Optimization and validation of integrated microscale technologies for low-cost, automated production of PET molecular imaging tracers for cancer research

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PROJECT SUMMARY Positron-emission tomography (PET) probes (or “tracers”) are biological molecules containing positron-emitting isotopes, the decay of which can be detected with high sensitivity to perform a variety of in vitro or 3D in vivo assays of biochemical processes for cancer research. A significant advantage of radiolabels is the high tissue penetration of gamma rays – this allows discoveries at the cellular level to be translated to new animal models (e.g. to study the mechanisms and treatment of disease) and then to assays in patients (e.g. to predict response to treatment or assess efficacy of treatment), all with the same probe. Thousands of PET tracers have been reported for assessing angiogenesis, tumor microenvironment (e.g. hypoxia), metabolism (e.g., glucose or amino acids), density of receptors, etc. Another advantage is that many PET tracers are labeled with a single radioactive atom, typically causing less disruption to biological function compared to bulky labels such as fluorophores. Current methods for routine production of these short-lived PET tracers are aimed largely at the clinical market, i.e. for production of large, multi-patient batches. For a few tracers (e.g. [18F]FDG), there is sufficient demand that scheduling can be coordinated (i.e. many patient scans and research projects on the same day) and the high production cost can be divided among many patients and researchers. In cases where demand is insufficient to enable cost-sharing, PET tracers are prohibitively expensive. Since the radioisotope is only a fraction of the production cost, scaling down to a smaller amount of radioactivity does not provide significant cost reduction for researchers that only need a small quantity of the probe. Other drivers of cost are the expensive equipment and specialized facilities (i.e. hot cells, to protect operators when using high amounts of radioisotope) that are not available to cancer researchers at many institutions, and the high cost of reagents consumed for each batch of tracer produced. Due to the high cost, many researchers choose alternative labeling methods (e.g. fluorescent, bioluminescent) despite the limitations of these approaches. Our preliminary data have shown that microfluidic synthesizers can successfully produce diverse PET tracers while providing unique advantages to solve the above problems: (1) Droplet microreactors consume 10-1000x less reagents than conventional systems; (2) Unlike conventional systems, molar activity in microreactors remains high even when producing small quantities (radioactivity) of the tracer; (3) The compact size of microreactors enables local radiation shielding and avoids the need for hot cells; (4) Production of small batches for individual researcher use will require much less radiation shielding (thickness), compared to typical hot cells. Previous studies have established feasibility and suggest that microdroplet synthesizers are poised to enable routine, low-cost production of tracers on demand. This could “commoditize” PET and make diverse tracers available to any investigator. This proposal seeks to perform advanced development and validation of this technology to make radiolabeled tracers widely available for assays in a variety of cancer research applications.