Multifunctional in Vivo EPR Imaging of Tumor Microenvironment

肿瘤微环境的多功能体内 EPR 成像

• 批准号: 9165285
• 负责人: Mark Tseytlin
• 金额: $ 23.8万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9165285
• 关键词: 4D Imaging; Acidity; Address; Affect; Algorithms; Animals; Biological; Chemicals; Chicago; Complex; Computer software; Computers; Data; Dependency; Detection; Development; Electron Spin Resonance Spectroscopy; Electrons; Four-dimensional; Frequencies; Functional Imaging; Future; Geometry; Goals; Image; In Vitro; Individual; Lifting; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Maps; Measurement; Measures; Metals; Methods; Monitor; Morphologic artifacts; Noise; Oxygen; Pattern; Phase; Problem Solving; Protons; Relaxation; Research Personnel; Resolution; Route; Sampling; Scanning; Series; Shapes; Signal Transduction; Signaling Molecule; Solid Neoplasm; Spectrum Analysis; Surface; Techniques; Testing; Time; Tissues; Transforming Growth Factors; Transgenic Mice; Translating; Treatment Efficacy; Treatment outcome; Tumor Angiogenesis; Tumor Volume; Uncertainty; Work; attenuation; base; computerized data processing; design; digital; extracellular; image reconstruction; imaging modality; imaging system; improved; in vitro testing; in vivo; in vivo imaging; innovation; inorganic phosphate; instrument; interest; interstitial; malignant breast neoplasm; mathematical algorithm; mouse model; novel; radiofrequency; reconstruction; research study; signal processing; success; tool; tumor; tumor microenvironment; tumor progression; tumorigenesis

PROJECT SUMMARY/ABSTRACT The tumor microenvironment (TME) is the chemical and biological background that affects tumor malignancy, proliferation and metastatic activity because of chaotic angiogenesis tumors growing to become less oxygenated (low pO2) and more acidic (low pH). While pO2 and pH are known to be important factors for tumor growth and treatment, interstitial Pi has been recently identified as a new signaling molecule of importance in tumorigenesis. Newly synthesized stable paramagnetic molecules, spin probes, permit simultaneous in vivo monitoring of interstitial pO2, extracellular pH (pHe) and concentration of interstitial inorganic phosphate (Pi) using Electron Paramagnetic Resonance (EPR). Because tumors are highly heterogeneous, spectral-spatial EPR imaging is required to spatially resolve the parameters of interest. Spatial resolution is defined by EPR sensitivity. The amount of the spin probe molecules within a voxel decreases as spatial resolution is cubed, and may become undetectable if too small. Sensitivity also directly translates into functional resolution, the accuracy with which pH, pO2, and Pi can be measured. The proposal by the PI and his colleagues for a Rapid Scan (RS) EPR technique has been explored at 250 MHz frequency and showed improvement in signal-to-noise ratio up to two orders of magnitude compared to the standard field-modulated continuous wave (CW) method. An additional order of magnitude signal enhancement can be achieved for trityl-based multifunctional probes by increasing EPR frequency to 700 -800 MHz (optimal for small animal RS EPR studies) and scan frequency to 50-100 kHz (the current mathematical algorithm limits the upper scan frequency to about 10 kHz). RS EPR sensitivity enhancement will require both hardware (SA1) and software (SA2) developments. In addition, novel 4D spectral- spatial algorithm will be further developed to enable multi-functional multi-line EPR imaging, since the standard filtered backprojection (FBP) reconstruction fails to work with multi-functional spin probes that have a comparatively broad multi-line EPR spectra. A newly developed multi-functional EPR imager will first be tested in vitro on standard samples with known geometry, pO2, pH, and Pi patterns, followed by in vivo proof-of-concept imaging. A colony of PyMT transgenic mice will be used that spontaneously-develop breast cancer to perform the rapid scan multifunctional imaging and construct spatially-resolved pO2, pH, and Pi profiles of TME and normal mammary gland. We anticipate to achieve physiologically significant voxel-specific functional sensitivities of about 1-2 mmHg of pO2, 0.05 pH units and 0.1 mM of inorganic phosphate. Estimated spatial resolution will be smaller than 200 m. In summary, the success of this project may have a significant impact on the future of in vivo functional imaging to study TME and beyond.

项目摘要/摘要 肿瘤微环境（TME）是影响肿瘤恶性肿瘤的化学和生物背景 由于混乱的血管生成肿瘤的增殖和转移活性变为氧化较少 （低PO2）和更酸性（低pH）。众所周知，PO2和pH是肿瘤生长和 治疗，间质PI最近被确定为肿瘤发生中重要性的新信号分子。 新合成的稳定顺磁分子，自旋问题，允许同时进行体内监测 使用电子的间质性PO2，细胞外pH（PHE）和间质性无机磷酸盐（PI）的浓度 顺磁共振（EPR）。因为肿瘤高度异质，所以光谱空间EPR成像为 需要空间解决感兴趣的参数。空间分辨率由EPR敏感性定义。这 随着空间分辨率是立方体，体素探针分子的量下降，并且可能成为 如果太小，无法检测到。灵敏度还直接转化为功能分辨率，准确性 可以测量pH，PO2和PI。 PI和他的同事对快速扫描（RS）EPR提出的提议 技术以250 MHz的频率进行了探索，并显示出最高两个的信噪比的改善 与标准场调节连续波（CW）方法相比，数量级。另一个 可以通过增加基于trick虫的多功能探针实现数量级信号增强 EPR频率至700 -800 MHz（对于小动物RS EPR研究最佳）和扫描频率为50-100 kHz （当前的数学算法将上部扫描频率限制为约10 kHz）。 RS EPR敏感性 增强功能将需要硬件（SA1）和软件（SA2）开发。此外，新颖的4D光谱 - 由于标准 过滤后的反射（FBP）重建无法处理具有多功能的旋转问题 相对广泛的多行EPR光谱。新开发的多功能EPR成像器将首先进行测试 在具有已知几何，PO2，pH和PI模式的标准样品上的体外体外，然后体内概念验证证明 成像。将使用PYMT转基因小鼠的菌落，该菌落发育不断发展的乳腺癌 tme和 正常乳腺。我们预计将实现物理上显着的体素特异性功能灵敏度 大约1-2 mmHg的PO2，0.05个pH单位和0.1 mm的无机磷酸盐。估计的空间分辨率将 小于200m。总而言之，该项目的成功可能会对 体内功能成像，以研究TME及以后。