The Need to Pair Molecular Monitoring Devices with Molecular Imaging to Personalize Health.

By enabling the non-invasive monitoring and quantification of biomolecular processes, molecular imaging has dramatically improved our understanding of disease. In recent years, non-invasive access to the molecular drivers of health versus disease has emboldened the goal of precision health, which draws on concepts borrowed from process monitoring in engineering, wherein hundreds of sensors can be employed to develop a model which can be used to preventatively detect and diagnose problems. In translating this monitoring regime from inanimate machines to human beings, precision health posits that continual and on-the-spot monitoring are the next frontiers in molecular medicine. Early biomarker detection and clinical intervention improves individual outcomes and reduces the societal cost of treating chronic and late-stage diseases. However, in current clinical settings, methods of disease diagnoses and monitoring are typically intermittent, based on imprecise risk factors, or self-administered, making optimization of individual patient outcomes an ongoing challenge. Low-cost molecular monitoring devices capable of on-the-spot biomarker analysis at high frequencies, and even continuously, could alter this paradigm of therapy and disease prevention. When these devices are coupled with molecular imaging, they could work together to enable a complete picture of pathogenesis. To meet this need, an active area of research is the development of sensors capable of point-of-care diagnostic monitoring with an emphasis on clinical utility. However, a myriad of challenges must be met, foremost, an integration of the highly specialized molecular tools developed to understand and monitor the molecular causes of disease with clinically accessible techniques. Functioning on the principle of probe-analyte interactions yielding a transducible signal, probes enabling sensing and imaging significantly overlap in design considerations and targeting moieties, however differing in signal interpretation and readout. Integrating molecular sensors with molecular imaging can provide improved data on the personal biomarkers governing disease progression, furthering our understanding of pathogenesis, and providing a positive feedback loop toward identifying additional biomarkers and therapeutics. Coupling molecular imaging with molecular monitoring devices into the clinical paradigm is a key step toward achieving precision health.

Assessment of Tumor Redox Status through (S)-4-(3-[18F]fluoropropyl)-L-Glutamic Acid PET Imaging of System xc - Activity.

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc - maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here, we show that tumor cell retention of a system xc --specific PET radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment. SIGNIFICANCE: [18F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy.See related commentary by Lee et al., p. 701.