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成人原发性脑肿瘤的三分之一或每年18400例新病例。尽管近年来手术、放疗和抗癌化疗等常规治疗方案取得了进展，但治疗恶性脑肿瘤的临床结果仍然令人失望。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的能力，并确定哪种治疗可能起作用。一种开始在临床上取得成功的方法是利用大多数肿瘤通过新生血管生成增加血管生成的依赖性。靶向肿瘤内皮细胞的新生血管已被发现在广泛的方式影响癌症，随着越来越多的临床成功。西伦吉肽是一种靶向肿瘤及其血管系统的高选择性整合素抑制剂。我们将西伦吉肽应用于U87MG脑肿瘤大鼠模型，并采用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，我们建议开发针对肿瘤微环境特异性的多种癌症生物标志物的多功能树突MRI造影剂。我们将ph响应的GdDOTA-4Amp、T1松弛剂和ph不响应的NdDOTA-4AmC、PARACEST剂结合在同一树突分子中，以高分辨率、高灵敏度准确测量恶性胶质瘤细胞外pHe。我们将使用相同的纳米树突基ph响应造影剂来测量肿瘤血管通透性。为了靶向v3整合素，我们将环rgd肽偶联到PARACEST树状大分子上。最后，我们将使用这些树突MRI造影剂在治疗前后的单次MRI扫描中测量细胞外pHe， v3整合素表达和肿瘤血管通透性。因此，我们的多功能纳米树突MRI纳米探针在未来的临床应用中具有很大的潜力，可以用于无创测量体内pH值，以及在单次MRI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无创测量体内pH值的方法。因此，肿瘤组织内的细胞外pH （pHe）将被用作诊断性生物标志物，以确定病理预后，评估pH改变疗法的疗效，并预测pH依赖性化疗的疗效。此外，多功能纳米核磁共振探针将用于在一次MRI扫描中评估多种肿瘤特异性生物标志物，这一新技术将大大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.