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

基本信息

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
项目类别：
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

项目摘要

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）对脑肿瘤的靶向放疗带有螺旋发射的发射放射性核素。迈克尔·R·扎卢茨基（Michael R. Zalutsky）博士，项目负责人该项目的长期目标是开发更具体和有效的靶向放射治疗方法用于基于新型放射性核素输送系统的脑肿瘤治疗适应单个肿瘤的分子特征。这将通过结合杜克大学团队的专业知识在有针对性放疗，并以创新的方法开创性俄罗斯科学学院基因生物学研究所，模块化重组转运蛋白（MRT）。 MRT是由保留受体结合的域设计的工程分子，内体逃生和核易位，从而促进了药物从细胞表面递送到核。我们假设针对表皮生长因子受体（EGFR）的MRT可能成为利用高效力和亚细胞范围的理想工具放疗。在细胞核外腐烂时，螺旋钻电子具有低细胞毒性，即在细胞上表面或细胞外空间。因此，螺旋钻电子发射的MRT可能非常适合对流增强了交付正常的脑组织，在细胞外发生衰减的地方。具体来说，我们建议：1）调整标签已经开发出用于标记内部化mAb的策略以优化螺旋钻的附件发射捷运； 2）评估针对表达EGFR的人的放射性标记的EGF-MRT的细胞毒性单层和球体几何形状中的胶质瘤细胞； 3）确定组织分布并计算正常和肿瘤轴承小鼠的放射性标记的EGF-MRT的辐射剂量法； 4）评估最大放射性标记的EGF-MRT在皮下和肿瘤中的耐受剂量和治疗功效脑膜炎啮齿动物异种移植模型； 5）评估标记的螺旋钻电子的治疗潜力 EGF-MRT通过脑内微灌注到无脑胶质瘤的无胸腺大鼠的EGF-MRT 异种移植物。相关性（请参阅说明）：我们的目标是基于模块化开发更具体和更有效的脑肿瘤治疗方法重组转运蛋白（MRT）旨在结合存在于表皮生长因子受体中神经胶质瘤的高丰度，然后将放射性货物输送到这些细胞的核。标记这些 MRT带有螺旋钻电子发射器，该发射器仅在传递到细胞核时才高度细胞毒性。肿瘤选择性放射治疗的激动人心的前景，对正常组织的损害较小。