A Novel Approach to In Vivo EPR Spectroscopy for Repeatable Assessments of Oxygenation Levels in Tumors at Any Depth:...

There is widespread consensus that hypoxia limits the effectiveness of cancer therapy. This has led to interventions to increase oxygen (O₂) levels in tumors in patients, but success in clinical trials has been very limited and therefore clinical practice has not incorporated such interventions. The limiting step for successful intervention is the need to identify which tumors are hypoxic, whether they respond to interventions to increase O₂, and the timing of the response. Consequently, many techniques have been advanced to measure O₂ in tumors, but to date, none has been able to measure O₂ directly in the tumor repeatedly under clinically applicable conditions (i.e., without perturbing clinical flow). Initial efforts at Dartmouth demonstrated that in vivo electron paramagnetic resonance (EPR) spectroscopy, using three types of injected or implanted O₂ sensors, could provide the desired data under the desired conditions. Two types, injected paramagnetic India ink and an implanted coated derivative of lithium phthalocyanine, were successfully tested in clinical studies. However, their use is limited to tumors <1 cm of the surface. Consequently, Dartmouth developed a third O₂ sensor, an "implantable resonator" (IR), to allow measuring in tumors at any depth; the IR has been successfully tested in preclinical studies. However, because the IR requires implanting at greater depth than the other types, its invasiveness was considered to be a drawback for clinical studies. Therefore, Clin-EPR and colleagues at the University of Chicago made additional technical improvements to the IR and proposed a new approach, called the multisite oxygen sensor (MOS), that allows its use in clinical studies without adding any invasiveness to therapy the patient is already undergoing. Specifically, the MOS is being designed to use in conjunction with a frequently used therapeutic approach (HDR brachytherapy delivered with an afterloader), applied initially to cervical cancer. HDR brachytherapy requires the invasive placement of multiple needles into the tumor and leaves them in situ for days during the course of treatment. Using these same needles, modified to be permeable to O₂, would allow the MOS, inserted inside each needle, to simultaneously measure O₂ at multiple locations throughout the tumor. This O₂ measurement session could be repeated periodically during the course of therapy. We report preliminary technical studies of the modified MOS and the proposed modified brachytherapy needles, demonstrating in vitro the feasibility of our new approach to provide important information about tumor hypoxia during the course of radiation therapy without needing any additional invasiveness beyond standard of care therapy.