ADVANCED MR TECHNOLOGIES FOR PROBING THE TUMOR MICROENVIRONMENT

用于探测肿瘤微环境的先进 MR 技术

• 批准号: 8171671
• 负责人: Vikram D. Kodibagkar
• 金额: $ 0.52万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171671
• 关键词: Address; Affect; Albumins; Angiogenesis Inhibitors; Area; Brain; Breast; Breast Cancer Detection; Chemical Shift Imaging; Clinic; Clinical; Combination Drug Therapy; Computer Retrieval of Information on Scientific Projects Database; Contrast Media; Data; Data Quality; Data Set; Development; Frequencies; Funding; Funding Agency; Gadolinium DTPA; Goals; Grant; Hyperbaric Oxygen; Hypoxia; Image; Institution; Investigation; Kinetics; Lesion; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Methods; Modeling; Molecular; Monitor; Muscle; Operative Surgical Procedures; Oxygen saturation measurement; Patients; Photochemotherapy; Physiologic pulse; Protons; Radiation therapy; Radio; Rattus; Research; Research Personnel; Resources; Scanning; Silanes; Solid; Source; Specificity; Staging; Techniques; Technology; Therapeutic Intervention; Time; Tissue Differentiation; Tissues; Treatment outcome; Tumor Oxygenation; United States National Institutes of Health; base; cancer therapy; chemotherapy; improved; in vivo; interstitial; malignant breast neoplasm; nanoemulsion; nanoprobe; novel; prognostic indicator; reconstruction; response; silane; technology development; tissue oxygenation; tumor; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is a broad effort to improve our ability to monitor the microenvironment of a tumor. There are three sub-projects. First, It is well-known that hypoxic or even anoxic regions in solid-growing tumors may limit the efficacy of non-surgical therapy, including radiotherapy, photodynamic therapy, chemotherapy. Accurate assessment of tumor oxygenation at various stages of tumor growth and in response to interventions/therapy may provide a better understanding of tumor development and may serve as a prognostic indicator for treatment outcome, potentially allowing individualized cancer therapy. We have recently identified a 1H MRI probe of pO2: hexamethyldisiloxane (HMDSO). The PI has developed a new, HMDSO-based quantitative MR oximetry technique PISTOL (Proton Imaging of Silanes to Map Tissue Oxygenation Levels) for mapping of tissue interstitial pO2. This technique has been applied to study the tumor microenvironmenental response to therapy in this project. The goal of the first subproject is to optimize synthesis and characterization of HMDSO based nanoemulsions as pO2 nanoprobes (funding source 1) for 1H MRI based oximentry and uses them to study tumor response to combination chemotherapy. The goal of the second subproject (funding source 2) is to study the response of combining hyperbaric oxygen with pO2-sensitive photodynamic therapy of cancer with pO2 nanoprobes. In another area of technology development, three dimensional Chemical Shift Imaging (3D-CSI) is an MR-based non-invasive approach used in the clinic to quantify and monitor these metabolites. A major hurdle in routine clinical use of 3D-CSI is the long acquisition time and hence the time spent by the patient in the scanner. Therefore a strong need to address this problem exists to enable clinicians to make routine use of this powerful technology. The proposed project aims to overcome this limitation by the use of compressive sensing, which has been a revolutionary invention in the past few years. This technique has been successfully implemented for MRI and promises to be a new path for reducing acquisition times for MRI scans. We plan to conduct a retrospective analysis of brain and breast CSI data sets in order to compare metabolite maps obtained with conventional k-space reconstruction method to compressive sensing based reconstruction using undersampled data. We hypothesize that by exploiting the sparsity of k-space as well as the spectral data, we may be able to reduce CSI scan times for patients by a factor of 2 without significant reduction in the quality of data. A third area of investigation involves contrast agents for breast cancer. Small molecular contrast agents have a high sensitivity for breast cancer detection but a limited specificity for the characterization of the detected lesions. A similar approach, which uses large molecular (macromolecular) contrast agents, can provide this tissue differentiation but the sensitivity is low. One cannot use these two types of agents together as it would be impossible to distinguish between effects of the two. A novel class of contrast agents, called PARACEST agents, have been recently proposed for MRI applications and need to be urgently evaluated in vivo as the theoretically predicted sensitivity of these agents is higher than conventional Gd-based agents. These agents also have the advantage of having image contrast turned on at will using radio-frequency pulses. We planned to study the kinetics of such a macromolecular PARACEST agent albumin-EuDOTA-4Am-(Gly)2(OBz-Ser)2 in rat tumors and subsequently administer a conventional small molecular contrast agent Gd-DTPA. These two agents affect the image contrast using different mechanisms and hence administering the PARACEST agent before Gd-DTPA will not affect the subsequent Gd-DTPA contrast. Specific aims of this project are: 1) Optimization of PARACEST imaging sequence and contrast parameters. 2) Study dynamic PARACEST contrast enhancement (DPCE) kinetics in muscle tissue and tumors and develop kinetic model. 3) Use DPCE kinetics to study response to antiangiogenic therapy in two tumor lines.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 该项目是一项广泛的努力，旨在提高我们监测肿瘤微环境的能力。 共有三个子项目。 首先，众所周知，实体生长肿瘤中的缺氧甚至缺氧区域可能会限制非手术治疗的疗效，包括放射治疗、光动力治疗、化疗。准确评估肿瘤生长各个阶段的肿瘤氧合以及对干预/治疗的反应可以更好地了解肿瘤的发展，并可以作为治疗结果的预后指标，从而有可能实现个体化的癌症治疗。我们最近发现了 pO2 的 1H MRI 探针：六甲基二硅氧烷 (HMDSO)。 PI 开发了一种基于 HMDSO 的新型定量 MR 血氧测定技术 PISTOL（硅烷质子成像以绘制组织氧合水平），用于绘制组织间质 pO2。该技术已应用于本项目中研究肿瘤微环境对治疗的反应。第一个子项目的目标是优化基于 HMDSO 的纳米乳剂的合成和表征，作为基于 1H MRI 的血氧分析的 pO2 纳米探针（资金来源 1），并使用它们来研究肿瘤对联合化疗的反应。第二个子项目（资金来源 2）的目标是研究结合高压氧与 pO2 纳米探针对癌症的 pO2 敏感光动力疗法的反应。 在技​​术开发的另一个领域，三维化学位移成像 (3D-CSI) 是一种基于 MR 的非侵入性方法，用于临床量化和监测这些代谢物。 3D-CSI 常规临床使用的一个主要障碍是采集时间长，因此患者在扫描仪中花费的时间也较长。因此，迫切需要解决这个问题，以使临床医生能够常规使用这种强大的技术。该项目旨在通过使用压缩传感来克服这一限制，压缩传感在过去几年中是一项革命性的发明。该技术已成功应用于 MRI，并有望成为减少 MRI 扫描采集时间的新途径。我们计划对大脑和乳房 CSI 数据集进行回顾性分析，以便将传统 k 空​​间重建方法获得的代谢图与使用欠采样数据的基于压缩感知的重建进行比较。我们假设，通过利用 k 空间和光谱数据的稀疏性，我们也许能够将患者的 CSI 扫描时间减少 2 倍，而不会显着降低数据质量。 第三个研究领域涉及乳腺癌造影剂。 小分子造影剂对乳腺癌检测具有很高的敏感性，但对检测到的病变特征的特异性有限。使用大分子（大分子）造影剂的类似方法可以提供这种组织分化，但灵敏度较低。人们不能同时使用这两种类型的药剂，因为不可能区分两者的效果。最近提出了一种新型造影剂，称为 PARACEST 造影剂，用于 MRI 应用，并且需要紧急进行体内评估，因为理论上预测的这些造影剂的灵敏度高于传统的基于 Gd 的造影剂。这些试剂还具有使用射频脉冲随意打开图像对比度的优点。我们计划研究这种大分子 PARACEST 剂白蛋白 -EuDOTA-4Am-(Gly)2(OBz-Ser)2 在大鼠肿瘤中的动力学，然后施用传统的小分子造影剂 Gd-DTPA。这两种试剂使用不同的机制影响图像对比度，因此在 Gd-DTPA 之前施用 PARACEST 试剂不会影响随后的 Gd-DTPA 对比度。该项目的具体目标是： 1）优化 PARACEST 成像序列和对比度参数。 2) 研究肌肉组织和肿瘤中的动态 PARACEST 对比增强 (DPCE) 动力学并开发动力学模型。 3) 使用 DPCE 动力学研究两种肿瘤系对抗血管生成治疗的反应。