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: 7999282
• 负责人: Jennifer Gordon
• 金额: $ 18.99万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999282
• 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 Delivery; 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; tool; trafficking; tumor; uptake; 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 Delivery; 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; 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（由申请人提供）：髓母细胞瘤是儿童的原发性脑肿瘤，很难早日检测，并且在复发和转移方面重新评估了手术后。该项目将测试一种生物学工具，用于在表达与髓母细胞瘤相关的JC病毒癌蛋白T-抗原的细胞中对基因表达的无创定量。该工具是一种纳米缀合物，将具有超顺磁铁氧化铁的核心，可通过MRI检测，作为概念证明，将靶向T-抗原转化的癌细胞中的T-抗原。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。 MR成像将用于在体内跟踪纳米缀合物。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用于将纳米偶联物的运输与细胞与MR图像相关联。该平台将被用作概念证明，以快速有效地证明纳米偶联物能够选择性地归入T-抗原表达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，确定纳米颗粒的特异性T-抗原，定量每个细胞的颗粒吸收，并在体外和体内优化MRI参数。该策略将确定哪些肿瘤表达T抗原，对T抗原表达水平的定量分析，并通过MRI和图像后制过程分析监测对治疗治疗的反应。然后，可以为癌症的其他高度表达的细胞内或病毒分子靶标修改该技术。此外，在该提案中使用和开发的全面方法从目标特异性对比剂到成像和图像分析技术可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。 公共卫生相关性声明：当前的提案旨在开发一种新型的基于分子的对比剂，该对比剂将特别针对髓母细胞瘤细胞。该药物将改善对脑肿瘤的诊断，并提供新的方法来非侵入性监测对脑肿瘤治疗的反应。