Colon Cancer Specific Radiodiagnostic/Therapeutic Agents

结肠癌特异性放射诊断/治疗剂

• 批准号: 6458253
• 负责人: Wynn A Volkert
• 金额: $ 25.33万
• 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/6458253
• 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）：该提案描述了设计和 评估合成人大肠杆菌ST（STH）肽的新结合物 形成高特定活动现场定向的放射性射精，以选择性 表达鸟苷/鸟烯基的结直肠肿瘤的体内靶向 环酶-C（GC-C）受体。诊断或治疗性放射性药物 这项工作的结果将标记为11英寸，90年，149pm或177lu， 可作为无载体添加的（NCA）试剂可用的放射性核素 半衰期兼容用于制备放射线仪的avid肽 共轭。这项研究的具体目标是：1）合成新的 dota-x-phe19-sth类似物，表现出具有高特异性结合亲和力 表达GC-C受体的人类结肠癌细胞； 2）使用正常和 具有肿瘤的动物模型，以鉴定显示出表现出的放射性标记的肽 最佳体内药代动力学和肿瘤摄取和残差 特性; 3）评估最多的诊断或治疗功效 有希望的dota-x-phe19-sth构建体时。 111in或90年代， 149pm和177LU用于控制或消融人类LS-180/T-84结肠癌细胞 SCID小鼠中衍生的肿瘤。新的dota-x-phe19-sth（x =间隔者组）和 相应的111in，90y，149pm和177lu标记的偶联物将是 在宏观和示踪剂水平上合成，纯化和表征。 拟议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差。合成的能力 链接dota和phe19-sth的预定系绳（x）序列也可以启用 识别共轭构建体，以最大程度地减少残差 关键的非目标器官或组织的活性。这些研究的结果 应提供dota-x-phe19-sth类似物，当用111in+3标记时 90y+3，149pm+3，177lu+3及可能开发的其他辐射量 （通过未来的FDA批准临床试验）进入有效的放射性药物 用于监测或治疗过表达结肠肿瘤的患者 GC-C受体。