EVALUATION OF ANTIANGIOGENIC THERAPY OF BREAST CANCER USING PARACEST MRI

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 根据美国癌症协会2004年的统计数据，乳腺癌仍然是美国妇女癌症死亡的第二大原因。这突出表明需要研究乳腺癌检测技术，以促进在疾病的早期阶段进行检测和治疗。具有高灵敏度和特异性的检测技术也将降低目前乳腺肿块妇女的高阴性活检率，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）对乳腺癌检测具有高灵敏度，但对检测到的病变的表征具有有限的特异性。常规的大分子造影剂具有提供这种组织分化的潜力，但灵敏度低。不能同时使用这两种药剂，因为无法区分两者的效果。最近提出了一类基于化学交换饱和转移（CEST）效应的新型顺磁性造影剂用于MRI应用。这类新的 Paracest 造影剂迫切需要在体内进行评价，特别是因为这些造影剂的理论预测灵敏度高于常规的基于Gd的造影剂。由于与Gd-DTPA相比其T1弛豫率非常低，其给药不会影响随后对同一受试者进行的Gd-DTPA研究。在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将显示理论上预测的对盐水模型中浓度的依赖性，2）PARACEST试剂将不影响Gd-DTPA的弛豫率，3）在大鼠乳腺肿瘤中将在体内观察到动态PARACEST对比增强（DPCE），3）DPCE将允许提取组织参数，例如内皮渗透性KPS和血浆体积分数fPV，以及4）组合DPCE和DCE将允许对大鼠乳腺肿瘤中的抗血管生成疗法进行预后评估。1）确定最佳MRI方案以检测白蛋白-Eu-DOTA-4Am-（Gly）2（OBz-Ser）2的盐水模型中的最大对比度增强。2)测量MR图像对比度的浓度依赖性，并与理论进行比较。3)测试PARACEST试剂的存在对Gd-DTPA弛豫率的影响。4)在大鼠乳腺肿瘤中进行体内MRI研究，检测PCE并跟踪随时间推移的动力学。5)使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对抗血管生成治疗的反应，包括环磷酰胺的节拍时间表。这项工作为在乳腺癌诊断中使用新型MRI造影剂奠定了基础。在这个项目中，我们计划将联合收割机从大分子PARACEST造影剂在大鼠肿瘤中的造影动力学获得的信息与标准Gd-DTPA造影剂动力学获得的信息相结合。因此，我们希望联合收割机将高分子PARACEST试剂的高特异性和敏感性与Gd-DTPA的高敏感性结合起来。我们希望这些敏感的药物将提高乳腺癌恶性病变检测的特异性。 这个项目需要研究资源的成功完成。 PARACEST实验将与研究资源的核心2合作进行，并与Sherry博士密切合作。合成铕试剂的实验室。将使用中心磁体并在中心工作人员的技术支持下进行MR实验。

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. Sherrys lab who synthesize the Europium agents. MR experiments will be performed with Center magnets and with the technical support of Center staff.