EVALUATION OF ANTIANGIOGENIC THERAPY OF BREAST CANCER USING PARACEST MRI

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。 根据美国癌症协会2004年的统计数据，乳腺癌仍然是美国女性癌症死亡的第二大原因。这突显了研究乳腺癌检测技术的必要性，以促进在疾病的早期阶段发现和治疗。具有高灵敏度和高特异度的检测技术也将降低目前乳腺肿块妇女的高阴性活检比率，并有助于定制个性化的治疗方案。用常规的、改变T1的小分子造影剂增强的乳腺磁共振成像(MRI)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。传统的大分子造影剂有可能提供这种组织分化，但敏感性较低。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。基于化学交换饱和转移(CEST)效应的新型顺磁性造影剂最近被提出应用于磁共振成像。这种新型的PARACEST造影剂迫切需要在体内进行评估，特别是因为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。由于与Gd-DTPA相比，Gd-DTPA的T1弛豫度非常低，其给药不会影响随后对同一对象进行的Gd-DTPA研究。本项目期间要检验的具体假设是：1)PARACEST试剂白蛋白-Eu-DOTA-4AM-(Gly)2(OBZ-Ser)2将显示出理论上预测的盐水模体浓度依赖性；2)PARACEST试剂不会影响Gd-DTPA的松弛性能；3)将在大鼠乳腺肿瘤中观察到动态PARACEST对比增强(DPCE)；3)DPCE将允许提取组织参数，如内皮通透性KPS和血浆容量分数FPV；4)结合DPCE和DCE将可以对大鼠乳腺肿瘤的抗血管生成治疗进行预后评估。我们将通过以下步骤验证我们的假设：1)确定最佳MRI方案以检测白蛋白-Eu-DOTA-4Am-(Gly)2(OBZ-Ser)盐水模的最大对比度增强；2)测量MR图像对比度的浓度依赖关系，并与理论进行比较。3)测试PARACEST试剂的存在对Gd-DTPA弛豫度的影响。4)在大鼠乳腺肿瘤中进行体内MRI研究，检测PCE，并在时间过程中跟踪动力学。5)用标准药代动力学模型从DPCE数据中提取血管特征KPS和Fpv。6)比较DPCE和DCE对由环磷酰胺节律程序组成的抗血管生成治疗的反应。这项工作为新型核磁共振造影剂在乳腺癌诊断中的应用奠定了基础。在这个项目中，我们计划将大分子对比剂在大鼠肿瘤中的对比动力学获得的信息与标准Gd-DTPA对比剂动力学获得的信息相结合。因此，我们希望将大分子PARACEST试剂的高特异性和敏感性与Gd-DTPA的高敏感性结合起来。我们希望这些敏感试剂能提高检测乳腺癌恶性病变的特异性。此项目需要研究资源才能成功完成。PARACEST实验将与研究资源中心的核心2合作进行，并与合成铕试剂的Sherry博士的实验室密切合作。磁共振实验将在中心磁铁和中心工作人员的技术支持下进行。

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. Breast cancer continues to be the second leading cause of cancer deaths in American women according to American Cancer Society statistics for 2004. This highlights the need for research in breast cancer detection techniques to facilitate detection and treatment at an early stage in the disease. A detection technique with high sensitivity and specificity would also decrease the current high rate of negative biopsies of women with breast masses and help tailor individualized therapeutic options. Magnetic resonance imaging (MRI) of the breast enhanced with conventional, T1 altering, small molecular contrast agents have a high sensitivity for breast cancer detection but a limited specificity for characterization of the detected lesions. Conventional macromolecular contrast agents have the potential to 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 paramagnetic contrast agents based on the chemical exchange saturation transfer (CEST) effect has been recently proposed for MRI applications. This new class of "PARACEST" contrast agents needs to be urgently evaluated in vivo especially since the theoretically predicted sensitivity of these agents is higher than conventional Gd-based agents. Due to its very low T1 relaxivity compared to Gd-DTPA, its administration will not affect a Gd-DTPA study performed on the same subject subsequently. Specific hypotheses to be tested during this project are: 1) PARACEST agent albumin-Eu-DOTA-4Am-(Gly)2(OBz-Ser)2 will display the theoretically predicted dependence on concentration in saline phantoms, 2) the PARACEST agent will not affect the relaxivity of Gd-DTPA, 3) Dynamic PARACEST contrast enhancement (DPCE) will be observed in vivo in rat breast tumors, 3) DPCE will allow extraction of tissue parameters such as endothelial permeability KPS and fractional plasma volume fPV and 4) Combining DPCE and DCE will allow prognostic evaluation of anti-angiogenic therapy in rat breast tumors. We will test our hypotheses using the following steps.1) Determine optimal MRI protocols to detect maximum contrast enhancement in saline phantoms of albumin-Eu-DOTA-4Am-(Gly)2(OBz-Ser)2. 2) Measure concentration dependence of MR image contrast and compare with theory. 3) Test the effect of the presence of PARACEST agent on the relaxivity of Gd-DTPA. 4) Perform in vivo MRI studies in rat breast tumors detect PCE and to follow kinetics over the time course. 5) Extract the vascular characteristics KPS and fPV from DPCE data using standard pharmacokinetic model. 6) Compare DPCE and DCE response to antiangiogenic therapy consisting of metronomic scheduling of cyclophosphamide. This work serves to lay the groundwork for the use of a new class of MRI contrast agents in breast cancer diagnostics. In this project, we plan to combine the information obtained from contrast kinetics of macromolecular PARACEST agent in rat tumors and with that from standard Gd-DTPA contrast agent kinetics. We, thus hope to combine the higher specificity and sensitivity of a macromolecular PARACEST agent with the high sensitivity of Gd-DTPA. We are hopeful that these sensitive agents will improve the specificity of detection of malignant lesions in breast cancer. This project requires the Research Resource for successful completion. PARACEST experiments will be performed in collaboration with Core 2 of the Research Resource and in close concert with Dr. Sherry's lab who synthesize the Europium agents. MR experiments will be performed with Center magnets and with the technical support of Center staff.