Micro- and millifluidic platforms for imaging agent synthesis
Molecular imaging, the non-invasive visualization of cellular and sub-cellular events, holds great promise to improve the basic understanding of biochemical processes and clinical diagnosis of diseases. One widely used molecular imaging technique is positron emission tomography (PET) that is especially useful for clinical oncology applications. PET has seen remarkable growth recently due to improvements in the regulation of PET radiotracers and the development of multimodal imaging set-ups that combine the sensitivity of PET with X-ray computed tomography (CT) or magnetic resonance imaging (MRI) that provide anatomical details. To date the most widely used PET radiotracer is [18F]fluorodeoxyglucose ([18F]FDG). Despite the widespread use of [18F]FDG, 18F has a short half-life and [18F]FDG cannot detect certain cancers. There is a desire to develop radiometal-based radiotracers that have a wide selection of radioisotope half-lives from 10’s of minutes to days. Additionally, these tracers have the potential for flexible synthesis of tumor-specific tracers by easily changing the biomolecule (BM) utilized. However, radiometal-based PET radiotracers still face key challenges including (1) site-specific attachment of bifunctional chelators (BFCs), responsible for chelating the radiometal, to tumor-targeting biomolecules and (2) improving synthesis equipment to reduce reagent use and radiation shielding costs. My dissertation primarily focuses on addressing the challenges associated with radiometal-based PET radiotracer synthesis. “Click chemistry”, or more specifically Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), was utilized to address the concern regarding site-specific attachment of BFCs to BMs. CuAAC, like other “click reactions”, yields products with few side reactions under mild reaction conditions which is key when working with biomolecules. However, PET radiotracers are typically made in small batches because radioisotopes are utilized. Microfluidic platforms enable handling of small volumes, reducing reagent use and simultaneously minimizing radiation shielding costs due to their inherently small size. Here I describe how microfluidics was merged with the “click chemistry” concept to produce BM-BFC conjugates with the potential to be used as PET radiotracers. In Chapter 2 I describe the initial development and fabrication of a “click chip” with immobilized Cu(I) catalyst to facilitate CuAAC reactions that also minimizes purification requirements because the cytotoxic Cu(I) catalyst is immobilized to the microfluidic platform. Chapter 3 discusses how the “click chip” was improved to reduce solvent loss and enable longer reactions to conjugate BMs and BFCs. Nanoparticles (NPs) are another class of imaging agents that have some advantages over small molecule-based imaging agents (e.g., facile incorporation of multiple imaging modalities). However, many NPs are synthesized using low-yield synthetic strategies not amenable for scale up (e.g., microfluidics). Microfluidic mixers have been well characterized over the past decades, but few efforts have focused on millifluidic mixers and millifluidic platforms in general. Millifluidic devices offer some of the same advantages as microfluidics, such as rapid heat and mass transfer, but also enable higher throughput and are typically easier to fabricate. In Chapter 4 I discuss the design and fabrication of a millifluidic mixer that was validated by synthesizing gold nanoparticles (AuNPs). Ultimately, I was able to develop microfluidic and millifluidic platforms that have the potential to improve synthesis of imaging agents.
Microfluidics, Click chemistry, Cu(I)-catalyzed azide-alkyne cycloaddition, Radiotracers, Millifluidics, Mixing, Nanoparticles
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign