Research
Overview
My group is broadly interested in developing technologies that can facilitate the study of cancer and other diseases and accelerate the discovery and development of new drugs or cell-based therapies. We are particularly focused on the benefits of in vivo molecular imaging via positron-emission tomography (PET), which can be used to visualize and quantify the distribution of certain receptors or markers throughout the body, or measure the rate of certain metabolic processes. Such information can be used to increase our scientific knowledge about disease, provide diagnostic information, monitor response to treatment, or optimize the in vivo properties of new therapies. Though thousands of PET radiopharmaceuticals have been developed to image different receptors and metabolic processes, only a few are routinely available from commercial sources due to the high cost and complexity of manufacturing these short-lived compounds.
We strive to overcome this bottleneck by developing simpler, low-cost radiochemistry technologies and methods for the discovery and production of all types of radiopharmaceuticals (PET tracers, SPECT tracers, theranostics). We are developing (i) compact microfluidic radiochemical reactors for rapid, low-cost production of radiopharmaceuticals, (ii) new high-sensitivity instruments and methods for radiopharmaceutical analysis and cell uptake/binding assays, (iii) and novel high-throughput radiochemistry platforms for reaction optimization and radiopharmaceutical discovery. We are also interested in advancing the underlying tools (e.g., microfluidics) frequently used in the lab.
We are passionate about making an impact in medicine, and strive to move proof-of-concept technologies into real-world applications through collaborations and commercialization.
Projects to improve conventional radiosynthesizers
We have developed novel radiosynthesizers that are simpler to operate and have increased flexibility and compatibility with challenging radiosynthesis processes.
A disposable-cassette-based radiosynthesizer with high reaction flexibility (up to 3 reaction vessels, capability for high-temperature high-pressure reactions) and designed to facilitate simplified programming.
A novel, easy-to-use software interface for radiosynthesizers in which a particular radiosynthesis protocol is described as a short series of intuitive chemistry "unit-operations" rather than a long series of cryptic low-level hardware commands.
Projects in microscale production of PET tracers
We are developing key pieces of microfluidic radiochemistry technology that we believe will enable the production of small or large batches PET tracers on demand, at affordable cost.
Aliquoting system for radioactive solutions
Automated system for first calibrating the radioactivity concentration of a radioactive solution and then metering out the desired amount(s) of the solution. The system is used to safely divide batches of radioisotope to supply multiple users, and can also be used to prepare individual doses of a formulated tracer for preclinical or clinical imaging.
Microfluidic electrochemical cell to trap [F-18]fluoride from the [O-18]water solution output from a cyclotron and later release it into an anhydrous solvent or precursor solution for downstream reaction.
Several methods and systems have been developed for automatically concentrating [F-18]fluoride and other radionuclides into microliter volumes, including approaches based on solvent evaporation and solid-phase extraction.
High-pressure microreactor based on phase-change microvalves
A proof-of-concept using phase-change microvalves (based on DMSO "ice") to contain the pressure from a reaction mixture in a volatile organic solvent under super-heated conditions.
An electronically-actuated electrowetting-on-dielectric (EWOD) microfluidic device with digital reagent pathways and integrated heater for performing multi-step radiochemical syntheses at the microliter scale.
A compact automated radiosynthesizer based on a Teflon-coated silicon microreaction chip. Patterning of hydrophilic areas defines a "liquid trap" for the reaction zone and tapered pathways to transport reagent droplets into this zone from the periphery of the chip.
Microdroplet radiochemistry on surface-tension trap chip
Simplified Teflon-coated silicon microreaction chips with hydrophilic surface-tension traps form the basis for our ultra-compact (coffee-cup-sized) next-generation automated droplet radiosynthesizer.
Novel microscale methods for purification of radiopharmaceuticals
Development of novel microscale approaches for purification of radiopharmaceuticals, including (i) miniaturized solid-phase extraction, (ii) removal of unreacted [F-18]fluoride via alumina surfaces or particles in digital microfluidic devices, and (iii) preparative microchip electrophoresis. Some additional strategies are currently in development.
Automated microfluidic system based on membrane distillation for solvent evaporation to enable rapid reformulation of PET tracers. The device can also be used to concentrate PET tracers if radioactivity concentration would otherwise be too dilute for applications such as preclinical imaging.
Scaled-up microdroplet radiosynthesis
We have recently integrated our radionuclide concentration and microdroplet radiosynthesizer technologies to explore production of large batches tracers starting with up to ~1 Ci of activity.
Projects in radioanalytical methods
We are developing novel methods for the analysis of radiopharmacueticals and for the analysis of microfluidic radiochemistry devices and processes.
A technique for imaging the distribution of radioactivity within a planar microfluidic chip. This method can be used for qualitative troubleshooting or quantitative measurements.
Method to determine properties (volume, concentration, solvent, conductivity, etc.) of a droplet in a digital microfluidic device via impedance measurements.
We have been exploring the use of capillary electrophoresis (CE) and microchip electrophoresis (MCE) for more compact analysis of radiotracers, including determination of chemical and radiochemical purities for quality-control (QC) testing.
Projects in microfluidic high-throughput methods
In the area of radiochemistry, we are developing novel high-throughput techniques for reaction optimization or radiolabeling of compounds libraries. We are also interested in devices and systems for automated high-throughput cell studies, such as multi-parameter measurements of protein expression or cellular metabolism.
Platform for performing large numbers of chemical or radiochemical reactions in droplets in parallel. Can be used for rapid and thorough reaction optimization or simultaneous radiolabeling of a whole library of compounds.
High-throughput analysis for radiochemistry
Novel method and software interface for rapid radiochemical purity analysis of large numbers of samples.
Robotic system for high-throughput radiopharmaceutical synthesis optimization
Development of a robotic system that fits within a mini-cell for high-throughput automation of droplet reactions and reaction sampling.
Development of microfluidic chips containing arrays of cell chambers and development of a parallelized robotic fluidic delivery system to perform controlled flow of a series of reagents through these chambers. A demonstration of a multi-step, multi-parameter staining assay was performed.
Projects in microscale radiochemistry applications
We are interested in applying our microfluidic technologies to various radiolabeling applications to leverage the advantages of high radioisotope concentration, low precursor amounts, fast synthesis times, etc.
Microfluidic radiolabeling of biomolecules
We developed a programmable microfluidic slug generator to prepare small reaction mixtures with different compositions (concentrations, pH) to screen reaction conditions while consuming only tiny amounts of the biomolecule, enabling most of the batch to be optimally labeled. In a related project, we are exploring the labeling of biomolecules in a microdroplet radiochemistry chips.
High molar activity of microvolume radiosynthesis
A systematic study revealed that performing radiochemistry in microscale volumes results in high molar activity of PET tracers, even when producing only a very small (low-radioactivity) batch. We explored the impact of the molar activity on imaging with several different tracers.
Microfluidic isotopic exchange reactions
In isotopic exchange reactions, e.g. F-19 for F-18 exchange, the precursor and product molecules are chemically identical and cannot be separated; thus, to maximize specific activity it is critical to minimize the amount of excess precursor in the reaction while keeping the concentration high - a perfect application of microvolume radiochemistry.
Efficient and economical radiotracer synthesis in microdroplets
We have been developing and optimizing droplet-based radiosyntheses for a variety of tracers, including [F-18]FDG, [F-18]FET, [F-18]Florbetaben ([F-18]FBB), [F-18]FDOPA, as well as labeling of peptides with 18F-labeled prosthetic groups or radiometals. Droplet radiosyntheses often have comparable yields to their macroscale counterparts, but are faster, consume much less reagents, can be purified with faster methods, and can produce high molar activities even for small batches. These devices can also be a valuable tool during new tracer development where the available amount of precursor material may be very limited.
Projects in novel radiochemistry methods
We are interested in the development of novel labeling methods to simplify the overall radiosynthesis or purification processes, and to expand the scope of radiolabeled molecules that can be produced.
A novel microfluidic cell was developed to explore the acceleration of electrochemical fluorination reactions.
Novel fluorination method in which transition-metal-oxide (e.g. TiO2) nanoparticles facilitate the radiofluorination of tosylated precursors.
Microfluidic solid-phase methods for radiochemistry
Development of porous polymer monoliths within microchannels for performing steps of radiochemical syntheses, including separation of [F-18]fluoride from [O-18]water.
Projects in microfluidic engineering
We also try to improve the underlying technologies in our work.
Plug-and-play connectors for simplified and more robust interfacing with elastomeric microfluidic chips.
Novel chemically-resistant fluoropolymers for microfluidic chips
Novel elastomers (e.g. PFPE and clicked PFPE) have been developed for the fabrication of highly chemically-resistant microfluidic devices containing pneumatically-actuated microvalves.
Interfaces for loading non-aqueous solutions to EWOD chips
Several approaches for automated and precise delivery of reagents (both aqueous (non-wetting) and non-aqueous (wetting)) to digital microfluidic chips.
Acoustic mixing in droplets
A setup for rapid mixing of droplets actuated by a non-contact acoustic source away from the microfluidic chip.
Electrodewetting - new droplet actuation mechanism
Method for electronic control of droplets by addition of ionic surfactant enables digital microfluidics with reliability advantages of electrowetting-on-dielectric (EWOD). (Collaboration with Prof. Chang-Jin "CJ" Kim, Department of Mechanical & Aerospace Engineering, UCLA.)