After integrating a common resonator/coil platform permitting the sequential imaging with EPRI for tissue oxygen maps followed by MRI for anatomy, blood vessel density, blood flow etc, we have utilized the system for longitudinal monitoring of tumor oxygen status, blood vessel density and the corresponding changes in response to treatment with chemotherapeutic drugs which impact tumor oxygen status and blood vessel density. Effect of the anti-angiogenic drug, sunitinib on tumor oxygenation and blood vessel density: We have evaluated the effect of sunitinib, an anti-angiogenic drug in C3H mice implanted with squamous cell carcinoma (SCC) on the hind leg and monitored changes in oxygen and blood vessel density on several days after treatment initiation and compared with control untreated tumor bearing mice. These studies showed: a) it is possible to longitudinally monitor changes in tumor oxygen and blood vessel density;b) blood vessel density decreases after treatment with sunitinib;and d) there is a transient increase in tumor oxygenation after sunitinib treatment. These data are in agreement with the immunohistochemical data obtained on the markers for blood vessel density Effect of the mTOR inhibitor, rapamycin on tumor oxygenation and blood vessel density: Rapamycin is in active investigation in many tumor types in humans. Some of its effects on tumors include tumor vessel damage. EPR imaging and MRI studies were conducted on SCC tumor bearing mice during treatment with rapamycin. The studies show that rapamycin has significant influence in tumor vessel damage as early as one day after treatment initiation. However, the tumor vessel decrease was associated with a transient but significant increase in tumor oxygenation in agreement with results which suggest that there is a normalization of tumor vasculature which increases tumor oxygenation. Spatio-temporal fluctuations of tumor oxygen: It has been suggested that tumor oxygen profiles exhibit significant spatio-temporal fluctuations. These observations were made using invasive measurements at fixed locations using oxygen electrodes. With the capabilities developed using EPR where tumor oxygen maps in 3-dimensions can be made in under 3 minutes, we have examined the spatio-temporal profile of tumor oxygenation in two different tumor types: SCC and the colon cancer cell line HT-29 in mice implanted as xenografts. The EPRI maps show that in the SCC tumor, there is a significant spatial heterogeneity in tumor oxygen as well as significant temporal fluctuation in oxygen in some regions of the tumor. In the case of HT-29 tumor, the oxygen fluctuations were minimal. In both cases, the paramagnetic tracer, Oxo-63 levels were stable. Immunohistochemical analyses quantifying pericyte coverage on tumor vessels show that HT-29 tumor vessels have better coverage than SCC tumor vasculature. Scale up of the EPR imaging for larger size objects: We have developed resonators to study larger sized objects. A 7 cm bore size resonator was developed and images form phantom objects were obtained. One of the major issues with scale up is the ability to deliver sufficient RF power and to minimize RF heating. We have carried out sham experiments in rats to examine the ability to deliver sufficient RF power to obtain EPR signals and conduct the experiment with minimal change in the core body temperature. We have arrived at experimental conditions where it is possible to obtain image data with no observable change in body temperature.
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