ADVANCED MR TECHNOLOGIES FOR PROBING THE TUMOR MICROENVIRONMENT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个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。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。在肿瘤生长的不同阶段和对干预/治疗的反应中，对肿瘤氧合的准确评估可能会更好地了解肿瘤的发展，并可能作为治疗结果的预后指标，潜在地允许个体化的癌症治疗。我们最近发现了一种pO2：六甲基二硅氧烷(HMDSO)的1H磁共振探针。PI开发了一种新的、基于HMDSO的定量磁共振血氧仪技术PISTOL(硅烷质子成像以映射组织氧合水平)，用于绘制组织间质pO2的图谱。这项技术已被应用于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的纳米乳液的合成和表征，作为1H MRI基羟胺类药物的pO2纳米探针(资金来源1)，并将其用于研究肿瘤对联合化疗的反应。第二个子项目(资金来源2)的目标是研究高压氧与二氧化硅敏感的光动力疗法结合起来的反应，以及二氧化硅纳米探针对癌症的影响。 在另一个技术发展领域，三维化学位移成像(3D-CSI)是一种基于磁共振的非侵入性方法，用于临床对这些代谢物进行量化和监测。3D-CSI常规临床应用的一个主要障碍是采集时间较长，因此患者在扫描仪中花费的时间也较长。因此，迫切需要解决这一问题，以使临床医生能够常规使用这项强大的技术。拟议的项目旨在通过使用压缩传感来克服这一限制，这在过去几年是一项革命性的发明。这项技术已成功应用于磁共振成像，有望成为减少磁共振成像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，以比较使用传统k空间重建方法获得的代谢物图和使用欠采样数据进行基于压缩感知的重建。我们假设，通过利用k空间的稀疏性和光谱数据，我们可能能够在不显著降低数据质量的情况下将患者的CSI扫描时间减少2倍。 第三个研究领域涉及乳腺癌的造影剂。小分子造影剂对乳腺癌的检测具有很高的敏感性，但对检测到的病变特征的特异度有限。一种类似的方法，使用大分子(大分子)造影剂，可以提供这种组织分化，但敏感性低。人们不能同时使用这两种药剂，因为无法区分这两种药剂的效果。最近提出了一类新的造影剂，称为PARACEST造影剂，用于磁共振成像，由于这些造影剂的理论预测灵敏度高于传统的基于Gd的造影剂，因此迫切需要在体内进行评估。这些试剂还具有使用射频脉冲随意打开图像对比度的优势。我们计划研究这种大分子对比剂白蛋白-EuDOTA-4Am-(Gly)2(OBZ-Ser)2在大鼠肿瘤中的动力学，并随后给予常规小分子造影剂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之前使用PARACEST试剂不会影响随后的Gd-DTPA对比度。本项目的具体目标是：1)优化PARACEST成像序列和对比度参数。2)研究肌肉组织和肿瘤的动态增强动力学，建立动力学模型。3)用DPCE动力学方法研究两种肿瘤细胞对抗血管生成治疗的反应。

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.