Conventional cancer therapeutic regimens such as radiation or chemotherapy attempt to exploit physiological differences in oxygenation, redox status, and vasculature between normal and malignant tissues to provide selective killing of the tumor. Thus, methods that detect and quantify these metabolic differences should enable the development of more efficacious treatment strategies. Since localized tumor hypoxia is associated with cancer treatment failure, obtaining spatial information on such tumor volumes should also be valuable. The applicant has recently developed electron paramagnetic resonance imaging (EPRI) instrumentation capable of performing non-invasive physiological measurements in living objects. This technique can be adapted to measure in vivo tissue oxygenation and redox status using appropriate spin probes. Nitroxides, a class of stable free radical compounds, have been extensively used as probes for EPRI. Recently nitroxides have also been shown to provide selective radio protection of normal tissues, presumable due to their differential bioreduction rates of tumor versus normal tissue. Preliminary experiments have shown the feasibility of obtaining three-dimensional (3D) images of the pharmacokinetics of nitroxide distribution and oxygenation in murine tumor models. The goal of the present proposal is to utilize these new EPRI techniques as a noninvasive tool to evaluate tumor pathophysiology.
The Specific Aims are to: (i) Measure pharmacokinetics of redox sensitive nitroxides in normal and tumor tissues in vivo to evaluate heterogeneity in redox status. (ii) Perform in vivo 3D spatial EPRI of tumors with appropriate spin probes to obtain morphological (tissue heterogeneity) and mapping of physiological information as redox status and tissue perfusion. (iii) Perform spectral-spatial EPRI to obtain spatial mapping of oxygenation of malignant tissue and compare with normal tissue. (iv) Measure tumor hypoxic fractions for different tumor types using EPRI and compare with those obtained from other techniques such as microelectrode, in vitro radiobiology and nitromidazole binding. (v) Examine in vivo tumor vasculature using vasculature-specific spin labels and manipulations using vasoconstrictor and vasodilators on tissue perfusion and oxygenation. (vi) Obtain tissue reoxygenation profiles in tumors after therapeutic regimens such as radiation treatment or chemotherapeutic agents.
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