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

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Molecular & Cellular Analysis Technologies
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Not Applicable
PROJECT SUMMARYPositron-emission tomography (PET) probes (or ?tracers?) are biological molecules containing positron-emittingisotopes, the decay of which can be detected with high sensitivity to perform a variety of in vitro or 3D in vivoassays of biochemical processes for cancer research. A significant advantage of radiolabels is the high tissuepenetration 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 responseto treatment or assess efficacy of treatment), all with the same probe. Thousands of PET tracers have beenreported for assessing angiogenesis, tumor microenvironment (e.g. hypoxia), metabolism (e.g., glucose or aminoacids), density of receptors, etc. Another advantage is that many PET tracers are labeled with a single radioactiveatom, 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 demandthat scheduling can be coordinated (i.e. many patient scans and research projects on the same day) and thehigh production cost can be divided among many patients and researchers. In cases where demand is insufficientto enable cost-sharing, PET tracers are prohibitively expensive. Since the radioisotope is only a fraction of theproduction cost, scaling down to a smaller amount of radioactivity does not provide significant cost reduction forresearchers that only need a small quantity of the probe. Other drivers of cost are the expensive equipment andspecialized facilities (i.e. hot cells, to protect operators when using high amounts of radioisotope) that are notavailable to cancer researchers at many institutions, and the high cost of reagents consumed for each batch oftracer 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 tracerswhile providing unique advantages to solve the above problems: (1) Droplet microreactors consume 10-1000xless reagents than conventional systems; (2) Unlike conventional systems, molar activity in microreactorsremains high even when producing small quantities (radioactivity) of the tracer; (3) The compact size ofmicroreactors enables local radiation shielding and avoids the need for hot cells; (4) Production of small batchesfor 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 enableroutine, low-cost production of tracers on demand. This could ?commoditize? PET and make diverse tracersavailable to any investigator. This proposal seeks to perform advanced development and validation of thistechnology to make radiolabeled tracers widely available for assays in a variety of cancer research applications.