Time Domian Electron Paramagnetic Resonance Imaging

a）多模式分子成像研究评估肿瘤微环境的药理学改变以改善辐射反应。实体瘤中的低渗区有助于放射抗性。包括抗血管生成药物在内的药理学药物在放射前增加肿瘤氧合可以增强对放射疗法的治疗反应。然而，肿瘤氧合的成像评估，以确定一个时间窗口的放射治疗使用这种策略尚未得到充分的探讨。在这项研究中，我们利用电子顺磁共振（EPR）成像、光声（PA）成像、动态对比增强MRI和Gd-DTPA注射，和T2* 加权成像与USPIO注射。SCCVII和A549肿瘤通过将肿瘤细胞注射到小鼠的后腿中而生长。每天照射5天（2戈伊）并在照射前30 min静脉注射SQAP（2 mg/kg），可显著延迟肿瘤异种移植物的生长。3天的每日治疗改善了肿瘤氧合，降低了T2* 加权图像的肿瘤微血管密度，USPIO通过血管正常化解释。通过pO 2成像、sO2成像和Gd-DTPA对比增强成像检查SQAP对肿瘤氧合的急性影响。SQAP治疗导致SCCVII植入物中灌注和肿瘤pO 2（pO 2：3.1mmHg）改善，并伴有sO2降低（SQAP给药后20-30 min降低20 -30%）。这些结果提供了SQAP通过促进氧从氧合血红蛋白解离和改善肿瘤灌注而瞬时增强肿瘤氧合的证据。SQAP介导的体内放射增敏归因于SQAP引起的肿瘤氧合增加。B）自旋晶格弛豫时间，基于T1的定量高分辨率单点EPR成像和通过脉冲间延迟（TR）变化的体内血氧测定：我们报告了可能是时域小动物EPR血氧测定的最终方法，该方法使用快速信号平均并使信号自旋晶格弛豫时间（T1）加权。使用单点成像模式，进行高分辨率T1加权成像和血氧测定，与基于回波的方法相比，除了产生与自旋浓度无关的血氧测定外，还保证了最低的能量吸收。特别是在时域全局相位编码成像策略中的附加优点是与频率编码方法相比更有效地覆盖大带宽，特别是在FT-EPR成像的背景下。通过快速重复序列在2.1 - 40 μ s的重复时间下的饱和度来评估三芳基甲基探针Oxo 71对pO 2的T1依赖性。分别用T1和表观自旋-自旋弛豫时间T2* 测定了含2 mM Oxo 71溶液的三个玻璃管在0%、2%和5%氧下平衡的体模的pO 2图。T1和T2* 得出的pO 2图均与体模中溶液的pO 2水平一致。然而，pO 2图的直方图表明T1提供的pO 2分辨率优于T2*。最近的研究表明，自旋探针的自增宽对T2* 的贡献远高于T1，提示基于T1的血氧测定不需要浓度校正。此外，自旋探针的浓度不能在体内准确评估，因为在一个位置注射的自旋探针团逐渐分布到各种身体组织中。然而，由于高能量吸收和长扫描时间，通过标准脉冲序列的T1标测不适合于体内研究。在这份报告中，我们提出了血氧饱和度在体内的快速T1映射使用90脉冲适合在低吸收的体内工作。T1标测的扫描时间可使用范围为4 - 12 us的三次重复时间，降低到基于常规T2* 的血氧测定时间。

a) A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response. Hypoxic zones in solid tumors contribute to radio-resistance. Pharmacological agents including anti-angiogenic drugs increasing tumor oxygenation prior to radiation can enhance treatment response to radiotherapy. However, imaging assessments of tumor oxygenation to identify a time window for radiotherapy using such strategies have not been fully explored. In this study, we investigated the effects of alpha-sulfoquinovosylacyl-1,3-propanediol (SQAP) a synthetic derivative of an anti-angiogenic agent in altering the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion and microvessel density using electron Paramagnetic Resonance (EPR) imaging, photoacoustic (PA) imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with USPIO injection, respectively. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. The 5-days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 min prior to irradiation significantly delayed growth of tumor xenografts. The 3-days of daily treatment improved tumor oxygenation and decreased tumor microvascular density from T2*-weighted images with USPIO explained by vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO2 imaging, sO2 imaging, and Gd-DTPA contrast-enhanced imaging. SQAP treatment resulted in improved perfusion and tumor pO2 (pO2: 3.1mmHg) accompanied with decreased sO2 (20-30% decrease) in SCCVII implants 20-30 min after SQAP administration. These results provide evidence that SQAP enhanced tumor oxygenation transiently by facilitating oxygen dissociation from oxyhemoglobin and improved tumor perfusion. SQAP mediated in vivo radiation sensitization was attributed to increased tumor oxygenation caused by SQAP. b) Spin-lattice relaxation time, T1-based Quantitative High Resolution Single Point EPR imaging and oximetry in vivo by inter-pulse delay (TR) variation: We report what is likely to be the ultimate method of time-domain small animal EPR oximetry that uses rapid signal averaging and renders the signals spin lattice relaxation time (T1) weighted. Using the Single Point Imaging modality, high resolution T1-weighted imaging and oximetry were carried out that promises the lowest energy absorption compared to echo-based approaches besides yielding spin-concentration independent oximetry. An added advantage, especially in time-domain globally phase-encoded imaging strategy is the more effective coverage of the large bandwidth compared to frequency encoding approach, especially in the context of FT-EPR imaging. The T1 dependence of a triarylmethyl probe Oxo71 on pO2 was assessed by saturation by fast repetition sequence at repetition times from 2.1 - 40 us. The pO2 maps of a phantom containing three glass tubes containing 2mM Oxo71 solutions equilibrated at 0%, 2% and 5% of oxygen were determined by T1 and apparent spin-spin relaxation time T2* separately. Both the pO2 maps derived from T1 and T2* agreed well with the pO2 levels of the solutions in the phantom. However, the histograms of pO2 maps indicated that T1 offers better pO2 resolution than T2*. Recent studies indicated that the self-broadening of spin probe contributes much higher to T2* than T1 prompting that T1 based oximetry does not require concentration correction. Besides, the concentrations of the spin probe cannot be assessed accurately in vivo because, a bolus of spin probe injected at one location is gradually distributes in to various body tissues. Nevertheless, T1 mapping by standard pulse sequences is unsuitable to in vivo studies due to high energy absorption and long scan times. In this report, we present oximetry in vivo by fast T1 mapping using 90 pules suitable to in vivo work at low absorption. The scan time of T1 mapping can be brought down to routine T2* based oximetry times using three repetition times ranging from 4 - 12 us.