Assessments of Multiple Breast Cancer Biomarkers with Dendritic MRI Probes

描述（由申请人提供）：提出一项研究和职业发展计划，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项目。一个两级研究计划将首先侧重于开发新的MRI造影剂，然后侧重于将这些MRI造影剂应用于乳腺癌小鼠模型。该研究计划建立在新型MRI造影剂的开发和应用上，该造影剂可以在一次MRI扫描期间监测多种癌症生物标志物。我们提出的研究目标是A)开发一种新的T1松弛剂，可以准确测量转移性乳腺肿瘤组织的酸性细胞外pH值，同时还可以通过包含PARACEST MRI造影剂来计算该剂的浓度；B)开发一种靶向v3细胞整合素的PARACEST新药；C)将这些药物与一种新的PARACEST药物联合使用，该药物可以测量血管通透性，以评估肿瘤血管生成；D)在单次MRI扫描期间通过测量细胞外pH值、检测v3表达和评估血管通透性来评估乳腺癌小鼠模型的治疗反应。我们的产品由纳米级树状大分子组成，可以携带MRI造影剂，以提高检测灵敏度，并通过增强渗透性和保留效应提高肿瘤组织的特异性。成功完成这些特定目标将导致使用我们的新MRI方法来评估改变肿瘤pH值或v3表达水平的治疗效果。这种纳米颗粒和分子成像的独特结合构成了许多其他生物医学应用的平台技术。

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.