Measuring Tumor Acidosis with PET/MRI Contrast Agents

使用 PET/MRI 造影剂测量肿瘤酸中毒

• 批准号: 9750458
• 负责人: Mark David Pagel
• 金额: $ 24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750458
• 关键词: 4-nitrophenol; Acidosis; Address; Animals; Attention; Benchmarking; Bicarbonates; Biological Markers; Bladder; Chelating Agents; Clinical; Concentration measurement; Contrast Media; Cyclotrons; Data; Detection; Development; Diagnosis; Drug Kinetics; Ensure; Environment; Evaluation; Gadolinium; Goals; Immunotherapy; Inductively Coupled Plasma Mass Spectrometry; Infrastructure; Injections; Ions; Kidney; Label; Lead; Ligands; MRI Scans; Magnetic Resonance Imaging; Malignant neoplasm of pancreas; Maps; Measurement; Measures; Microelectrodes; Modeling; Mus; Nitrophenol; Patients; Pharmacotherapy; Positron-Emission Tomography; Problem Solving; Protocols documentation; Radioactivity; Radiochemistry; Radiolabeled; Receptor Cell; Relaxation; Reporting; Research; Research Personnel; Scanning; Small Animal Imaging Systems; Solid Neoplasm; System; Technology; Tissues; Tracer; Tumor Tissue; animal imaging; base; cancer imaging; cellular imaging; clinical translation; contrast imaging; design; experience; extracellular; human cancer mouse model; imaging modality; imaging study; improved; in vivo; innovation; metabolic abnormality assessment; metaiodobenzylguanidine; metal chelator; molecular imaging; non-invasive imaging; pre-clinical; predicting response; response; success; tumor; tumor microenvironment

Our goal is to quantitatively measure extracellular pH (pHe) in the tumor microenvironment to assess tumor acidosis. These assessments can be used to improve evaluations of solid tumors, to aid in predicting the response to immunotherapy before the treatment is initiated, and to evaluate the early response of tumors to many types of drug treatment. These multiple applications can provide strong impact for studies of mouse tumor models, and eventually for patients who have solid tumors. To meet this goal, we propose to develop PET/MRI contrast agents that can quantitatively measure pHe, and apply these agents during simultaneous PET/MRI studies in mouse models of human cancers. Dynamic changes in the relaxation-based MR image contrast are sensitive to tumor pHe as well as the concentration of the agent in tumor tissue, while the PET image can be used to measure the concentration of the agent in the tumor. Therefore, the PET results can be used to account for the effect of concentration on MR image contrast, which can improve the quantitative measurement of tumor pHe. To overcome the difference in detection sensitivities of PET and MRI, we will co-inject 0.01% “hot” radiolabeled agent and 99.99% “cold” MRI contrast agent. Notably, this approach would fail to image cell receptors or intracellular biomarkers, but is ideally suited to interrogate the extracellular tumor microenvironment. In particular, these agents are designed to have the same pharmacokinetic delivery to the extracellular tumor microenvironment during the first 10 minutes after co- injection, so that the MBq radioactivity measurement with PET can be used to evaluate the M concentration of the MRI contrast agent. Therefore, our development of contrast agents for simultaneous PET/MRI has strong innovation for cancer imaging. Accurate and precise measurements of tumor pHe requires great attention to rigor, especially to address potential inaccuracies and imprecisions with both imaging modalities. Therefore, we have designed a strong research approach with careful attention to rigor. We have assembled a team of strong investigators who have extensive experience in developing “smart” MRI contrast agents and PET tracers, and performing molecular imaging studies with small animal tumor models especially for imaging tumor acidosis. We have recently obtained one of the few commercial PET/MRI systems for small animal imaging world-wide, and MD Anderson has an extensive infrastructure for radiochemistry and small animal imaging, which attests to our strong environment. Our deliverable is a fundamentally new class of contrast agents for molecular imaging with PET/MRI. As a longer term goal, our PET/MRI contrast agents have outstanding potential for clinical translation, which will provide a transformative “game changing technology” for clinical PET/MRI.

我们的目标是定量测量肿瘤微环境中的细胞外pH值（pHe），以评估肿瘤微环境中的pH值。 酸中毒这些评估可用于改善实体瘤的评估，以帮助预测肿瘤的预后。 在治疗开始之前，评估肿瘤对免疫疗法的早期反应， 多种药物治疗。这些多重应用可以为小鼠肿瘤的研究提供强大的影响 模型，并最终用于患有实体瘤的患者。 为了实现这一目标，我们建议开发能够定量测量pHe的PET/MRI造影剂， 并在人类癌症小鼠模型的同步PET/MRI研究中应用这些药物。动态 基于弛豫的MR图像对比度的变化对肿瘤pHe以及 肿瘤组织中的药剂，而PET图像可用于测量肿瘤组织中药剂的浓度。 肿瘤因此，PET结果可用于解释浓度对MR图像对比度的影响， 其可改善肿瘤pHe的定量测量。为了克服检测上的差异 为了提高PET和MRI的灵敏度，我们将共同注射0.01%“热”放射性标记剂和99.99%“冷”MRI造影剂 剂值得注意的是，这种方法无法成像细胞受体或细胞内生物标志物，但非常适合 来研究肿瘤细胞外的微环境。特别地，这些代理被设计为具有 在共同给药后的前10分钟期间，向细胞外肿瘤微环境的药代动力学递送相同。 因此，使用PET进行的MBq放射性测量可用于评估 MRI造影剂。因此，我们开发的同步PET/MRI造影剂具有很强的 癌症成像的创新。 肿瘤pHe的准确和精确测量需要高度重视严谨性，特别是要解决潜在的 两种成像模式的不准确性和不精确性。因此，我们设计了一个强大的研究 仔细注意严谨的方法。我们已经组建了一个强大的调查小组， 在开发“智能”MRI造影剂和PET示踪剂以及进行分子成像研究方面的经验 与小动物肿瘤模型，特别是用于成像肿瘤酸中毒。我们最近获得了为数不多的 MD安德森拥有广泛的基础设施， 用于放射化学和小动物成像，这证明了我们强大的环境。 我们的产品是一种全新的PET/MRI分子成像造影剂。作为 长期目标是，我们的PET/MRI造影剂具有出色的临床转化潜力， 为临床PET/MRI提供一种变革性的“改变游戏规则的技术”。