; ligands; mass spectrometry; neoplasm /cancer radionuclide therapy; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; pharmacokinetics; radionuclides; receptor binding; synthetic peptide

Description (provided by applicant): This proposal describes the design and evaluation of new conjugates of synthetic human E. coli ST (STh) peptides that form high specific activity site-directed radiopharmaccuticals for selective in vivo targeting of colorectal neoplasias that express guanylin/guanylate cyclase-C (GC-C) receptors. Diagnostic or therapeutic radiopharmacouticals that result from this work will be labeled with 11In, 90Y, 149Pm or 177Lu, radionuclides that are available as no-carrier-added (NCA) reagents that have half-lives compatible for preparing radiometallated receptor-avid peptide conjugates. The specific objectives of this research are to: 1) synthesize new DOTA-X-Phe19-STh analogues that exhibit high specific binding affinities with human colon cancer cells expressing GC-C receptors; 2) use normal and tumor-bearing animal models to identify radiolabeled peptides that exhibit optimal in vivo pharmacokinetics and tumor uptake and residualization properties; 3) evaluate the diagnostic or therapeutic efficacy of the most promising DOTA-X-Phe19-STh constructs when labeled with. 111In or with 90Y, 149Pm and 177Lu for controlling or ablating human LS-180/T-84 colon cancer cell derived tumors in SCID mice. The new DOTA-X-Phe19-STh (X=spacer group) and the corresponding 111In, 90Y, 149Pm and 177Lu labeled conjugates will be synthesized, purified and characterized at both macroscopic and tracer levels. The experimental approaches used in the proposed research are designed to characterize structures that maximize cancer cell uptake and GC-C receptor-mediated intracellular residualization. The ability to synthesize predetermined tether (X) sequences linking DOTA and Phe19-STh also enables identification of conjugate constructs that minimize residualization of activity in critical non-target organs or tissues. The results of these studies should provide DOTA-X-Phe19-STh analogues that, when labeled with 111In+3, 90Y+3, 149Pm+3, 177Lu+3 and potentially other radiometals, could be developed (via future FDA approved clinical trials) into effective radiopharmaccuticals for monitoring or treatment of patients with colonic neoplasias overexpressing GC-C receptors.

描述（由申请人提供）：本建议书描述了设计和 合成人大肠杆菌的新缀合物的评价大肠杆菌ST（STh）肽， 形成高比活度定点放射性药物， 表达鸟苷素/鸟苷酸的结肠直肠肿瘤的体内靶向 环化酶-C（GC-C）受体。诊断或治疗放射性药物， 本工作的结果将用11 In、90 Y、149 Pm或177 Lu标记， 作为无载体添加（NCA）试剂的放射性核素， 用于制备放射性标记的亲受体肽的半衰期相容性 结合物。本研究的具体目标是：1）合成新的 DOTA-X-Phe 19-STh类似物，其表现出与 表达GC-C受体的人结肠癌细胞; 2）使用正常和 携带肿瘤的动物模型，以鉴定表现出 最佳体内药代动力学和肿瘤摄取和残留 性质; 3）评价大多数人的诊断或治疗效果 有希望的DOTA-X-Phe 19-STh构建体。111 In或90 Y， 149 Pm和177 Lu对人LS-180/T-84结肠癌细胞的控制或消融作用 来源的肿瘤。新的DOTA-X-Phe 19-STh（X=间隔基团）和 相应的111 In、90 Y、149 Pm和177 Lu标记的缀合物将被 在宏观和示踪剂水平上合成、纯化和表征。 在拟议的研究中使用的实验方法旨在 表征最大化癌细胞摄取和GC-C的结构 受体介导的细胞内残留。合成能力 连接DOTA和Phe 19-STh的预定系链（X）序列也使得 最小化缀合物残基化的缀合构建体的鉴定 关键非靶器官或组织中的活性。这些研究的结果 应提供DOTA-X-Phe 19-STh类似物，当用111 In +3标记时， 90 Y +3、149 Pm +3、177 Lu +3和潜在的其他放射性金属， (via未来FDA批准的临床试验）转化为有效的放射性药物 用于监测或治疗结肠肿瘤过度表达的患者 GC-C受体。