Time Domian Electron Paramagnetic Resonance Imaging

时域电子顺磁共振成像

• 批准号: 10262093
• 负责人: Murali Krishna
• 金额: $ 119.11万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262093
• 关键词: Agreement; Algorithms; Angiogenesis Inhibitors; Blood Vessels; Blood flow; Cells; Characteristics; Chemotherapy and/or radiation; Clinical; Combined Modality Therapy; Electron Spin Resonance Spectroscopy; Functional Imaging; Glycolysis; Goals; Heterogeneity; Human; Hypoxia; Image; Imaging Techniques; Ionizing radiation; Label; Lactate Dehydrogenase; Magnetic Resonance Imaging; Malignant Neoplasms; Masks; Measures; Metabolic; Metabolism; Methods; Modality; Monitor; Neoplasms in Vascular Tissue; Oxidation-Reduction; Oxygen; Pancreatic Ductal Adenocarcinoma; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physics; Physiological; Physiology; Pimonidazole; Positron-Emission Tomography; Prodrugs; Production; Property; Pyruvate; Radiation; Radiation therapy; Residual Tumors; Resolution; Stains; Testing; Time; Tissue imaging; Tracer; Treatment outcome; Tumor Oxygenation; Xenograft Model; anatomic imaging; animal imaging; anticancer treatment; cancer imaging; cancer therapy; cell killing; chemotherapeutic agent; chemotherapy; cytotoxic; density; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose uptake; hexokinase; image reconstruction; imaging approach; imaging modality; imaging properties; improved; improved outcome; in vivo; instrumentation; metabolic imaging; metabolic profile; molecular imaging; multimodality; non-invasive imaging; pre-clinical; prognostic; radioresistant; response; scale up; spatial relationship; treatment choice; treatment effect; treatment optimization; treatment planning; treatment response; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor xenograft; uptake

a) Multi-modal metabolic and physiologic assessment of tumor microenvironment: Tumor microenvironment is an important determinant in the choice of treatments and treatment outcomes. Molecular imaging approaches for metabolic and physiologic imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiologic and metabolic aspects of tumors is not fully understood. Positron Emission Tomography using 18F-depxyglucose (18FDG) is widely used to identify hypermetabolic regions in vivo. 18FDG is transported in cells with high expression of GLT transporters typical in malignancies and trapped in cells using hexokinase. This is one of the widely used clinical method to identify malignancies relying on GLT transporters and hexokinase activity. Tumors also have high levels of LDHA activity. 13C MRI using hyperpolarized 13C labeled pyruvate is used to detect malignancies by monitoring its conversion rates to lactate. Thus this method relies on monocarboxylate transporters and LDHA activity. In this study, using well defined pancreatic ductal adenocarcinoma xenograft models Here, we used hyperpolarized MRI and electron paramagnetic resonance imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiologic and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between 18F-FDG-PET and lactate production, while pO2 was inversely related to lactate production and 18F-2-fluoro-2-deoxy- D-glucose (18F-FDG) uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging. 18F-FDG uptake negatively correlated with pO2 in the center of the tumor and positively correlated with pO2 on the periphery. In contrast to pO2 and 18F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multi- modal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. b) The hypoxia activated prodrug Evofosfamide improves tumor oxygenation. Tumors have regions with low. Levels of oxygen called hypoxic zones, These regions are resistant to radiation therapy and chemotherapy. Hypoxia activated prodrugs such as Evofosfamide are developed to specifically kill cells in hypoxic regions. In hypoxic tumor microenvironments, the strongly reducing redox state converts evofosfamide (TH-302) to a reduced form and releases a cytotoxic bromo-isophosphoramide (Br-IPM) moiety. This drug therefore preferentially attacks hypoxic regions in tumors where other standard anti-cancer treatments such as chemotherapy and radiation therapy are often ineffective. Various combination therapies with evofosfamide have been proposed and tested in preclinical and clinical settings. However, the treatment effect of evofosfamide monotherapy on tumor hypoxia has not been fully understood, partly due to the lack of quantitative methods to assess tumor pO2 in vivo. Here, we use quantitative pO2 imaging by EPR to evaluate the change in tumor hypoxia in response to evofosfamide treatment using two pancreatic ductal adenocarcinoma xenograft models; MIA Paca-2 tumors responding to evofosfamide and Su.86.86 tumors which do not respond. EPR imaging showed oxygenation improved globally after evofosfamide treatment in hypoxic MIA Paca-2 tumors, in agreement with the ex vivo results obtained from hypoxia staining by pimonidazole and in apparent contrast to the decrease in Ktrans observed in DCE MRI. The observation that evofosfamide not only kills the hypoxic region of the tumor but also improves oxygenation in the residual tumor regions provides a rationale for combination therapies using radiation and anti-proliferatives post evofosfamide for improved outcomes.

a）肿瘤微环境的多模式代谢和生理评估：肿瘤微环境是选择治疗和治疗结果的重要决定因素。肿瘤的代谢和生理成像的分子成像方法对于治疗计划和反应监测已经很重要。但是，尚不完全了解肿瘤的生理和代谢方面之间的关系。使用18F-脱皮葡萄糖（18FDG）的正电子发射断层扫描被广泛用于鉴定体内的多代谢区域。 18FDG在恶性肿瘤中典型的GLT转运蛋白表达高表达的细胞中运输，并使用己糖激酶捕获在细胞中。这是鉴定依赖GLT转运蛋白和己糖激酶活性的恶性肿瘤的广泛临床方法之一。肿瘤也具有高水平的LDHA活性。使用超极化13C标记的丙酮酸的13C MRI用于通过监测其转化率向乳酸来检测恶性肿瘤。因此，该方法依赖于单羧酸盐转运蛋白和LDHA活性。在这项研究中，使用明确定义的胰管导管腺癌异种移植模型，我们使用了超极化的MRI和电子顺磁共振成像程序，以定量地进行更直接评估肿瘤糖酵解和氧合状态。我们研究了三种人类胰腺导管腺癌肿瘤异种移植物中缺氧，葡萄糖摄取和糖酵解之间的空间关系，具有不同的生理和代谢特征。在大容量肿瘤水平上，18F-FDG-PET和乳酸产生之间存在很强的正相关，而PO2与乳酸产生和18F-2-Fluoro-2-脱氧-d-葡萄糖（18F-FDG）的摄取成反比。然而，整个肿瘤中的新陈代谢并不统一，整个肿瘤结果掩盖了成像时变得明显的不同局部化。 18F-FDG摄取与肿瘤中心的PO2负相关，并与周围的PO2正相关。与PO2和18F-FDG摄取相反，在整个肿瘤中，乳酸脱氢酶活性分布相对均匀。每种措施揭示的异质性表明，多模态分子成像方法可以改善肿瘤的表征，这可能会导致癌症治疗的预后更好。 b）缺氧激活的前药evofosfamide改善了肿瘤的氧合。肿瘤的区域低。氧气水平称为低氧区域，这些区域对放射疗法和化学疗法具有抗性。缺氧活化的前药（如evofosfamide）是开发出来特异性杀死缺氧区域的细胞的。在低氧肿瘤微环境中，强烈降低的氧化还原状态将Evofosfamide（TH-302）转化为减少形式，并释放出细胞毒性的溴 - 异磷酰胺（BR-IPM）部分。因此，该药物优先攻击其他标准抗癌治疗（例如化学疗法和放射疗法）的肿瘤中缺氧区域。已经在临床前和临床环境中提出并测试了与Evofosfamide的各种组合疗法。然而，尚未完全理解evofosfamide单药治疗对肿瘤缺氧的治疗效果，部分原因是缺乏评估体内肿瘤PO2的定量方法。在这里，我们使用EPR的定量PO2成像来评估使用两种胰腺导管腺癌异种移植模型，以响应Evofosfamide处理，以评估肿瘤缺氧的变化。 MIA PACA-2肿瘤对Evofosfamide和SU.86.86肿瘤反应。 EPR成像显示，在低氧MIA PACA-2肿瘤中，EPR成像在全球范围内改善了全球范围，这与偶膜甲苯性唑低氧染色所获得的离体结果一致，并且显然与DCE MRI观察到的KTRANS的减少相反。观察结果是，evofosfamide不仅杀死肿瘤的低氧区域，而且还可以改善残留肿瘤区域的氧合，为使用辐射和抗增殖剂后的Evofofosfamide结合疗法提供了一种理由，以改善结果。