TARGETED RADIOTHERAPHY OF BRAIN TUMORE USING MODULAR RECOMBINANT

使用模块化重组对脑肿瘤进行靶向放射治疗

• 批准号: 7738051
• 负责人: Michael Rod Zalutsky
• 金额: $ 5.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738051
• 关键词: Academy; Antibodies; Binding; Biological Preservation; Biology; Brain; Brain Neoplasms; Cell Line; Cell Nucleus; Cell membrane; Cell surface; Cells; Chemistry; Clinical; Convection; Data; Doctor of Philosophy; Dose; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; EGF gene; Effectiveness; Electrons; Engineering; Epidermal Growth Factor Receptor; Extracellular Space; Genes; Glioma; Goals; Grant; Half-Life; Heterogeneity; Human; Individual; Institutes; Instruction; Label; Lead; Ligands; Maximum Tolerated Dose; Metastatic Neoplasm to the Leptomeninges; Methodology; Methods; Molecular Profiling; Molecular Target; Mus; Nature; Normal tissue morphology; Nuclear Translocation; Nude Rats; Patients; Primary Neoplasm; Radiation; Radiation therapy; Radioactive; Radioisotopes; Radiolabeled; Radiometry; Recombinants; Rodent; Safety; Science; Site; System; Targeted Radiotherapy; Therapeutic; Toxic effect; Treatment Efficacy; Universities; Work; Xenograft Model; Xenograft procedure; base; brain tissue; cancer cell; cell killing; comparative; cytotoxic; cytotoxicity; design; effective therapy; expectation; experience; innovation; monolayer; neoplastic cell; novel; particle; radiotracer; receptor; receptor binding; receptor expression; research clinical testing; subcutaneous; trafficking; tumor

Project 1. Targeted Radiotherapy of Brain Tumors Using Modular Recombinant Transporters (RT) Labeled with Auger-Electron Emitting Radionuclides. Michael R. Zalutsky, Ph.D., Project Leader The long-term objective of this project is to develop more specific and effective targeted radiotherapeutics for brain tumor treatment that are based on a novel radionuclide delivery system that ultimately might be adaptable to the molecular signature of an individual tumor. This will be pursued by combining the expertise of the Duke University team in targeted radiotherapy with the innovative approaches pioneered at the Institute of Gene Biology, Russian Academy of Sciences, in modular recombinant transporters (MRT). MRT are engineered molecules that have been devised with domains that retain receptor binding, endosomal escape and nuclear translocation, thereby facilitating the delivery of drugs from the cell surface to the nucleus. We hypothesize that MRT targeted to the epidermal growth factor receptor (EGFR) might be an ideal vehicle for exploiting the high potency and sub-cellular range of Auger electrons for targeted radiotherapy. Auger electrons have low cytotoxicity when decaying outside the cell nucleus, i.e. on the cell surface or in the extracellular space. For this reason, Auger electron emitting MRT might be well suited to convection enhanced delivery because their sub-cellular range of action should minimize radiation dose to normal brain tissue, where decays occur outside the cell. Specifically, we propose to: 1) adapt labeling strategies already developed for labeling internalizing mAbs to optimize the attachment of Auger electron emitters to MRT; 2) evaluate the cytotoxicity of radiolabeled EGF-MRT against EGFR-expressing human glioma cells in both monolayer and spheroid geometry; 3) determine the tissue distribution and calculated radiation dosimetry of radiolabeled EGF-MRT in normal and tumor bearing mice; 4) evaluate the maximum tolerated dose and therapeutic efficacy of radiolabeled EGF-MRT in subcutaneous and neoplastic meningitis rodent xenograft models; and 5) evaluate the therapeutic potential of Auger electron labeled EGF-MRT administered by intracerebral microinfusion to athymic rats with intracerebral human glioma xenografts. RELEVANCE (See instructions): Our goal is to develop more specific and effective treatments for brain tumors based on a modular recombinant transporter (MRT) designed to bind to epidermal growth factor receptors that are present in high abundance on glioma and then deliver a radioactive cargo to the nucleus of these cells. Labeling these MRT with Auger electron emitters, which only are highly cytotoxic when delivered to the cell nucleus, offers the exciting prospect of more tumor selective radiation therapy with less damage to normal tissue.

项目1. 使用标记的模块化重组转运蛋白（RT）对脑肿瘤进行靶向放射治疗 与俄歇电子发射放射性核素。 Michael R. Zalutsky 博士，项目负责人 该项目的长期目标是开发更特异、更有效的靶向放射治疗药物 用于基于新型放射性核素输送系统的脑肿瘤治疗，该系统最终可能会 适应个体肿瘤的分子特征。这将通过结合 杜克大学团队在靶向放射治疗方面的专业知识以及首创的创新方法 俄罗斯科学院基因生物学研究所的模块化重组转运蛋白（MRT）。 MRT 是经过设计的分子，其结构域保留了受体结合， 内体逃逸和核转位，从而促进药物从细胞表面的递送 到细胞核。我们假设针对表皮生长因子受体 (EGFR) 的 MRT 可能 成为利用俄歇电子的高效能和亚细胞范围进行靶向治疗的理想工具 放射治疗。俄歇电子在细胞核外（即细胞上）衰变时具有较低的细胞毒性 表面或细胞外空间。因此，俄歇电子发射 MRT 可能非常适合 对流增强递送，因为它们的亚细胞作用范围应最大限度地减少辐射剂量 正常脑组织，其腐烂发生在细胞外。具体来说，我们建议：1）调整标签 已经开发出标记内化单克隆抗体的策略，以优化俄歇电子的附着 地铁发射器； 2) 评估放射性标记的EGF-MRT对表达EGFR的人的细胞毒性 单层和球状几何形状的神经胶质瘤细胞； 3）确定组织分布并计算 正常小鼠和荷瘤小鼠中放射性标记 EGF-MRT 的辐射剂量测定； 4）评估最大值 放射性标记 EGF-MRT 在皮下和肿瘤治疗中的耐受剂量和治疗效果 脑膜炎啮齿动物异种移植模型； 5) 评估俄歇电子标记的治疗潜力 通过脑内微量输注对患有脑内人胶质瘤的无胸腺大鼠施用 EGF-MRT 异种移植物。 相关性（参见说明）： 我们的目标是基于模块化的方法开发更具体、更有效的脑肿瘤治疗方法 重组转运蛋白（MRT）设计用于结合存在于表皮生长因子受体 神经胶质瘤上有高丰度，然后将放射性货物输送到这些细胞的细胞核。标记这些 配备俄歇电子发射器的 MRT 仅在传递到细胞核时才具有高度细胞毒性，可提供 对正常组织损伤较小的更多肿瘤选择性放射治疗的令人兴奋的前景。