Radiation Biology of EPR Oxygen Images

EPR 氧气图像的放射生物学

• 批准号: 10362573
• 负责人: HOWARD J HALPERN
• 金额: $ 30.16万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362573
• 关键词: 3D Print; Achievement; Animal Model; Animals; Applications Grants; Area; Breast Carcinoma; Carcinoma; Cell Line; Classification; Clinical; Conformal Radiotherapy; Data; Dependence; Development; Dose; Dose Fractionation; Electron Spin Resonance Spectroscopy; Elements; Failure; Fatty acid glycerol esters; Female; Fractionation; Funding; Gastrocnemius Muscle; Gender; HIF1A gene; Human; Hypoxia; Image; Immunologics; Leg; Life; Location; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Mammals; Mammary Duct; Measurement; Measures; Miso; Misonidazole; Modeling; Molecular; Monitor; Mus; Nitroimidazoles; Nude Mice; Organ; Oxygen; PC3 cell line; Partial Pressure; Patients; Positron-Emission Tomography; Prostate carcinoma; Proteins; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation therapy; Radiobiology; Reporting; Research Project Grants; Resistance; Resolution; Roentgen Rays; Short Interspersed Nucleotide Elements; Solid Neoplasm; System; Technology; Time; Tissues; Tumor Tissue; Tumor Volume; Tungsten; Validation; Variant; Vascular Endothelial Growth Factors; Work; Xenograft procedure; base; cancer imaging; expectation; experimental study; fibrosarcoma; fractionated radiation; human imaging; human subject; immunogenic; immunogenicity; improved; in vivo; innovative technologies; male; mammary; novel; pre-clinical; preclinical imaging; programs; radiation delivery; radiation resistance; radiation response; sarcoma; side effect; single fraction radiation; subcutaneous; success; tumor; tumor hypoxia

For over a century, resistance of radiation to living tissues has been associated with hypoxia, a local lack of molecular oxygen, or low pO₂. The focus of the past funding cycle has been to validate the hypothesis that has been assumed, but not proven over the past century, that treatment focused specifically on regions of tumors with low pO₂, voxels less than 10 torr, hypoxia boosts, would improve tumor curability. This research grant has used Electron Paramagnetic Resonance (EPR) imaging to provide absolute pO₂ images in volume elements or voxels of murine tumors with 1 torr pO₂ resolution and 0.5 mm spatial resolution in FSa carcinomas in the legs of C₃H mice. The voxel pO₂ correlates with local Oxylite measurements. EPR pO₂ image based hypoxic fractions, HF10 (fraction of tumor voxels with pO₂ less than 10 torr) correlates with hypoxia proteins VEGF, CAIX, and HIF1α, and with the curability of tumors given a dose of radiation sufficient to cure 50% of 450 µl tumors (TCD50). This established EPR pO₂ imaging as a reliable locator of relevant radiobiologically relevant hypoxia. To determine if pO₂ based dose painting improves tumor cure, we implemented the XRAD₂₂₅Cx system to deliver gantry based x-ray treatments to mouse tumors accurately registered with EPR pO2 images. We implemented rapid 3D printing Tungsten loaded, conformal plastic blocks to compare treating ~100% of hypoxic tumor voxels with hypoxia avoidance. Only then did we observe significant (p=0.02) tumor control differences between hypoxic boosts and anti-boosts. This is the first validation of hypoxia based dose painting in mammalian tumors. The systematics of the differences between hypoxic and normal pO₂ tumor tissue now need to be determined in several animal models with different immunologic conditions and with fractionation to guide eventual human use, possibly based on reductive retention of ¹⁸F-nitroimidazole PET images. We propose the following program investigating the systematics of EPR pO₂ image based dose painting: 1) Determine the in vivo hypoxic and separate normally oxygenated tumor tissue pO₂ control doses (TCD₅₀Hypox and TCD₅₀Ox), an in vivo oxygen enhancement ratios (OER) for orthotopic FSa and RIF1 fibrosarcomas, MCa4 mammary carcinomas grown orthotopically and, to determine the immunogenic status dependence, in human PC3 prostate carcinoma xenografts in athymic nude mice. 2) Determine the influence of three dose fractionation on hypoxic tumor control and oxygen enhancement ratios (₃fTCD₅₀Hypox, ₃fTCD₅₀Ox: ₃fOER) These experiments will provide ranges of in vivo variation from which to estimate in vivo oxygen enhancement ratios to guide early human trials of hypoxic boost/dose painting treatment. The success of preclinical determination of OER in multiple model tumors may suggest means by which to correct PET based human hypoxic tumor imaging. We also show technology suggesting EPR imaging in human subjects.

一个多世纪以来，辐射对活组织的抗性一直与缺氧有关 缺乏分子氧或低po₂。过去的资金周期的重点是验证假设 在过去的一个世纪中，这种治疗专门集中在过去的一个世纪中，但没有证明 PO₂，体素小于10 TOR的肿瘤可促进缺氧，可以改善肿瘤可治疗性。这 研究赠款已使用电子顺磁共振（EPR）成像来提供绝对PO₂图像 鼠肿瘤的体积元素或体素，具有1个Torrpo₂分辨率和0.5 mm空间分辨率的FSA C₃H小鼠的腿中的癌。体素PO₂与局部的氧化岩测量值相关。 EPRpo₂图像 基于缺氧的级分，HF10（PO₂的肿瘤体素的一部分小于10托尔）与缺氧相关 蛋白质VEGF，CAIX和HIF1α，并具有肿瘤的可疗法，给定辐射剂量足以治愈 450 µL肿瘤的50％（TCD50）。这已建立的EPRPO₂成像是相关的可靠定位者 放射生物学上相关的缺氧。为了确定基于PO₂的剂量绘画是否改善了肿瘤的治疗，我们 实施了Xrad₂₂₅CX系统，以准确地将基于龙门的X射线处理提供给小鼠肿瘤 用EPR PO2图像注册。我们实施了快速的3D打印钨，加载了保形塑料 比较约100％的低氧肿瘤体素与避免缺氧的块。只有这样我们才观察到 低氧启动和抗增强剂之间的显着（P = 0.02）控制肿瘤控制差异。这是第一个 哺乳动物肿瘤中基于缺氧的剂量绘画的验证。差异之间的系统学 现在需要在几种不同的动物模型中确定低氧和正常的肿瘤组织 免疫条件和分馏以指导最终的人类使用，可能基于减少 保留αf-硝基咪唑宠物图像。我们提出以下计划，以调查 基于图像的剂量绘画： 1）确定体内低氧和单独的正常氧合肿瘤组织PO₂对照剂量 （TCD₅₀HYPOX和TCD₅₀OX），原位FSA和RIF1的体内氧增强比（OER） 纤维肉瘤，MCA4乳腺癌在原位上生长并确定免疫原性状态 依赖性，在人类PC3前列腺癌Xenoma Xenoma Xenoma Xenomagraphics中的依赖性。 2）确定三剂分馏对缺氧肿瘤控制和氧气增强的影响 比率（₃FTCD₅₀HYPOX，₃FTCD₅₀OX：₃foer） 这些实验将提供体内变化的范围，从中估算体内氧气增强的范围 指导低氧升高/剂量绘画治疗的早期人类试验的比率。临床前的成功 多种模型肿瘤中OER的确定可能建议纠正基于PET的人的手段 低氧肿瘤成像。我们还展示了在人类受试者中提出EPR成像的技术。

项目成果

Frequency dependence of electron spin relaxation times in aqueous solution for a nitronyl nitroxide radical and perdeuterated-tempone between 250 MHz and 34 GHz.

• DOI: 10.1016/j.jmr.2012.10.002
• 发表时间: 2012-12
• 期刊: JOURNAL OF MAGNETIC RESONANCE
• 影响因子: 2.2
• 作者: Biller, Joshua R.;Meyer, Virginia M.;Elajaili, Hanan;Rosen, Gerald M.;Eaton, Sandra S.;Eaton, Gareth R.
• 通讯作者: Eaton, Gareth R.

(2)H,(15)N-substituted nitroxides as sensitive probes for electron paramagnetic resonance imaging.

• DOI: 10.1021/jo1011619
• 发表时间: 2010-10-01
• 期刊: JOURNAL OF ORGANIC CHEMISTRY
• 影响因子: 3.6
• 作者: Burks, Scott R.;Bakhshai, Justin;Makowsky, Mallory A.;Muralidharan, Sukumaran;Tsai, Pei;Rosen, Gerald M.;Kao, Joseph P. Y.
• 通讯作者: Kao, Joseph P. Y.

Orthogonal resonators for pulse in vivo electron paramagnetic imaging at 250 MHz.

用于 250 MHz 脉冲体内电子顺磁成像的正交谐振器。

• DOI: 10.1016/j.jmr.2013.12.015
• 发表时间: 2014
• 期刊: Journal of magnetic resonance (San Diego, Calif. : 1997)
• 作者: Sundramoorthy,SubramanianV;Epel,Boris;Halpern,HowardJ
• 通讯作者: Halpern,HowardJ

Electron Paramagnetic Resonance pO2 Image Tumor Oxygen-Guided Radiation Therapy Optimization.

电子顺磁共振 pO2 图像肿瘤氧引导放射治疗优化。

• DOI: 10.1007/978-3-319-55231-6_39
• 发表时间: 2017
• 期刊: Advances in experimental medicine and biology
• 作者: Epel,Boris;Maggio,Matt;Pelizzari,Charles;Halpern,HowardJ
• 通讯作者: Halpern,HowardJ

Optimization-based image reconstruction from sparsely sampled data in electron paramagnetic resonance imaging.

电子顺磁共振成像中稀疏采样数据的基于优化的图像重建。

• DOI: 10.1016/j.jmr.2018.06.015
• 发表时间: 2018
• 期刊: Journal of magnetic resonance (San Diego, Calif. : 1997)
• 作者: Qiao,Zhiwei;Zhang,Zheng;Pan,Xiaochuan;Epel,Boris;Redler,Gage;Xia,Dan;Halpern,Howard
• 通讯作者: Halpern,Howard