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

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值（pHe）。我们的MRI方法使用化学交换饱和转移（CEST）试剂，可以准确和精确地测量pH值。我们使用我们的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。我们的研究具有很强的影响，因为肿瘤pH测量可用于预测弱碱和弱酸化疗的效果，然后再给予患者。肿瘤pHe测量也可用于监测可增加存活率和减少转移的碱化疗法。我们建议确定我们的CEST MRI方法可以足够准确和精确地测量肿瘤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，使其具有更大的化学位移。具体目标2：使用肿瘤pHe测量监测碱化治疗的效果。我们假设，监测pH可用于优化碱化治疗的剂量，以提高肿瘤pH，而不影响肾脏pH。具体目标3：通过肿瘤pHe测量定量预测化疗效果。我们假设在开始化疗前测量单个肿瘤的pH值可以定量预测对肿瘤生长的治疗效果。我们的交付成果是一种临床可翻译的成像方法，可以深刻影响个性化医疗。通过定量测量实体肿瘤的酸度，医生可以选择对个体患者具有更好治疗效果的弱碱或弱酸化疗。通过监测肿瘤和肾脏的pH，医生可以调整碱化治疗剂量，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病理的个性化医疗。 公共卫生相关性：该研究项目将完善CEST试剂和CEST MRI方法，用于测量临床前肿瘤模型中的细胞外pH值（pHe）。这些方法将用于优化碱化治疗的剂量，并预测弱碱和弱酸化疗的疗效。

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. PUBLIC HEALTH RELEVANCE: This research project will refine CEST agents and CEST MRI methods that measure extracellular pH (pHe) in pre-clinical tumor models. These methods will be used to optimize the dose of an alkalinizing therapy and to predict the efficacy of weak-base and weak-acid chemotehrapies.