MR Imaging of pHe and Chemotherapeutic Response in a Rat Glioma

大鼠胶质瘤 pHe 和化疗反应的 MR 成像

• 批准号: 7845511
• 负责人: Meser M. Ali
• 金额: $ 17.9万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845511
• 关键词: Accounting; Address; Adult; Biological Markers; Blood Vessels; Brain Neoplasms; Cell Line; Cilengitide; Clinical; Contrast Media; Coupling; Dendrimers; Dependence; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Endothelial Cells; Foundations; Future; Glioma; Goals; Grant; Growth; Hand; Heterogeneity; Human; Image; Institution; Integrins; Ligands; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Methods; Modeling; Molecular; Neoplasm Metastasis; New Approaches to Brain Tumor Therapy Consortium; Operative Surgical Procedures; Outcome; Pathology; Patients; Phase II Clinical Trials; Primary Brain Neoplasms; Process; RGD (sequence); Radiation therapy; Radiosurgery; Rattus; Recording of previous events; Regimen; Relaxation; Research Personnel; Resistance; Resolution; Staging; Therapeutic; Tissues; Translational Research; Tumor Tissue; United States; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; base; cancer therapy; chemotherapy; clinical application; extracellular; glioma cell line; in vivo; inhibitor/antagonist; nanoparticle; nanoprobe; nanoscale; nanosized; neovascularization; new technology; non-invasive monitor; outcome forecast; public health relevance; response; success; treatment strategy; tumor; tumor progression

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.

描述（由申请人提供）：恶性神经胶质瘤约占成人所有原发性脑肿瘤的三分之一，即美国每年新发病例 18400 例。尽管近年来手术、放射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。神经胶质瘤对手术、放疗和化疗等常规治疗方案的耐药性仍不清楚。恶性神经胶质瘤的成功治疗高度依赖于在疾病早期诊断患者并确定哪种疗法可能有效的能力。一种在临床上开始取得成功的方法是利用大多数肿瘤对通过新血管形成增加血管生成的依赖性。人们发现，针对肿瘤新生血管内衬的内皮细胞可以广泛地影响癌症，并且这种方法在临床上取得了越来越大的成功。西仑吉肽是一种高度选择性的整合素抑制剂，针对肿瘤及其血管系统。我们将使用西仑吉肽治疗 U87MG 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，该造影剂将针对肿瘤微环境特有的多种癌症生物标志物。我们将pH响应性的GdDOTA-4Amp、T1松弛剂和pH不响应性的NdDOTA-4AmC、PARACEST制剂合并在同一树枝状大分子中，以便以高分辨率和高灵敏度准确测量恶性胶质瘤的细胞外pHe。我们将使用相同的基于纳米树枝状聚合物的 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 肽与 PARACEST 树枝状聚合物缀合。最后，我们将使用这些树枝状 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枝状 MRI 纳米探针在未来临床应用中具有巨大的潜力，可用于非侵入性测量体内 pH 值以及在单次 MRI 过程中评估恶性脑肿瘤的多种生物标志物。公共健康相关性：该项目的结果将提供一种非侵入性测量体内 pH 值的直接方法。因此，肿瘤组织内的细胞外pH (pHe)将被用作诊断生物标志物，以确定病理学预后、评估pHe改变疗法的功效以及预测pHe依赖性化疗的功效。此外，多功能纳米级 MRI 探针将用于在单次 MRI 扫描过程中评估多种肿瘤特异性生物标志物，这项新技术将显着增强脑癌的早期诊断和治疗。