(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

基本信息

批准号：
8913906
负责人：
SUSANN M BRADY-KALNAY
金额：
$ 61.7万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913906
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 Health 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 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 contrast enhanced density extracellular gadolinium oxide image processing image registration imaging agent imaging modality imaging probe improved in vivo in vivo imaging interest molecular imaging neoplastic cell novel optical emission spectroscopy quantitative imaging radiologist reconstruction research study restraint tumor tumor microenvironment white matter

项目摘要

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（由适用提供）：早期肿瘤检测是肿瘤成像至关重要的目标，因为它可以在疾病的早期阶段实现治疗（或重定向）。但是，挑战是对肿瘤细胞的少量集合进行成像，因为常规的体内成像方法的分辨率和肿瘤对比度有限。 MRI呈现出独家解剖学细节和许多对比机制，但仍经常被证明无法检测到肿瘤细胞的小簇。我们的策略将是开发具有巨大扩增潜力的磁共振成像（MRI）剂，并使用磁共振（MR）采集和图像处理技术提供足够的对比度以检测到很小的肿瘤。我们的建议建立在大量初步数据的基础上，并汇集了探针化学，肿瘤模型，肿瘤生物学，独特的3D微观冷冻模仿，高级MR技术和定量图像分析方面的重要多学科专业知识。迄今为止，我们通过靶向PTP的细胞外片段发现了一种新颖的分子成像策略。在肿瘤微环境中成功发现；创建了胶质瘤的小鼠原位模型；开发了3D脑重建中的肿瘤大小，细胞分散，白质和血管密度的可视化和量化的冷冻成像方法；并发现荧光PTP。探针迅速标记为主肿瘤以及分散细胞，甚至距离主要肿瘤质量3.5 mm的单个迁移细胞。最近，使用Gadolinium共轭PTP探针进行初步研究，表明我们可以使用MRI看到小肿瘤。我们寻求资金来证明使用PTP分子成像探针通过MRI来描述分散肿瘤边界的描述并检测癌细胞的微小簇。即使是熟练的放射科医生，直到肿瘤大于5x5x5 mm3之前，即使典型的空间分辨率约为1x1x15 mm3，也将没有信心诊断出肿瘤。我们的方法是通过PTP MRI探针（PTP-GD），硬件，获取和软件改进的放大特性，将MR信号相对于背景解剖学变化的对比度很大。我们假设我们可以通过使用PTP分子靶向剂与高分辨率和定量MR相结合的PTP分子靶向剂来特定鉴定和表征2-3个数量级的肿瘤2-3个数量级。具体目的是：1。优化和测试分子PTP数字探针检测原位异种移植物中脑肿瘤的能力，并与“常规”脑肿瘤MRI进行比较。 2。确定PTP数字能够与微观模仿的金色标准GFP标记的肿瘤相比，确定PTP数字准确分散脑肿瘤的能力。 3.使用临床上可行的（3T）双手方法来测试检测A中小型孤立脑肿瘤的极限，优化定量MRI 非常分散的肿瘤模型。