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Epel B.,Center for Imaging In Vivo Physiology | Epel B.,University of Chicago | Redler G.,Center for Imaging In Vivo Physiology | Redler G.,University of Chicago | And 4 more authors.
Advances in Experimental Medicine and Biology | Year: 2016

Electron paramagnetic resonance imaging (EPRI) has been used to noninvasively provide 3D images of absolute oxygen concentration (pO2) in small animals. These oxygen images are well resolved both spatially (~1 mm) and in pO2 (1–3 mmHg). EPRI preclinical images of pO2 have demonstrated extremely promising results for various applications investigating oxygen related physiologic and biologic processes as well as the dependence of various disease states on pO2, such as the role of hypoxia in cancer. Recent developments have been made that help to progress EPRI towards the eventual goal of human application. For example, a bimodal crossed-wire surface coil has been developed. Very preliminary tests demonstrated a 20 dB isolation between transmit and receive for this coil, with an anticipated additional 20 dB achievable. This could potentially be used to image local pO2 in human subjects with superficial tumors with EPRI. Local excitation and detection will reduce the specific absorption rate limitations on images and eliminate any possible power deposition concerns. Additionally, a large 9 mT EPRI magnet has been constructed which can fit and provide static main and gradient fields for imaging local anatomy in an entire human. One potential obstacle that must be overcome in order to use EPRI to image humans is the approved use of the requisite EPRI spin probe imaging agent (trityl). While nontoxic, EPRI trityl spin probes have been injected intravenously when imaging small animals, and require relatively high total body injection doses that would not be suitable for human imaging applications. Work has been done demonstrating the alternative use of intratumoral (IT) injections, which can reduce the amount of trityl required for imaging by a factor of 2000- relative to a whole body intravenous injection. The development of a large magnet that can accommodate human subjects, the design of a surface coil for imaging of superficial pO2, and the reduction of required spin probe using IT injections all are crucial steps towards the eventual use of EPRI to image pO2 in human subjects. In the future this can help investigate the oxygenation status of superficial tumors (e.g., breast tumors). The ability to image pO2 in humans has many other potential applications to diseases such as peripheral vascular disease, heart disease, and stroke. © Springer Science+Business Media, New York 2016.


Redler G.,Center for Imaging In Vivo Physiology | Redler G.,University of Chicago | Epel B.,Center for Imaging In Vivo Physiology | Epel B.,University of Chicago | And 2 more authors.
Advances in Experimental Medicine and Biology | Year: 2014

Chronic hypoxia strongly affects the malignant state and resistance to therapy for tumors. Transient hypoxia has been hypothesized, but not proven to be more deleterious. Electron paramagnetic resonance imaging (EPRI) provides non-invasive, quantitative imaging of static pO2 in vivo. Dynamic EPRI produces pO2 movies, enabling non-invasive assessment of in vivo pO2 changes, such as transient hypoxia. Recent developments have been made to enable Dynamic EPRI. Maximally spaced projection sequencing has been implemented to allow for more accurate and versatile acquisition of EPRI data when studying dynamic systems. Principal component analysis filtering has been employed to enhance SNR. Dynamic EPRI studies will provide temporally resolved oxygen movies necessary to perform in vivo studies of physiologically relevant pO2 changes in tumors. These oxygen movies will allow for the localization/quantification of transient hypoxia and will therefore help to disentangle the relationship between chronic and transient hypoxia, in order to better understand their roles in therapeutic optimization and outcome. © Springer Science+Business Media, LLC 2014.


Epel B.,Center for Imaging In Vivo Physiology | Epel B.,University of Chicago | Redler G.,Center for Imaging In Vivo Physiology | Redler G.,University of Chicago | And 2 more authors.
Advances in Experimental Medicine and Biology | Year: 2014

The partial pressure of oxygen (pO2) in tissues plays an important role in the pathophysiology of many diseases and influences outcome of cancer therapy, ischemic heart and cerebrovascular disease treatments and wound healing. Over the years a suite of EPR techniques for reliable oxygen measurements has been developed. This is a mini-review of pulse EPR in vivo oxygen imaging methods that utilize soluble spin probes. Recent developments in pulse EPR imaging technology have brought an order of magnitude increase in image acquisition speed, enhancement of sensitivity and considerable improvement in the precision and accuracy of oxygen measurements. © Springer Science+Business Media, LLC 2014.


Redler G.,Center for Imaging In Vivo Physiology | Redler G.,University of Chicago | Epel B.,Center for Imaging In Vivo Physiology | Epel B.,University of Chicago | And 2 more authors.
Advances in Experimental Medicine and Biology | Year: 2014

Distributions of oxygen concentration (pO2) are a critical determinant of normal tissue health as well as tumor aggressiveness and response to therapy. A number of studies show the value of normal tissue and tumor tissue oxygenation images and some of these will be discussed here. A strong correlation between tumor hypoxic fraction as measured with electron paramagnetic resonance oxygen imaging and radiation treatment success or failure has been found in two separate cancer types. Oxygen images of the torso of wild type mice show initial reduction of lung, liver, visceral, and muscle pO2 with cyclic halving of fraction of inspired oxygen (FiO2), but variation is blunted over an hour. Spontaneous breast cancers in Mouse Mammary Tumor Viral (MMTV) promoted-polyoma middle T antigen (PyMT) mice with BNIP3, a major factor in promotion of mitochondrial autophagy, knocked out will be compared with wild type animals. Preliminary studies for the BNIP3 knock out animals show extremely low pO2. The wide variety of studies, in which oxygen images can play an integral role, serve to demonstrate the importance of oxygen images. © Springer Science+Business Media, LLC 2014.


Redler G.,Center for Imaging In Vivo Physiology | Redler G.,University of Chicago | Elas M.,Center for Imaging In Vivo Physiology | Elas M.,University of Chicago | And 7 more authors.
Advances in Experimental Medicine and Biology | Year: 2013

The reduced oxygen in tumors (hypoxia) generates radiation resistance and limits tumor control probability (TCP) at radiation doses without significant normal tissue complication. Modern radiation therapy delivery with intensity-modulated radiation therapy (IMRT) enables complex, high-dose gradient patterns, which avoid sensitive human tissues and organs. EPR oxygen images may allow selection of more resistant parts of a tumor to which to deliver more radiation dose to enhance TCP. EPR O2 images are obtained using injected narrow-line, low relaxation rate trityl spin probes that enable pulse radiofrequency EPR O2 images of tumors in the legs of mice, rats, and rabbits, the latter exceeding 4 cm in size. Low relaxation rates of trityls have enabled novel T1-, rather than T2-, based oximetry, which provides near absolute pO2 imaging. Tomographic image formation and filtered back projection reconstruction are used to generate these images with fixed, linear stepped gradients. Images obtained both with T2 and T1 oximetric images have demonstrated the complex in vivo mechanism explaining the unexpected efficacy of TNFerade, a radiation-inducible adenoviral construct to locally produce TNF-induced vascular as well as radiation damage [1, 2]. The unexpected efficacy of large-dose radiation fractions is seen to be due to an interaction between host microvasculature and tumor cells producing a prompt (15 min) postradiation hypoxia, paralyzing tumor cell repair, and sensitizing tumors. Finally, cure of tumors treated to a single 50 % control dose shows a significant dependence on EPR O2 image hypoxic fractions, best shown with the fraction of voxels less than 10 Torr (HF10). We show that these O2 images provide a quantitative basis for measuring tumor and normal tissue response to abnormally low O2 levels. Measurements of vascular endothelial growth factor (VEGF) production in a specific syngeneic mouse fibrosarcoma, FSa versus fraction of tissue voxels with pO2 less than 10 Torr, produced a slope of 0.14 pg VEGF protein/mg total protein/% HF10. We argue that this quantification may be diagnostic of tumor versus normal tissue, and it may be etiologic in the development of malignancy. © 2013 Springer Science+Business Media New York.

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