Colon Cancer Specific Radiodiagnostic/Therapeutic Agents

结肠癌特异性放射诊断/治疗剂

• 批准号: 6732720
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732720
• 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)：本建议书描述设计和 人工合成人大肠杆菌ST(Sth)多肽的新结合物的评价 形成高比活度的靶向放射性药物用于选择性In 表达鸟苷素/鸟苷的大肠肿瘤的体内靶向研究 环化酶-C(GC-C)受体。诊断或治疗性放射性药物 这项工作的结果将被标记为11In、90Y、149 Pm或177Lu， 可作为无载体(NCA)试剂使用的放射性核素 制备放射性金属受体亲和肽的半衰期相容方法 共轭关系。本研究的具体目标是：1)合成新的 DOTA-X-Phe19-Sth类似物具有高特异性结合亲和力 表达GC-C受体的人结肠癌细胞；2)使用正常和 用荷瘤动物模型识别放射性标记的多肽 最佳体内药代动力学与肿瘤摄取和残留 属性；3)评估MOST的诊断或治疗效果 当标记DOTA-X-Phe19-Sth时，前景看好。111在90年中或在90年中， ~(149)Pm和~(177)Lu对人结肠癌LS-180/T-84细胞的控制或消融作用 SCID小鼠体内的衍生肿瘤。新的DOTA-X-Phe19-Sth(X=间隔基)和 相应的111In、90Y、149Pm和177Lu标记的偶联物将 在宏观和示踪水平上合成、提纯和表征。 拟议研究中使用的实验方法旨在 描述使癌细胞摄取和GC-C最大化的结构 受体介导的细胞内残留物。人工合成的能力 链接DOTA和Phe19-Sth的预定系绳(X)序列还使得 最小化残差的共轭结构的识别 在关键的非靶器官或组织中的活动。这些研究的结果 应提供DOTA-X-Phe19-Sth类似物，当用111In+3标记时， 可以开发90Y+3、149Pm+3、177Lu+3以及潜在的其他放射性金属 (通过FDA未来批准的临床试验)进入有效的放射性药物 用于监测或治疗结肠肿瘤过度表达的患者 GC-C受体。

项目成果

Selective targeting of E. coli heat-stable enterotoxin analogs to human colon cancer cells.

大肠杆菌热稳定肠毒素类似物选择性靶向人类结肠癌细胞。

• 发表时间: 2006
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Giblin,MichaelF;Sieckman,GaryL;Watkinson,LisaD;Daibes-Figueroa,Said;Hoffman,TimothyJ;Forte,LeonardR;Volkert,WynnA
• 通讯作者: Volkert,WynnA

In vitro and in vivo comparison of human Escherichia coli heat-stable peptide analogues incorporating the 111In-DOTA group and distinct linker moieties.

包含 111In-DOTA 基团和不同接头部分的人大肠杆菌热稳定肽类似物的体外和体内比较。

• DOI: 10.1021/bc049974x
• 发表时间: 2004
• 期刊: Bioconjugate chemistry.
• 作者: Giblin,MichaelF;Gali,Hariprasad;Sieckman,GaryL;Owen,NellieK;Hoffman,TimothyJ;Forte,LeonardR;Volkert,WynnA
• 通讯作者: Volkert,WynnA