Time Domian Electron Paramagnetic Resonance Imaging

Abstract public domain (NIH RePORTER)

EPR Oxygen imaging with enhanced dynamic range: Electron Paramagnetic Resonance imaging is a low field MRI technique which uses paramagnetic agents which can be imaged using magnetic field gradients as in MRI. Oxo-63, an extensively derivatized trityl radical has been used extensively for EPR Imaging to image hypoxic regions in tumors. The echo signals from the EPR imaging experiment last longer in hypoxic regions and hence the sensitivity of the imaging is enhanced in hypoxic regions in the pO2 range of 0-25 mmHg. In normoxic regions with pO2 between 25 - 50 mm Hg, the signal intensity is lower making these regions not assessable. However to assess physiology in normal tissue with higher pO2, we examined the use of the trityl radical Oxo-71 which is a deuterated version of Oxo-63. Oxo-71 has signals which last longer than that with Oxo-63. Even in regions with higher pO2, phantom studies showed that there is sufficient signal to obtain reliable maps of oxygen. From phantom studies we used solutions of Oxo-71 equilibrated with 0%, 2%, 5%, 10%, and 21% oxygen and obtained a reliable estimate of oxygen between 0-160 mm Hg while we could get such estimates from 0-80 mmHg with Oxo-63. For in vivo imaging studies in hypoxic regions we used the MiaPaCa-2 tumor implanted on the hind leg of a mouse. Tumor pO2 values between0-40 mmHg were detected using Oxo-71 while using Oxo-63, only values up to 30 mmHg were registered. Using kidneys for imaging normal tissues using Oxo-71, pO2 values up to 50 mm Hg were identified. These studies showed that using Oxo-71, EPR imaging can be conducted to image pO2 in the entire range of hypoxia to normoxia. With this range, it is possible to study the physiology associated with normal and aberrant physiology in vivo non-invasively. Pharmacologic ascorbate enhances the efficacy Evofosfamide, a hypoxia activated pro-drug in the treatment of pancreatic ductal adenocarcinoma: Hypoxic tumors pose significant challenge in treatment. Recently, hypoxia-activated prodrugs have been developed to kill hypoxic tumors. Avenues to enhance the efficacy of such drugs to treat non-hypoxic regions in the tumors are being explored. Pharmacologic ascorbate (high dose intravenous delivered) is known to kill tumors selectively by exerting pro-oxidant effects. We hypothesized that the pro-oxidant effects exerted by pharmacologic ascorbate is associated with oxygen consumption thereby depleting oxygen from tumors and can potentially enhance the efficacy of the hypoxia-activated pro-drugs. Imaging experiments were conducted to identify the profile of oxygen changes after administration of pharmacologic ascorbate. Combining the sub-lethal levels of high dose ascorbate with the hypoxia activated prodrug Evofosfamide significantly prolonged the tumor volume doubling time compared to monotherapy with either agent. This study demonstrates that pharmacologic ascorbate can be used as an adjuvant to hypoxia-activated prodrugs such as Evofosfamide to elicit improved response.