Nanoconjugates for Imaging in vivo Gene Expression in Medulloblastoma

用于髓母细胞瘤体内基因表达成像的纳米缀合物

• 批准号: 7789218
• 负责人: Jennifer Gordon
• 金额: $ 16.31万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-08 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789218
• 关键词: Adult; Animal Model; Binding; Biological; Brain; Brain Neoplasms; Cell Line; Cells; Characteristics; Child; Clinical; Contrast Media; Detection; Development; Diagnosis; Diagnostic Imaging; Excision; Fluorescence Microscopy; Future; Gene Expression; Generations; Histology; Histopathology; Home environment; Human; Image; Image Analysis; Imaging Device; Immunoglobulin Fragments; Immunohistochemistry; Implant; In Vitro; Infratentorial Neoplasms; Intracranial Neoplasms; JC Virus; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Methodology; Methods; Molecular; Molecular Target; Monitor; Nanoconjugate; Neoplasm Metastasis; Neuraxis; Noise; Non-Invasive Cancer Detection; Normal Cell; Nuclear Antigens; Nude Mice; Oncogene Proteins; Operative Surgical Procedures; Organ; Polyomavirus; Posterior Fossa; Primary Brain Neoplasms; Primitive Neuroectodermal Tumor; Process; Proteins; Radioisotopes; Radiolabeled; Reagent; Recurrence; Relaxation; Resolution; Specificity; Spinal; Staining method; Stains; Surface Antigens; Survival Rate; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translations; Validation; Viral; Viral Tumor Antigens; base; cancer cell; improved; in vitro testing; in vivo; iron oxide; irradiation; medulloblastoma; mouse model; nanoparticle; neoplastic cell; novel; particle; public health relevance; radiotracer; response; sialosyl-T antigen; tool; trafficking; tumor; uptake

DESCRIPTION (provided by applicant): Medulloblastoma, the primary brain tumor in children, is difficult to detect early and to reassess post-surgery with respect to recurrence and metastasis. This project will test a biological tool for non-invasive quantitation of gene expression in cells expressing the JC virus oncoprotein, T-antigen, which has been associated with medulloblastoma. The tool, a nanoconjugate, will have a core of superparamagnetic iron oxide for detection by MRI and, as proof of concept, will target T-antigen in T-antigen transformed cancer cells. An antibody fragment which recognizes JC virus T-antigen will be used to recognize cell-surface antigens appearing on tumor cells for targeting. MR imaging will be used to track the nanoconjugate in vivo. Studies will be done to characterize and quantify the uptake by tumor cells in vitro and in an animal model. Histopathology and radionuclide studies will be used to correlate the nanoconjugate trafficking to cells with the MR images. This platform will be used as a proof of concept to rapidly and effectively demonstrate that the nanoconjugate is able to selectively home to T-antigen expressing tumor cells but not normal cells. This project will allow us to optimize composition of the nanoparticle, determine specificity of the nanoparticle for T-antigen, quantitate particle uptake per cell, and optimize MRI parameters in vitro and in vivo. This strategy will enable determination of which tumors express T-antigen, quantitative analysis of the level of T-antigen expression, and monitoring of response to therapeutic treatment non-invasively through MRI and image post-process analysis. This technology may then be modified for other highly expressed intracellular or viral molecular targets of cancer. Furthermore the comprehensive methodology used and developed in this proposal from synthesis of the target-specific contrast agent to imaging and image analysis techniques may be used for translation into clinical imaging of human tumors and potentially into a vehicle for targeted therapy. PUBLIC HEALTH RELEVANCE STATEMENT: The current proposal seeks to develop a novel molecular based contrast agent which will specifically target medulloblastoma tumor cells. This agent would improve diagnosis of brain tumors and provide novel methods to non-invasively monitor response to brain tumor treatment.

描述(申请人提供)：髓母细胞瘤，儿童的原发脑肿瘤，很难早期发现，术后很难重新评估复发和转移。该项目将测试一种生物工具，用于非侵入性定量表达JC病毒癌蛋白T抗原的细胞中的基因表达，T抗原已与髓母细胞瘤相关。该工具是一种纳米结合物，将以超顺磁性氧化铁为核心，用于核磁共振检测，并将针对T抗原转化的癌细胞中的T抗原进行概念验证。识别JC病毒T抗原的抗体片段将用于识别出现在肿瘤细胞上的细胞表面抗原，以进行靶向。磁共振成像将被用来追踪体内的纳米偶联物。将进行研究，以表征和量化肿瘤细胞在体外和动物模型中的摄取。组织病理学和放射性核素研究将被用来将纳米结合物运输到细胞与磁共振图像相关联。这一平台将被用作概念的证明，以快速有效地证明纳米结合物能够选择性地结合表达T抗原的肿瘤细胞，而不是正常细胞。该项目将使我们能够优化纳米颗粒的组成，确定纳米颗粒对T抗原的特异性，定量每个细胞的颗粒摄取，并优化体外和体内的MRI参数。这一策略将通过MRI和图像后处理分析，确定哪些肿瘤表达T抗原，定量分析T抗原的表达水平，并通过非侵入性监测治疗反应。然后，这项技术可能会被修改，以用于其他高表达的细胞内或病毒分子靶点的癌症。此外，从靶点特异性造影剂的合成到成像和图像分析技术，本提案中使用和开发的综合方法可以用于转化为人类肿瘤的临床成像，并可能转化为靶向治疗的载体。 公共卫生相关声明：目前的提案寻求开发一种新的分子基础造影剂，该造影剂将专门针对髓母细胞瘤肿瘤细胞。该试剂将提高对脑肿瘤的诊断，并为非侵入性监测脑肿瘤治疗反应提供新的方法。