PET probe concentrator
The current gold standard for purification of PET tracers is high performance liquid chromatography (HPLC). The crude sample after radiosynthesis is loaded into an injection loop, and a mobile phase (separation buffer) carries the sample through the HPLC column under high pressure (Wikipedia article). The output of the column is monitored with a UV absorbance detector and a radiation detector. When the desired compound emerges, a valve is switched to collect the purified compound.
Although highly effective for purification, the high flow rates used in semi-preparative HPLC can result in the collection of significant volume of mobile phase. As a result, the purified sample may be too dilute. for certain applications such as in vivo imaging small animals (i.e. the low volume that can be injected limits the quantity of tracer that can be injected), or performing in vitro pharmacological assays looking at drug uptake or binding .
The current method for concentration relies on using rotary evaporator systems. Even ones that are specially modified to be more compact than commercial systems are bulky, thus taking up valuable space inside hot cells (reducing space for synthesizing additional tracers). Furthermore, rotary evaporators also concentrate relatively slowly (~1 mL / min) which causeses loss of the tracer due to radioactive decay. Lastly, use of the rotary evaporator generally requires manual transfer to and from upstream and downstream processes which increases the complexity and chance for errors in the production process.
To overcome these difficulties, we developed a microfluidic device for rapid concentration of PET tracers based on the concept of microscale membrane distillation (Wikipedia article). The aqueous PET probe sample to be concentrated is loaded on one side of a porous hydrophobic membrane. The pores prevent the passage of liquid but allow vapor to be transported across. As solvent is removed, room is created for additional volume of the original sample to flow into the chip. Starting with an arbitrary volume, concentration continues until just the chip is filled with liquid, or it can be continued even longer to result in volumes smaller than the chip. Final volumes on the order of 1 mL or less are possible.
Figure 1: (Top left) Photograph of the microfluidic concentrator. (Bottom left) Schematic cross-section of the microfluidic concentrator. The inset illustrates the operating principle of vapor transport through the membrane. (Top right) Channel pattern in the sample layer of the chip, including connections to other system components. (Bottom right) Channel pattern and connections for the gas flow layer of the chip. The number of passes of the serpentine channel illustrated in these schematics is reduced (compared to the actual device) for clarity.
In our first generation chip, we were able to successfully concentrate PET probes at a rate similar to rotary evaporator systems, and demonstrated successful concentration of several molecules including [F-18]FDG, D-[F-18]FAC, and [F-18]SFB with high overall efficiency. Furthermore, the device was capable of concentrating probes that were suspended in aqeuous HPLC buffers with organic solvent content up to ~20% ethanol and ~15% acetonitrile.
Current Status / Next Steps
In our latest generation chip, the evaporation rate has been improved to exceed 2mL/min at 100°C. Several tracers have been tested and are stable at this temperature. Using an improved device architecture, different materials can be used for the sample layer, allowing the chip be tailored to the particular tracer to minimize adsorption and result in the highest possible overall sample recovery. Furthermore, using an improved membrane, aqueous media with up to ~60% ethanol and ~80% acetonitrile can be concentrated. We are currently preparing a manuscript for our newest findings.
- W.-Y. Tseng and R. M. van Dam, “Compact microfluidic device for rapid concentration of PET tracers,” Lab Chip, vol. 14, no. 13, p. 2293, 2014. (PMC Link)
- Philip Chao (graduate student)
- Jeff Collins (staff radiochemist)
- Wei-Yu ("Tim") Tseng (postdoctoral scholar)
- Graciela Flores (staff radiochemist)