Positron emission tomography (PET) is an advanced imaging technique, relying on the injection of radioactive ?tracers? to image specific biochemical processes in living subjects. By developing appropriate tracers, PET can provide measurements of the abundance of cell surface markers/receptors, degree of enzyme activity, or the rate of a biological processes. These measurements help understand the biology of cancer, discover and develop new drugs, and provide critical information for clinical trials or clinical decision making. Though basic research has led to the discovery of many new cancer markers and potential therapeutic targets, the development of suitable PET tracers to image these targets typically lags years behind. Beginning with approaches such as library screening to identify candidate tracers, the candidates are ranked based on in vitro criteria (e.g. affinity, selectivity). Due to high costs, only a very tiny number of these candidates are usually labeled for further evaluation. This leads to a slow, incremental tracer development process, exacerbated by the issue that in vitro selection criteria don't correlate well with in vivo performance. This proposal seeks to address this issue by making it practical and affordable to perform in vivo screening of much larger candidate libraries. High-throughput methods already exist for generation of (unlabeled) libraries of candidate tracers, and the potential for high-throughput in vivo imaging has also been reported. However, there does not currently exist a practical approach for performing the middle step in a high-throughput fashion, i.e. rapidly radiolabeling a compound library. This is due not only to the lack of technology for high-throughput radiosynthesis, but also the large volume used in conventional radiosynthesis methods, which leads to high precursor cost and low specific activity. Recent advances in microfluidic radiochemistry, in which reactions are performed in microliter-scale droplets, can overcome all of these limitations. This proposal leverages these advances to create a high-throughput radiolabeling platform.
Aim 1 develops a microfluidic reaction array to perform at least 48 simultaneous reactions.
In Aim 2, a liquid delivery system is developed to efficiently and rapidly distribute precursor, radiolabeling agent etc. to the reaction sites as needed. An integrated, automated system is developed in Aim 3 and validated using various commonly-used labeling chemistries. Finally, in Aim 4, UPLC chromatography and SPE plates are evaluated as potential means for performing high-throughput purification and formulation so the synthesized tracers are ready for injection. Ultimately, this proposal seeks to make screening a practical, routinely-available tool to accelerate and reduce the cost of novel PET tracer development.
There is currently a delay of many years between the time biologists discover a novel cancer biomarker or potential therapeutic target, and the time when this target can be observed in living subjects via whole-body imaging. The goal of this proposal is to address this issue by creating a new high-throughput technology to accelerate the discovery/development of the novel ?tracers? that are needed to enable positron emission tomography (PET) imaging of the biological target. By offering practical, simultaneous production of many candidate tracers, the proposed platform will enable high-throughput in vitro and in vivo screening to rapidly find a molecule with suitable in vivo qualities for pre-clinical or clinical imaging.
| Wang, Jia; Chao, Philip H; Hanet, Sebastian et al. (2017) Performing multi-step chemical reactions in microliter-sized droplets by leveraging a simple passive transport mechanism. Lab Chip 17:4342-4355 |
| Ha, Noel S; Sadeghi, Saman; van Dam, R Michael (2017) Recent Progress toward Microfluidic Quality Control Testing of Radiopharmaceuticals. Micromachines (Basel) 8: |
