MR Imaging of pHe and Chemotherapeutic Response in a Rat Glioma

描述（申请人提供）：恶性神经胶质瘤约占成人所有原发性脑肿瘤的三分之一，在美国每年有18400例新发病例。尽管近年来传统的手术、放疗和化疗等治疗方法取得了很大进展，但恶性脑肿瘤的临床疗效仍然令人失望。胶质瘤对手术、放疗和化疗等常规治疗方案的耐药性尚不清楚。成功的恶性胶质瘤治疗高度依赖于在疾病早期诊断患者并确定哪种治疗可能有效的能力。临床上开始成功的一种方法是利用大多数肿瘤对通过新血管形成增加的血管生成的依赖性。已经发现靶向肿瘤新血管形成内衬的内皮细胞以广泛的方式影响癌症，这种方法的临床成功越来越多。西仑吉肽是一种高度选择性的整合素抑制剂，靶向肿瘤及其血管系统。我们将西仑吉肽应用于U87 MG脑肿瘤大鼠模型，并应用我们的MRI方法测量治疗前后细胞外pHe，v3整合素表达和肿瘤血管通透性的纵向变化。为了实现这些目标，我们建议开发多功能树突状MRI造影剂，其将靶向肿瘤微环境特异性的多种癌症生物标志物。我们将在同一树枝状分子中掺入pH响应性GdDOTA-4AmC、T1松弛剂和pH非响应性NdDOTA-4AmC、PARACEST试剂，以便以高分辨率和高灵敏度准确地测量恶性胶质瘤的细胞外pH。我们将使用相同的基于纳米树枝状聚合物的pH响应性造影剂来测量肿瘤血管通透性。为了靶向v3整联蛋白，我们将环状-RGD肽缀合至PARACEST树枝状聚合物。最后，我们将使用这些树枝状的MRI造影剂来测量细胞外pHe，v3整合素表达和肿瘤血管通透性在治疗前后的单次MRI扫描会话。因此，我们的多功能纳米尺寸的树枝状MRI纳米探针在未来的临床应用中具有很大的潜力，可以非侵入性地测量体内pH值，以及在单个MRI会话期间评估恶性脑肿瘤的多种生物标志物。公共卫生相关性：该项目的结果将提供一种直接的方法来测量体内pH值的非侵入性。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的预后、评估pH改变疗法的功效以及预测pH依赖性化学疗法的功效。此外，多功能纳米尺寸的MRI探针将用于在一次MRI扫描中评估多种肿瘤特异性生物标志物，这项新技术将显著提高脑癌的早期诊断和治疗。

DESCRIPTION (provided by applicant): Malignant glioma accounts for approximately one-third of all primary brain tumors in adults or 18400 new cases in the United States annually. Despite advances in recent conventional therapeutic regimen of surgery, radiation and anticancer chemotherapies, the clinical outcome in treating malignant brain tumors remains disappointing. The resistance of glioma to the conventional therapeutic regimen of surgery, radiation therapy, and chemotherapy is still not well understood. Successful malignant glioma treatment is highly dependent on the ability to diagnose patients at early stages of disease and to identify which therapy might respond. One approach that is beginning to succeed clinically is to exploit the dependence of most tumors on increased angiogenesis through neovascularization. Targeting the endothelial cells lining the tumor neovascularization has been found to impact cancers in a broad manner, with growing clinical success of this approach. Cilengitide is a highly selective integrin inhibitor targeting the tumor and its vasculature. We will apply Cilengitide therapy to rat models of U87MG brain tumors, and apply our MRI methods to measure longitudinal changes in extracellular pHe, v3 integrin expression and tumor vascular permeability before and after therapy. To achieve these goals, we are proposing to develop multifunctional denritic MRI contrast agents that will target multiple cancer biomarkers which are specific to tumor microenvironment. We will incorporate pH-responsive GdDOTA-4Amp, T1 relaxation agents and pH-unresponsive NdDOTA-4AmC, PARACEST agents in the same dendrimer molecule in order to measure extracellular pHe of malignant glioma accurately with high resolution and high sensitivity. We will use same nano-sized dendrimer-based pH-responsive contrast agent to measure tumor vascular permeability. In order to target v3 integrin, we will conjugate cyclic-RGD peptides to the PARACEST dendrimers. Finally, we will use these dendrimeric MRI contrast agents to measure extracellular pHe, v3 integrin expression and tumor vascular permeability in single MRI scan session before and after therapy. Therefore, our multifunctional nano-sized dendrimeric MRI nanoprobes have great potential for future clinical applications in measuring in vivo pH non-invasively as well as to assess multiple biomarkers of malignant brain tumor during a single MRI session. 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 brain cancer.