Batch-reactor microfluidic device: first human use of a microfluidically produced PET radiotracer

Abstract

The very first microfluidic device used for the production of 18F-labeled tracers for clinical research is reported along with the first human Positron Emission Tomography scan obtained with a microfluidically produced radiotracer. The system integrates all operations necessary for the transformation of [18F]fluoride in irradiated cyclotron target water to a dose of radiopharmaceutical suitable for use in clinical research. The key microfluidic technologies developed for the device are a fluoride concentration system and a microfluidic batch reactor assembly. Concentration of fluoride was achieved by means of absorption of the fluoride anion on a micro ion-exchange column (5 μL of resin) followed by release of the radioactivity with 45 μL of the release solution (95 ± 3% overall efficiency). The reactor assembly includes an injection-molded reactor chip and a transparent machined lid press-fitted together. The resulting 50 μL cavity has a unique shape designed to minimize losses of liquid during reactor filling and liquid evaporation. The cavity has 8 ports for gases and liquids, each equipped with a 2-way on-chip mechanical valve rated for pressure up to 20.68 bar (300 psi). The temperature is controlled by a thermoelectric heater capable of heating the reactor up to 180 °C from RT in 150 s. A camera captures live video of the processes in the reactor. HPLC-based purification and reformulation units are also integrated in the device. The system is based on “split-box architecture”, with reagents loaded from outside of the radiation shielding. It can be installed either in a standard hot cell, or as a self-shielded unit. Along with a high level of integration and automation, split-box architecture allowed for multiple production runs without the user being exposed to radiation fields. The system was used to support clinical trials of [18F]fallypride, a neuroimaging radiopharmaceutical under IND Application #109,880.

Radiolabelling diverse positron emission tomography (PET) tracers using a single digital microfluidic reactor chip

“…A mass-produced universal chip may be disposable and fresh for each radiosynthesis, allowing imaging centers to produce multiple, different radiotracers back-to-back by simply swapping the chips and reagents. [30].…”

“…Because of its open-to-air configuration, the EWOD chip facilitates evaporative removal of solvent, unlike many other types of microfluidic devices [30)]. Solvent exchange is performed on the 9 EWOD chip by heating until the solvent has been evaporated and its vapours removed with a nitrogen stream, leaving behind a solute residue at the heater region.…”

Advantages of Radiochemistry in Microliter Volumes

“…Using this platform, our laboratory has reported the successful synthesis of [ 18 [26,27]. These results suggest that the EWOD-based synthesizer can meet the requirements for on-demand production of diverse PET tracers to meet preclinical or clinical needs.…”

“…Typically in 18 F-radiochemistry, the amount of precursor is many of orders of magnitude higher than the amount of This means that at the end of the synthesis, there are vast amounts of unreacted (or hydrolyzed) precursor that must be separated from a much smaller amount of the desired product. Because of the high amounts or precursor, large reaction volume, and the chemical similarity between precursor (native or hydrolyzed) and product, long semi-preparative HPLC purification times may be needed, resulting in a large solvent volume in the purified product.…”

“…While the PDMS chip was not suitable for processing [ 18 F]fluoride, the capability to react small volumes was found to be useful for screening radiolabeling conditions for the reaction of [ 18 F]SFB with an engineered antibody [18]. Using <100 nL per droplet, many reaction conditions could be tested, and then the whole batch could be labeled once optimal conditions were found.…”