TARGETED RADIOTHERAPHY OF BRAIN TUMORE USING MODULAR RECOMBINANT

项目1。RT标记的重组转运蛋白靶向放射治疗脑肿瘤 俄歇电子发射放射性核素Michael R. Zalutsky博士，项目负责人 本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 基于新型放射性核素输送系统的脑肿瘤治疗， 适应于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， 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是被设计成具有保留受体结合的结构域的工程分子， 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。我们假设靶向表皮生长因子受体（EGFR）的MRT可能 是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载体。 放疗俄歇电子在细胞核外即在细胞上衰变时具有低细胞毒性 表面或细胞外空间中。出于这个原因，俄歇电子发射MRT可能非常适合于 对流增强递送，因为它们的亚细胞作用范围应使辐射剂量最小化， 正常的脑组织，在细胞外发生衰变。具体而言，我们建议：1）调整标签 已经开发的标记内化mAb以优化俄歇电子附着的策略 2）评价放射性标记的EGF-MRT对表达EGFR的人的细胞毒性; 胶质瘤细胞在单层和球体几何形状; 3）确定组织分布和计算 放射性标记的EGF-MRT在正常和荷瘤小鼠中的辐射剂量测定; 4）评估放射性标记的EGF-MRT在正常和荷瘤小鼠中的最大剂量。 放射性标记的EGF-MRT在皮下和肿瘤中的耐受剂量和治疗效果 脑膜炎啮齿动物异种移植模型;和5）评估俄歇电子标记的 脑内微量输注EGF-MRT治疗脑胶质瘤的实验研究 异种移植 相关性（参见说明）： 我们的目标是开发更具体和有效的治疗脑肿瘤的基础上，模块化 重组转运蛋白（MRT），其被设计为结合存在于表皮细胞中的表皮生长因子受体， 高丰度的神经胶质瘤，然后将放射性货物运送到这些细胞的细胞核。标签这些 MRT与俄歇电子发射器，这是只有高度细胞毒性时，交付给细胞核，提供 对正常组织损伤更小的肿瘤选择性放射治疗的令人兴奋的前景。

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.