Browsing by Author "Pagel, Mark D"

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    Contrast Agent Development for Molecular Imaging of Cancer
    (2021-12-03) Pollard, Alyssa Camille; Pagel, Mark D; Kolomeisky, Anatoly
    This dissertation focuses on the design, synthesis, and application of contrast agents for molecular imaging. Specifically, these agents have been designed to probe specific tumor biomarkers such as pH or cancer metabolism to provide information related to tumor biology. Two sets of positron emission tomography/magnetic resonance imaging (PET/MRI) co-agents have been designed to measure tumor extracellular pH. One set of agents is metal-based using gadolinium or a radiometal, and the other introduces a fluorine-18 or fluorine-19 tag. While both the radiometal and fluorine-based co-agents were able to measure pH in solution, the fluorine-based co-agents reached a lower standard error of 0.06 pH units. In addition, the fluorine-based co-agents demonstrated high stability in solution and in vivo, while the radiometal-based agents underwent dechelation of the radiometal upon injection. Finally, the fluorine-based agents were able to measure tumor pH in a 4T1 breast cancer cell line. To apply the PET/MRI co-agents, extensive work had to first be performed to characterize the small animal PET/MRI system and determine how the two modalities affected the other’s image quality. After correcting for PET quantification, radioactivity could be accurately measured by the PET detector with errors of less than 5% for fluorine-18 and less than 20% for gallium-68. Despite the larger errors for gallium-68, they did not largely influence pH measurements using 68Ga-labeled PET co-agents. The power of PET/MRI was also utilized to identify lung tumor metastases and measure [18F](2S,4R)-4-fluoroglutamine ([18F]FGln) uptake in a clear cell renal cell carcinoma lung metastasis model. Due to the high anatomical contrast of PET/MRI, lung tumors were clearly identified versus normal lung tissue, and 1.5-fold higher [18F]FGln uptake was observed in lung tumors versus the healthy lungs in a set of control mice. In addition, we found that [18F]FGln uptake was decreased after treatment with the glutaminase inhibitor CB-839. Finally, a novel fullerene-based nanomaterial with potential biomedical applications was radiolabeled with copper-64 to answer questions about its in vivo biodistribution and pharmacokinetic profile using PET imaging. Interestingly, this highly water-soluble fullerene conjugated with serinolamide groups displayed rapid renal clearance in mice.