UCLA

Radiopharmaceuticals labeled with short-lived positron-emitting or gamma-emitting isotopes are injected into patients just prior to performing a positron emission tomography (PET) or single photon emission computed tomography (SPECT) scan. These imaging modalities are widely used in clinical care, as well as in the development and evaluation of new therapies via clinical trials. Unlike ordinary pharmaceuticals, the short lifetime of radiopharmaceuticals requires that they be produced in relatively small batches close to the geographical location where the patient is scanned.

Since PET tracers are classified as drugs by regulatory agencies, they must pass stringent quality control (QC) tests after their production to ensure patient safety prior to injection. Performing and documenting these tests is cumbersome and time-consuming, and requires an array of expensive analytical chemistry equipment and significant dedicated lab space, and there is considerable interest in the development of automated and lower-cost approaches.

By replacing conventional techniques with lab-on-a-chip technologies, it may be possible to achieve further reductions in the size, cost, and complexity of automated QC testing platforms. While some advances have been made for some of the many QC tests, high-resolution miniaturized methods suitable for assessment of chemical or radiochemical identity and purity are notably missing. We have been exploring microchip capillary electrophoresis (MCE) as a potential means to fill this gap. We have shown the potential to perform chemical identity and purity analysis by successful separation of the PET tracer [18F]FLT from all of its side products, with comparable limit of detection as HPLC. More recently, we demonstrated first-in-field work to add radiation detection to the MCE system, using a high-resolution positron detector to perform the radiochemical identity analysis of PET tracers.

Microfluidic systems are also useful for the synthesis of radiopharmaceuticals such as radiolabeled peptides and antibody fragments, which provide a means to image disease-specific targets with extremely high specificity. To substantially reduce the high cost of radiolabeling, we have explored the feasibility of using a microdroplet reactor approach. As an example, a thiol-containing RGD peptide was labeled with fluorine-18 in a site-specific manner via the maleimide-based prosthetic group, [18F]FBEM on a microfluidic chip. We have also explored the site-specific radiofluorination of engineered antibody fragments (diabody) for ImmunoPET imaging via this microfluidic approach.

These studies, and other work on small-molecule synthesis, have shown that there are advantages in performing radiochemistry in microdroplets. Active means of manipulating microdroplets, such as electrowetting-on-dielectric (EWOD) provides more flexibility of reaction implementation than passive methods, but EWOD devices are well known to suffer from a charging effect and the dielectric and hydrophobic layers have been found to suffer defects during harsh chemical reactions. Therefore, a novel droplet actuation mechanism, electro-dewetting, has been developed to address these challenges. Electro-dewetting uses an electric field formed inside a droplet to manipulate the adsorption of ionic surfactant molecules on the solid surface to change the contact angle. The underlying mechanism of this pheromone has been elucidated.

We believe that all the work described here shows the potential for dramatic miniaturization of the complete PET tracer production process, and ultimately increasing the availability of diverse PET tracers for research use, further development, and clinical translation via lowering the cost and complexity of tracer production.