MR Imaging of pHe and Chemotherapeutic Response in a Rat Glioma

描述(由申请人提供)：恶性胶质瘤约占美国所有成人原发脑瘤的三分之一，每年新增病例18400例。尽管最近手术、放射和抗癌化疗等常规治疗方案取得了进展，但在治疗恶性脑肿瘤方面的临床结果仍然令人失望。胶质瘤对手术、放射治疗和化疗等常规治疗方案的耐药性仍不清楚。成功的恶性胶质瘤治疗高度依赖于在疾病早期阶段诊断患者并确定哪种治疗方法可能有效的能力。一种开始在临床上取得成功的方法是利用大多数肿瘤对新生血管增加的依赖性。靶向肿瘤衬里的内皮细胞新生血管已经被发现以广泛的方式影响癌症，这种方法在临床上越来越成功。Cilengiide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。我们将对U87 MG脑瘤模型的大鼠应用西伦吉特治疗，并应用我们的MRI方法检测治疗前后细胞外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核磁共振造影剂，这些造影剂将针对肿瘤微环境特异性的多个癌症生物标志物。我们将pH响应型GdDOTA-4Amp，T1弛豫剂和pH非响应型NdDOTA-4AmC，PARACEST试剂引入同一树枝状大分子分子中，以高分辨率和高灵敏度准确测量恶性胶质瘤的细胞外Phe。我们将使用相同的纳米树枝状大分子pH响应型造影剂来测量肿瘤血管的通透性。为了靶向v3整合素，我们将环状RGD多肽偶联到PARACEST树枝状大分子上。最后，我们将使用这些树状大分子MRI造影剂在治疗前后的单次MRI扫描中检测细胞外Phe、v3整合素的表达和肿瘤血管的通透性。因此，我们的多功能纳米树枝状核磁共振纳米探针在未来的临床应用中具有巨大的潜力，可以无创地测量体内的pH值，以及在一次磁共振成像过程中评估恶性脑肿瘤的多个生物标志物。公共卫生相关性：该项目的结果将提供一种非侵入性地测量活体PH值的直接方法。因此，肿瘤组织中的细胞外pH(Phe)将作为一种诊断生物标志物来确定病理预后，评估Phe改变治疗的疗效，并预测Phe依赖的化疗的疗效。此外，多功能纳米MRI探针将在一次MRI扫描中用于评估多个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.