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：肿瘤微环境是治疗选择和治疗结果的重要决定因素。用于肿瘤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变得重要。然而，肿瘤的生理和代谢方面之间的关系尚未完全了解。使用18F-depxyglucose（18FDG）的正电子发射断层扫描被广泛用于识别体内高代谢区域。18 FDG在恶性肿瘤中典型的GLT转运蛋白高表达的细胞中转运，并使用己糖激酶捕获在细胞中。这是临床上广泛使用的方法之一，以确定依赖于GLT转运蛋白和己糖激酶活性的恶性肿瘤。肿瘤也具有高水平的LDHA活性。使用超极化13 C标记的丙酮酸盐的13 C MRI用于通过监测其转化为乳酸盐的速率来检测恶性肿瘤。因此，该方法依赖于单羧酸转运蛋白和LDHA活性。在这项研究中，使用明确的胰腺导管腺癌异种移植模型在这里，我们使用超极化MRI和电子顺磁共振成像程序，允许更直接的评估肿瘤糖酵解和氧合状态定量。我们研究了三种具有不同生理和代谢特征的人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。在肿瘤块水平，18F-FDG-PET与乳酸产生之间存在强正相关性，而pO 2与乳酸产生和18F-2-氟-2-脱氧-D-葡萄糖（18F-FDG）摄取呈负相关。然而，整个肿瘤的代谢并不均匀，整个肿瘤的结果掩盖了成像时变得明显的不同定位。18F-FDG摄取与肿瘤中心的pO 2呈负相关，与周围的pO 2呈正相关。与pO 2和18F-FDG摄取相反，乳酸脱氢酶活性在整个肿瘤中分布相对均匀。每种测量揭示的异质性表明多模式分子成像方法可以改善肿瘤表征，可能导致癌症治疗中更好的生物学特性。B）缺氧激活的前药Evofosfamide改善肿瘤氧合。肿瘤具有低的区域。氧气水平称为缺氧区，这些地区是抵抗放射治疗和化疗.缺氧激活的前药如Evofosfamide被开发用于特异性杀死缺氧区域中的细胞。在缺氧肿瘤微环境中，强还原氧化还原状态将evofosfamide（TH-302）转化为还原形式并释放细胞毒性溴异磷酰胺（Br-IPM）部分。因此，这种药物优先攻击肿瘤中的缺氧区域，而其他标准抗癌治疗，如化疗和放疗通常无效。已经提出了与evofosfamide的各种组合疗法，并在临床前和临床环境中进行了测试。然而，evofosfamide单药治疗对肿瘤缺氧的治疗效果尚未完全了解，部分原因是缺乏定量方法来评估体内肿瘤pO 2。在这里，我们使用定量pO 2成像EPR评价肿瘤缺氧的变化，在evofosfamide治疗反应使用两种胰腺导管腺癌异种移植模型; MIA Paca-2肿瘤evofosfamide和苏86.86肿瘤不响应。EPR成像显示，缺氧MIA Paca-2肿瘤中evofosfamide治疗后氧合得到全面改善，与pimonidazole缺氧染色获得的离体结果一致，与DCE MRI中观察到的Ktranss降低形成明显对比。观察到evofosfamide不仅杀死肿瘤的缺氧区域，而且还改善了残留肿瘤区域的氧合，这为evofosfamide后使用放射和抗增殖剂的联合治疗提供了理论基础，以改善结局。