(PQC5) Detecting small clusters of tumor cells with a PTPmu probe

(PQC5) 使用 PTPmu 探针检测小簇肿瘤细胞

• 批准号: 8589825
• 负责人: SUSANN M BRADY-KALNAY
• 金额: $ 64.56万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589825
• 关键词: Algorithms; Animals; Binding; Blood Vessels; Brain; Brain Neoplasms; Cell Size; Cells; Characteristics; Chemistry; Cleaved cell; Collection; Computer software; Contrast Media; Coupled; Data; Detection; Diagnosis; Diffuse; Disease; Dose; Excision; Funding; Gadolinium; Glioma; Goals; Gold; Head; Human; Image; Image Analysis; Imagery; Injection of therapeutic agent; Label; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Metastatic Lesion; Microscopic; Modeling; Molecular; Molecular Target; Mus; Nature; Noise; Operative Surgical Procedures; Optics; Plasma; Process; Prohance; Protocols documentation; Radiation therapy; Relative (related person); Resolution; Signal Transduction; Staging; Stream; Techniques; Testing; Time; Tumor Biology; Variant; Xenograft procedure; base; cancer cell; clinically relevant; density; emission spectroscopy; extracellular; gadolinium oxide; image processing; image registration; imaging modality; imaging probe; improved; in vivo; interest; molecular imaging; neoplastic cell; novel; public health relevance; radiologist; reconstruction; research study; restraint; tumor; tumor microenvironment; white matter

DESCRIPTION (provided by applicant): Early tumor detection is a critically important goal in oncologic imaging because it would enable treatment (or redirection of treatment) at earlier stages of disease. However, the challenge is imaging small collections of tumor cells because conventional in vivo imaging methods suffer from limited resolution and tumor contrast. MRI, which presents exquisite anatomical detail and many contrast mechanisms, still often proves incapable of detecting small clusters of tumor cells. Our strategy will be to develop a magnetic resonance imaging (MRI) agent with great amplification potential and to use magnetic resonance (MR) acquisition and image processing techniques to provide contrast sufficient to detect even very small tumors. Our proposal builds upon substantial preliminary data and brings together significant multi-disciplinary expertise in probe chemistry, tumor models, tumor biology, unique 3D microscopic cryo-imaging, advanced MR techniques, and quantitative image analysis. To date, we have discovered a novel molecular imaging strategy by targeting extracellular fragments of PTP¿ abundantly found in the tumor microenvironment; created mouse orthotopic models of gliomas; developed cryo-imaging methods to visualize and quantify tumor size, cell dispersal, white matter tracts and blood vessel density in 3D brain reconstructions; and discovered that a fluorescent PTP¿ probe quickly labeled main tumor as well as dispersed cells and even single migrating cells up to 3.5 mm away from the main tumor mass. Recently preliminary studies using a gadolinium conjugated PTP¿ probe indicate that we can see small tumors using MRI. We seek funding to demonstrate delineation of the dispersing tumor boundary and detection of tiny clusters of cancer cells using the PTP¿ molecular imaging probe by MRI. Even a skilled radiologist will not have the confidence to specifically diagnose a tumor until it is bigger than 5x5x5 mm3 even though typical spatial resolution is about 1x1x5 mm3 because of the non-specific, non-quantitative nature of the MR signal. Our approach will be to greatly increase contrast of the MR signal relative to background anatomical variations through amplification characteristics of PTP¿ MRI probe (PTP¿-Gd), hardware, acquisition, and software improvements. We hypothesize that we can specifically identify and characterize tumors 2-3 orders of magnitude smaller than currently possible through the use of the PTP¿ molecular targeting agent combined with high resolution and quantitative MR. The Specific Aims are: 1. Optimize and test the ability of the molecular PTP¿-Gd probe to detect brain tumors in orthotopic xenografts and compare to "conventional" brain tumor MRI. 2. Determine the ability of PTP¿-Gd to accurately image dispersing brain tumors as compared to gold-standard GFP-labeled tumor from microscopic cryo-imaging. 3. Optimize quantitative MRI using a clinically feasible (3T) dual-agent approach to test the limits for detecting small isolated brain tumors in a very highly dispersing tumor model.

描述（由申请人提供）：早期肿瘤检测是肿瘤成像中极其重要的目标，因为它可以在疾病的早期阶段进行治疗（或重新调整治疗）。然而，挑战在于对少量肿瘤细胞进行成像，因为传统的体内方法。成像方法的分辨率和肿瘤对比度有限，但 MRI 呈现出精细的解剖细节和许多对比机制，但仍然经常被证明无法检测小簇肿瘤细胞。巨大的放大潜力，并使用磁共振（MR）采集和图像处理技术来提供足以检测甚至非常小的肿瘤的对比度，我们的建议建立在大量的初步数据之上，并汇集了探针化学、肿瘤模型、肿瘤方面的重要多学科专业知识。迄今为止，我们已经发现了一种针对 PTP 细胞外片段的新型分子成像策略。在肿瘤微环境中大量发现；创建了神经胶质瘤的小鼠原位模型；开发了冷冻成像方法来可视化和量化 3D 大脑重建中的肿瘤大小、细胞分散、白质束和血管密度；探针快速标记主要肿瘤以及分散的细胞，甚至距离主要肿瘤块达 3.5 毫米的单个迁移细胞，最近使用钆缀合 PTP 进行了初步研究。探针表明我们可以使用 MRI 看到小肿瘤，我们寻求资金来展示分散的肿瘤边界的描绘以及使用 PTP 检测微小的癌细胞簇。通过 MRI 进行分子成像探针。由于 MR 的非特异性、非定量性质，即使典型的空间分辨率约为 1x1x5 mm3，即使是熟练的放射科医生也没有信心具体诊断肿瘤大于 5x5x5 mm3。我们的方法是通过 PTP 的放大特性大大提高 MR 信号相对于背景解剖变化的对比度。我们发现，通过使用 MRI 探头 (PTP¿-Gd)、硬件、采集和软件，我们可以具体识别和表征比目前小 2-3 个数量级的肿瘤。结合高分辨率和MR的分子靶向剂具体目标是： 1. 优化和测试定量分子PTP的能力。 -Gd 探针检测原位异种移植物中的脑肿瘤并与“传统”脑肿瘤 MRI 进行比较 2. 确定 PTP 的能力。 -Gd 与显微冷冻成像的金标准 GFP 标记肿瘤相比，能够准确地对分散性脑肿瘤进行成像 3. 使用临床上可行的 (3T) 双试剂方法优化定量 MRI，以测试检测小型孤立脑肿瘤的极限。在一个 高度分散的肿瘤模型。