Measuring extracellular pH in pre-clinical tumor models with CEST MRI

使用 CEST MRI 测量临床前肿瘤模型中的细胞外 pH 值

基本信息

批准号：
8817152
负责人：
Mark David Pagel
金额：
$ 39.33万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8817152
关键词：
Acidity Acids Address Affect Alkalinization Bicarbonates Biological Markers Blood flow Breast Carcinoma Buffers Chemical Agents Chemicals Chlorambucil Clinic Clinical Detection Development Dose Doxorubicin Engineering Goals Individual Injection of therapeutic agent Kidney Kidney Neoplasms Lung MDA MB 231 Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant Neoplasms Maps Measurement Measures Methodology Methods Modeling Monitor Mus Neoplasm Metastasis Pathology Patients Pharmaceutical Preparations Physicians Physiologic pulse Research Research Project Grants Resolution Solid Neoplasm Testing Therapeutic Effect Translating Translations base cancer therapy chemotherapy design dosage drinking water extracellular imaging modality improved in vivo innovation malignant breast neoplasm meetings mouse model non-invasive imaging personalized medicine pre-clinical preclinical study response success tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): This proposal will continue the development of an innovative MRI method that can measure the extracellular pH (pHe) of the tumor microenvironment. Our MRI method uses Chemical Exchange Saturation Transfer (CEST) agents that accurately and precisely measure pH. We have used our CEST agents and CEST MRI methods to map tumor pHe in mouse tumor models. We propose to improve the detection sensitivity of CEST MRI to facilitate our pre-clinical studies eventual clinical translation. Our research has strong impact because tumor pHe measurements may be used to predict the effects of weak-base and weak-acid chemotherapies before they are administered to a patient. Tumor pHe measurements may also be used to monitor alkalinizing therapies that can increase survival and decrease metastasis. We propose to establish that our CEST MRI method can measure tumor pHe with sufficient accuracy and precision to impact the choice of cancer therapies. ¿ Specific Aim 1: To improve the detection sensitivity of CEST MRI methods and CEST agents that measure tumor pHe. We will optimize the saturation period of the CEST MRI pulse sequence, and improve our paramagnetic CEST agents to have larger chemical shifts. ¿ Specific Aim 2: To monitor the effect of alkalinizing therapy using tumor pHe measurements. We hypothesize that monitoring pHe can be used to optimize the dose of an alkalinizing therapy to raise tumor pHe without affecting kidney pHe. ¿ Specific Aim 3: To quantitatively predict chemotherapeutic effects with tumor pHe measurements. We hypothesize that a single tumor pHe measurement before initiating chemotherapy can quantitatively predict the therapeutic effect on tumor growth. Our deliverable is a clinically-translatable imaging method that can profoundly impact personalized medicine. By quantitatively measuring the acidity of a solid tumor, a physician may then select the weak-base or weak- acid chemotherapy that should have a better therapeutic effect for that individual patient. By monitoring the pHe of the tumor and kidney, a physician may adjust an alkalinizing treatment dosage to provide an optimal therapeutic effect for an individual patient. Although our research focuses on breast cancer, our methodology can impact personalized medicine for many other cancers and other pathologies.

描述（由申请人提供）：该提案将继续开发一种创新的 MRI 方法，该方法可以测量肿瘤微环境的细胞外 pH (pHe)。我们的 MRI 方法使用化学交换饱和转移 (CEST) 试剂，可以准确、精确地测量 pH。我们已经使用我们的 CEST 试剂和 CEST MRI 方法来绘制小鼠肿瘤模型中的肿瘤 pHe，我们建议提高 CEST MRI 的检测灵敏度，以促进我们的临床前研究最终的临床转化，因为我们的研究具有很大的影响。肿瘤 pHe 测量可用于在对患者进行弱碱和弱酸化疗之前预测其效果。我们建议建立肿瘤 pHe 测量，以监测可提高存活率和减少转移的碱化治疗。我们的 CEST MRI 方法可以以足够的准确度和精确度测量肿瘤 pHe，以影响癌症治疗的选择。具体目标1：提高CEST MRI方法和测量肿瘤pHe的CEST试剂的检测灵敏度我们将优化CEST MRI脉冲序列的饱和周期，并改进我们的顺磁性CEST试剂以具有更大的化学位移。具体目标 2：使用肿瘤 pHe 测量值监测碱化治疗的效果我们发现，监测 pHe 可用于优化碱化治疗的剂量，从而在不影响肾脏 pHe 的情况下提高肿瘤 pHe。具体目标 3：通过肿瘤 pHe 测量定量预测化疗效果我们追求在开始化疗之前进行一次肿瘤 pHe 测量可以定量预测对肿瘤生长的治疗效果。通过定量测量实体瘤的酸度，医生可以选择对个别患者具有更好治疗效果的弱碱或弱酸化疗。医生可以调整碱化治疗剂量，以为个体患者提供最佳治疗效果虽然我们的研究重点是乳腺癌，但我们的方法可以影响许多其他癌症和其他疾病的个性化医疗。