Assessments of Multiple Breast Cancer Biomarkers with Dendritic MRI Probes

使用树突状 MRI 探针评估多种乳腺癌生物标志物

• 批准号: 8133527
• 负责人: Meser M. Ali
• 金额: $ 13.13万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133527
• 关键词: Accounting; Address; Animal Model; Bicarbonates; Binding; Biological Markers; Biomedical Engineering; Blood Vessels; Breast; Breast Cancer Cell; Cancer Biology; Cancer Patient; Cancer cell line; Cancerous; Cells; Characteristics; Chemicals; Chemistry; Cilengitide; Clinic; Contrast Media; Dendrimers; Detection; Development; Development Plans; Diagnosis; Diagnostic; Disease; Doxorubicin; Early Diagnosis; Early treatment; Evaluation; Goals; Growth; Image; Integrin Binding; Integrins; Lead; Lesion; Longitudinal Studies; MCF7 cell; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Measurement; Measures; Mentors; Methods; Molecular; Monitor; Neoplasm Metastasis; Normal tissue morphology; Pathology; Patients; Permeability; Phenotype; Process; Radiology Specialty; Relaxation; Research; Research Personnel; Specificity; Structure; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; Training; Translating; Treatment Efficacy; Tumor Angiogenesis; Tumor Tissue; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; anticancer research; base; bioimaging; cancer therapy; career development; chemotherapy; cyclo(S,S)KYGCRGDWPC; extracellular; imaging modality; imaging probe; improved; in vivo; malignant breast neoplasm; molecular imaging; mouse model; nanoparticle; nanoscale; nanosized; neovasculature; new technology; outcome forecast; programs; public health relevance; receptor; research and development; response; skills; tumor

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.

描述（由申请人提供）：提出了一项研究和职业发展计划，以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。一个两层的研究计划将首先专注于开发新的 MRI 造影剂，然后专注于将这些 MRI 造影剂应用于乳腺癌小鼠模型。该研究计划基于新型 MRI 造影剂的开发和应用，该造影剂可以在单次 MRI 扫描过程中监测多种癌症生物标志物。我们拟议研究的目标是 A) 开发一种新的 T1 松弛剂，它可以准确测量转移性乳腺肿瘤组织的酸性细胞外 pH 值，同时还通过包含 PARACEST MRI 造影剂来解释该剂的浓度； B) 开发一种针对 v3 细胞整合素的新型 PARACEST 药物； C) 将这些药物与可测量血管通透性的新型 PARACEST 药物结合起来，以评估肿瘤血管生成；D) 通过在单次 MRI 期间测量细胞外 pH、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扫描会话。我们的产品包括纳米尺寸的树枝状聚合物，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。成功完成这些具体目标将导致使用我们的新 MRI 方法评估改变肿瘤 pH 或 v3 表达水平的治疗效果。纳米粒子和分子成像的这种独特组合构成了许多其他生物医学应用的平台技术。 还将制定两级职业发展计划。生物医学成像培训将在生物医学工程和放射学专家的指导下完成。导师委员会还将在开展建立新研究计划所需的活动时提供指导。在第二年，癌症生物学的高级导师将提供癌症研究应用和专业发展活动的指导。还提出了一项渐进计划，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开发一个独立的、人员配备齐全的研究项目。 公共健康相关性：该项目的结果将提供一种非侵入性测量体内 pH 值的直接方法。因此，肿瘤组织内的细胞外pH (pHe)将被用作诊断生物标志物，以确定病理学预后、评估pHe改变疗法的功效以及预测pHe依赖性化疗的功效。此外，多功能纳米级 MRI 探针将用于在一次 MRI 扫描过程中评估多种肿瘤特异性生物标志物，这项新技术将显着增强乳腺癌的早期诊断和治疗。此外，结构化的职业发展计划将使项目 PI 成为一名独立研究者。