Radiation Biology of EPR Oxygen Images

EPR 氧气图像的放射生物学

基本信息

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
项目类别：
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

项目摘要

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，活体组织对辐射的抵抗力一直与缺氧有关，缺氧是一种局部现象。缺乏分子氧，或低氧分压过去资助周期的重点是验证这一假设。在过去的一个世纪中，人们一直假设，但尚未得到证实，治疗专门针对以下区域：氧分压低、体素低于 10 托、缺氧增强的肿瘤将提高肿瘤的治愈率。研究资助使用电子顺磁共振 (EPR) 成像来提供绝对 pO2 图像 FSa 中具有 1 托 pO2 分辨率和 0.5 毫米空间分辨率的小鼠肿瘤的体积元素或体素 C₃H 小鼠腿部的癌症。体素 pO2 与局部 EPR pO2 图像相关。基于缺氧分数，HF10（pO2 小于 10 托的肿瘤体素分数）与缺氧相关 VEGF、CAIX 和 HIF1α 蛋白，以及给予足以治愈肿瘤的辐射剂量的肿瘤的治愈性 450 µl 肿瘤的 50% (TCD50) 这确立了 EPR pO2 成像作为相关相关肿瘤的可靠定位器。为了确定基于 pO2 的剂量涂抹是否可以改善肿瘤治愈，我们进行了放射生物学相关的缺氧研究。实施 XRAD22₅Cx 系统，对小鼠肿瘤进行基于龙门的 X 射线精确治疗使用 EPR pO2 图像进行注册，我们实施了快速 3D 打印钨负载保形塑料。块来比较治疗约 100% 的缺氧肿瘤体素与缺氧避免。低氧加强和抗加强之间的肿瘤控制差异显着（p=0.02）这是第一个。哺乳动物肿瘤中基于缺氧的剂量绘制的验证。现在需要在几种不同动物模型中测定缺氧和正常 pO2 肿瘤组织免疫条件和分级指导最终人类使用，可能基于还原 18F-硝基咪唑 PET 图像的保留我们提出了以下程序来研究系统学。基于 EPR pO2 图像的剂量绘制： 1) 确定体内缺氧并分离正常氧合的肿瘤组织 pO2 控制剂量（TCD₅₀Hypox 和 TCD₅₀Ox），原位 FSa 和 RIF1 的体内氧增强比 (OER) 纤维肉瘤、MCa4 乳腺癌原位生长，并确定免疫原性状态依赖性，在无胸腺裸鼠的人 PC3 前列腺癌异种移植物中。 2)确定三剂量分割对缺氧肿瘤控制和氧增强的影响比率（₃fTCD₅₀Hypox，₃fTCD₅₀Ox：₃fOER）这些实验将提供体内变化范围，从中估计体内氧气增强指导缺氧加强/剂量涂抹治疗的早期人体试验的比率。多种模型肿瘤中 OER 的测定可能会提出纠正基于 PET 的人类肿瘤的方法我们还展示了人类受试者的缺氧肿瘤成像技术。

项目成果

期刊论文数量（104）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
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
影响因子：
0
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)
影响因子：
0
作者：
Qiao,Zhiwei;Zhang,Zheng;Pan,Xiaochuan;Epel,Boris;Redler,Gage;Xia,Dan;Halpern,Howard
通讯作者：
Halpern,Howard