Development Of Nanoparticle-Based Contrast Agents For Applications With Conventional And Photon-Counting Ct Imaging

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Doctor of Philosophy (PhD)
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X-ray computed tomography
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Kim, Johoon

X-ray computed tomography (CT) is one of the most widely used clinical imaging modalities, and recent developments in CT detectors and reconstruction methods are fueling its rapid innovation and expansion of its diagnostic values. However, despite the advancement in nanotechnology and nanoparticle-based contrast agents, small molecule-based iodinated contrast agents with several drawbacks, such as short blood half-lives, low CT contrast generation at high tube potential, and potential adverse effects, remain to be the only FDA approved CT contrast agents for intravascular administration. Development of novel nanoparticle-based CT contrast agents will not only resolve these drawbacks, but also facilitate the emergence of new CT technologies, such as photon-counting CT (SPCCT), and novel CT imaging applications. In this thesis, we present the development of nanoparticles that are specifically designed for numerous CT and SPCCT imaging applications. Sub-5 nm tantalum oxide nanoparticles (TaONP) were developed after investigating CT contrast generation properties and material differentiation of several candidate elements for SPCCT-specific contrast agent. To prolong blood circulation time and improve CT contrast production, TaONP were encapsulated in polymeric nanoparticles along with other sub-5 nm nanoparticles made of cerium (CeONP) and gold (AuNP). These polymeric nanoparticles produced consistently high CT attenuation across multiple clinical settings and were efficiently degraded into small nanoparticles within 7 days in biological fluids. Our CT contrast generation results also revealed that CeONP were able to produce higher CT contrast when compared to other experimental contrast agents especially at low tube potentials. Understanding that CeONP can also have immunomodulatory properties, we further investigated them as both CT contrast agents and therapeutic agents for targeted imaging and treatment of inflammatory diseases, expanding the potential CT imaging applications. Moreover, 85 % of the injected dose were excreted within 24 hours of intravenous injection, indicating CeONP’s feasibility of clinical translation. To further expand the CT imaging applications to cell tracking, sub-5 nm AuNP were encompassed in lipid-based transfection reagents to label chimeric antigen receptor (CAR)-T cells to monitor their behavior in cancer immunotherapy against solid tumors. This work highlights key considerations in the development of CT and SPCCT-specific contrast agents and the potential use of nanoparticle-based contrast agents for broadening CT and SPCCT imaging applications.

David P. Cormode
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