Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

奥豪瑟增强磁共振成像 (OMRI)

• 批准号: 10014376
• 负责人: Murali Krishna
• 金额: $ 118.3万
• 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/10014376
• 关键词: Aftercare; Agreement; Biochemical; Cell Nucleus; Cell physiology; Chemical Shift Imaging; Chemicals; DU145; Data; Dependence; Detection; Disease model; Evaluation; Glucose; Heart; Histologic; Human; Hypoxia; Image; In Vitro; Kidney; Kinetics; Label; Lactate Dehydrogenase; Liver; Lung; Magnetic Resonance Imaging; Magnetism; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Monitor; Mus; Nature; Normal Cell; Organ; Oxidative Phosphorylation; Oxides; Oxygen; PC3 cell line; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phosphate Buffer; Physiology; Positioning Attribute; Prodrugs; Protons; Pyruvate; Pyruvate Metabolism Pathway; Pyruvic Acid; Radiation therapy; Reactive Oxygen Species; Relaxation; Signal Transduction; Spin Trapping; Techniques; Time; Tracer; Tumor Oxygenation; Warburg Effect; Water; Xenograft procedure; aerobic glycolysis; cancer cell; chemotherapy; density; gemcitabine; imaging biomarker; improved; in vivo; interest; intravenous injection; magnetic resonance spectroscopic imaging; metabolic imaging; metabolic profile; metabolomics; molecular imaging; pancreatic neoplasm; predicting response; pressure; prostate cancer cell line; pyrroline; response; therapy resistant; treatment effect; treatment response; treatment strategy; tumor; tumor growth; tumor xenograft

a) Metabolic MRI to profile prostate cancer to target glycolytic pathways: Hyperpolarized (HP) MRI using pyruvate allows imaging kinetics of important bio-energetic pathways such as aerobic glycolysis or oxidative phosphorylation. Since malignant cells process glucose/pyruvate through aerobic glycolysis vs normal cells which rely on oxidative phosphorylation, this imaging allowed biochemically profiling regions of interest in vivo non-invasively using 13C MRI using hyperpolarized tracers. Hyperpolarization bridges the 4-orders in sensitivity needed for 13C MRI in vivo. Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-13C]-pyruvate MRSI after systemic delivery of [1-13C] pyruvic acid. Steady state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady state lactate concentrations were measured with proton (1H) MRSI. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11. DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-13C]-pyruvate MRSI compared to PC3, and a corresponding greater sensitivity to LDH inhibition. We showed that hyperpolarized [1-13C]-pyruvate MRSI magnetic resonance spectroscopic imaging (MRSI) of prostate cancer predicts efficacy of targeting the Warburg effect. b) Synthesis and evaluation of 13C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized 13C-MRI: 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) is a spin trap agent frequently used to detect reactive oxygen species (ROS) in vitro. In this study, we synthesized 13C-labeled DMPO to be applied to hyperpolarized 13C-MRI in which 13C MR signal increases more than 10000 folds, and investigated feasibility of in vivo ROS detection by the 13C-labeled DMPO combined with hyperpolarized 13C-MRI. DMPO was 13C-labeled at C5 position, and deuterated to prolong the T1 relaxation time. Overall yield achieved for 5-13C-DMPO-d9 was 15%. Hyperpolarized 5-13C-DMPO-d9 provided a single peak at 76 ppm on the 13C-spectrum, and the T1 relaxation time was 60 sec in phosphate buffer. The solution of hyperpolarized 5-13C-DMPO-d9 was injected into a mouse placed in a 3T scanner, and 13C-spectra was acquired every 1 sec. The signal of 5-13C-DMPO-d9 was detected in the living mouse body, and the T1 decay of 13C signal of hyperpolarized 5-13C-DMPO-d9 in the mouse body was 29 sec. 13C-chemical shift imaging revealed that 5-13C-DMPO-d9 was distributed through the mouse body in a minute after the intravenous injection. The strong signal of 5-13C-DMPO-d9 was detected in heart/lung and kidney, whereas the signal in liver was small compared to other organs. The results indicate hyperpolarized 5-13C-DMPO-d9 provided sufficient magnitude of the 13C signal to be detected in the mouse body, and can be applied to some disease models to evaluate the capability for detection of ROS in vivo. c) Molecular imaging of the microenvironment of pancreatic tumor xenografts in mice guides treatment strategy with radiotherapy- or hypoxia-activated prodrugs: Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches, leading to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling will contribute to improved treatment strategies. Here, we demonstrated the ability of two imaging biomarkers to predict differences in tumor response to therapy: 1) partial oxygen pressure (pO2), measured by EPR imaging; and 2) [1-13C] pyruvate metabolism rate, measured by hyperpolarized 13C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa-2, and Su.86.86) were grown in mice. The median pO2 of the mature Hs766t, MiaPaCa-2, and Su.86.86 tumors was 9.1, 11.1, and 17.6mmHg, and the rate of pyruvate-to-lactate conversion was 2.72, 2.28, and 1.98 min-1, respectively(n=6, each). The results are in agreement with steady state data of matabolites quantitatively measured by mass spectroscopy and histological analysis indicating glycolytic and hypoxic profile in Hs766t and MiaPaca-2 tumors. Fractionated radiation therapy (5 Gy x 5) resulted in a tumor growth delay of 16. and 18. days in MiaPaca-2 and Su.86.86 tumors, respectively, compared to 6. days in hypoxic Hs766t tumors. Treatment with gemcitabine, a first-line chemotherapy, or the hypoxia-activated prodrug TH-302 was more effective against Hs766t tumors (20. and 25. days' increase in survival time, respectively) than MiaPaCa-2 (2. and 6. days) and Su.86.86 (4. and 0.7 days) tumors. Collectively, these results demonstrate the ability of molecular imaging biomarkers to predict the response of PDAC to treatment with radiation therapy and TH-302.

a）代谢MRI介绍前列腺癌靶向糖酵解途径：使用丙酮酸超极化（HP）MRI允许成像重要的生物能途径的动力学，例如有氧糖酵解或氧化磷酸化。由于恶性细胞通过有氧糖酵解与依赖氧化磷酸化的正常细胞处理葡萄糖/丙酮酸，因此这种成像允许使用超极化示踪剂使用13C MRI在体内生化兴趣的生化区域。超极化桥梁在体内13c MRI所需的灵敏度中桥接4个order。两种人类前列腺癌细胞系（DU145和PC3）作为异种移植物生长。全身递送[1-13C]丙酮酸后，用超极化[1-13C] - 丙酮酸MRSI测量丙酮酸向异种移植物中的乳酸转化。用质谱法对异种移植肿瘤进行稳态代谢组分析，并用质子（1H）MRSI测量稳态乳酸浓度。通过FX-11抑制乳酸脱氢酶（LDH）后，评估肿瘤生长。与PC3相比，DU145肿瘤表现出丙酮酸对超极化[1-13C] - 丙酮酸MRSI的转化增强，并且对LDH抑制的敏感性更高。我们表明，前极化[1-13C] - 丙酮酸MRSI磁共振光谱成像（MRSI）的前列腺癌预测靶向Warburg效应的功效。 b）合成和评估13C标记的5-5-二甲基-1-吡咯氨酸-N-氧化物，旨在使用超极化13C-MRI：5,5-二甲基-1-吡咯氨酸-N-氧化物（DMPO）进行体内检测活性氧，是一种经常用于检测反应型氧化物的自旋型物种（ROS）。在这项研究中，我们合成了13C标记的DMPO，用于应用于超极化的13C-MRI，其中13C MR信号增加了10000倍以上，并通过13C标记的DMPO与超极化13C-MRI结合研究了体内ROSSTOUCTION的可行性。 DMPO在C5位置被标记为13C，并进行了剥离以延长T1松弛时间。 5-13C-DMPO-D9的总收益率为15％。超极化的5-13C-DMPO-D9在13C谱上以76 ppm的形式提供了一个峰，而T1弛豫时间在磷酸盐缓冲液中为60秒。将超极化的5-13C-DMPO-D9的溶液注入放置在3T扫描仪中的小鼠中，每1秒获取13c-spectra。在活小鼠体中检测到5-13C-DMPO-D9的信号，小鼠体中超极化5-13C-DMPO-D9的T1衰减的T1衰减为29秒。 13C化学移位成像表明，静脉注射后一分钟，将5-13C-DMPO-D9通过小鼠体分布。在心脏/肺和肾脏中检测到5-13C-DMPO-D9的强信号，而与其他器官相比，肝脏中的信号很小。结果表明，超极化的5-13C-DMPO-D9提供了足够的13C信号，可以在小鼠体中检测到，并可以应用于某些疾病模型以评估检测ROS在体内的能力。 c）小鼠中胰腺肿瘤异种移植物的微环境的分子成像指导放疗或缺氧激活的前药：胰腺导管腺癌（PDAC）以缺氧壁ches的特征表征胰腺导管腺癌（PDAC）。因此，对肿瘤氧合和代谢分析的研究将有助于改善治疗策略。在这里，我们证明了两个成像生物标志物预测肿瘤对治疗反应差异的能力：1）通过EPR成像测量的部分氧气压力（PO2）； 2）[1-13C]丙酮酸代谢率，通过超极化13C MRI测量。在小鼠中生长了三种具有不同治疗敏感性的人PDAC异种移植物（HS766T，Miapaca-2和Su.86.86）。成熟HS766T，Miapaca-2和SU.86.86肿瘤的中位PO2为9.1、11.1和17.6mmHg，丙酮酸到乳酸转化率的速率分别为2.72、2.28和1.98 min-1，分别为1.98 min-1（n = 6，n = 6，每个）。结果与通过质谱法和组织学分析定量测量的马金代代理的稳态数据一致，表明HS766T和MIAPACA-2肿瘤中的糖酵解和低氧概况。分级放射治疗（5 Gy x 5）导致肿瘤生长延迟为16。和SU.86.86肿瘤的肿瘤生长延迟分别为18.天，而低氧HS766T肿瘤的肿瘤生长延迟为86.86个肿瘤。用吉西他滨，一线化学疗法或缺氧激活的前药TH-302治疗比Miapaca-2（2。和6。和6。天）和SU.86.86（4。和0.7天和0.7天）更有效地针对HS766T肿瘤（分别为20。和25天生存时间）。总的来说，这些结果表明了分子成像生物标志物预测PDAC对放射治疗和TH-302治疗的反应的能力。