Assessments of Multiple Breast Cancer Biomarkers with Dendritic MRI Probes

描述(由申请人提供)：一个研究和职业发展计划建议从化学背景过渡到生物医学成像和癌症生物学的独立研究计划。一个两级研究计划将首先专注于开发新的MRI造影剂，然后将重点放在将这些MRI造影剂应用于乳腺癌的小鼠模型上。这项研究计划建立在开发和应用新型MRI造影剂的基础上，这种造影剂可以在单个MRI扫描过程中监测多个癌症生物标志物。我们建议进行的研究的目标是：A)开发一种新的T1松弛剂，它可以准确测量转移性乳腺癌组织的细胞外酸性pH，同时通过包含一种PARACEST磁共振对比剂来解释药物的浓度；B)开发一种新的针对v3细胞整合素的PARACEST试剂；C)将这些试剂与一种新的PARACEST试剂相结合，这种试剂可以测量血管通透性以评估肿瘤血管生成；以及D)通过测量细胞外pH值、检测v3的表达和评估血管通透性来评估乳腺癌小鼠模型的治疗效果。我们的产品包括可携带磁共振造影剂的纳米树枝状大分子，以提高检测灵敏度，并通过增强渗透性和滞留效应提高肿瘤组织的特异性。这些特定目标的成功完成将导致使用我们新的MRI方法对改变肿瘤pH或v3表达水平的治疗效果进行评估。这种纳米粒子和分子成像的独特组合构成了许多其他生物医学应用的平台技术。 还将制定一个两级职业发展计划。生物医学成像方面的培训将通过生物医学工程和放射学专家的指导来实现。指导委员会还将提供指导，同时引导建立新研究计划所需的活动。在第二年，癌症生物学的高级导师将在癌症研究应用和专业发展活动中提供指导。还提出了一个进步性计划，以在整个过程中培养作为导师、领导者、网络工作者、演讲者、作家、合作者和企业家的技能，以便在生物医学成像和癌症研究方面发展一个独立的、配备人员和充分资源的研究计划。 公共卫生相关性：该项目的结果将提供一种非侵入性地测量活体PH值的直接方法。因此，肿瘤组织中的细胞外pH(Phe)将作为一种诊断生物标志物来确定病理预后，评估Phe改变治疗的疗效，并预测Phe依赖的化疗的疗效。此外，多功能纳米MRI探针将用于在一次MRI扫描中评估多个肿瘤特异性生物标志物，这项新技术将显著提高乳腺癌的早期诊断和治疗。此外，有组织的职业发展计划将使PI项目成为独立的调查员。

DESCRIPTION (provided by applicant): A research and career development plan is proposed to transition from a background in chemistry to an independent research program in biomedical imaging and cancer biology. A two-tiered research plan will first focus on developing new MRI contrast agents, and then focus on applying these MRI contrast agents to mouse models of breast cancer. This research plan is founded on the development and application of new types of MRI contrast agents that can monitor multiple cancer biomarkers during a single MRI scan session. Our objectives of the proposed research are A) to develop a new T1 relaxation agent that can accurately measure the acidic extracellular pH of metastatic breast tumor tissues, while also accounting for the concentration of the agent by including a PARACEST MRI contrast agent; B) to develop a new PARACEST agent that targets v3 cell integrin; C) to combine these agents with a new PARACEST agent that can measure vascular permeabilities in order to assess tumor angiogenesis and D) to assess therapeutic responses in breast cancer mouse models by measuring extracellular pH, detecting v3 expression and evaluating vascular permeability during a single MRI scan session. Our deliverable consists of nano-sized dendrimers that can carry the MRI contrast agents for improved detection sensitivity, and for improved specificity for tumor tissues through the Enhanced Permeability and Retention effect. Successful completion of these specific aims will lead to evaluations of therapeutic efficacies that change tumor pH or v3 expression levels using our new MRI methods. This unique combination of nanoparticles and molecular imaging constitutes a platform technology for many other biomedical applications. A two-tiered career development plan will also be established. Training in biomedical imaging will be achieved through guidance by experts in biomedical engineering and radiology. A mentor committee will also provide guidance while navigating the activities required to establish a new research program. During the second year, senior mentors in cancer biology will provide guidance in cancer research applications and professional development activities. A progressive plan is also proposed to develop skills as a mentor, leader, networker, presenter, writer, collaborator, and entrepreneur throughout this process, in order to develop an independent, staffed and fully resourced research program in biomedical imaging and cancer research. PUBLIC HEALTH RELEVANCE: The results of this project will provide a direct method to measure in vivo pH non-invasively. Thus, the extracellular pH (pHe) within tumor tissues will be used as a diagnostic biomarker to determine the prognosis of pathology, to evaluate the efficacy of pHe-altering therapies and to predict the efficacy of pHe-dependent chemotherapies. Besides, multifunctional nano-sized MRI probes will be used to assess multiple, tumor specific biomarkers in a single MRI scan session and this novel technology will significantly enhance in the early diagnosis and treatment of breast cancer. In addition, a structured career development plan will make project PI as an independent investigator.