Synthesis and Optimization of Cell-Permeable Contrast Agents for Magnetic Resonance Imaging

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Magnetic resonance imaging (MRI) is a technique widely used in both clinical and experimental settings to produce high-resolution images of opaque living organisms without utilizing ionizing radiation. Currently, MR imaging is augmented by contrast agents; however, these small molecule Gd(III) chelates are confined to extracellular and vascular regions of the specimen, reducing their ability to provide information about cell physiology or molecular pathology. However, as compared to other imaging modalities, MRI has a relatively low sensitivity to exogenous contrast agents. As a result, the system has an inherent difficulty exploiting any newly developed contrast agent, especially if the probe shows specificity and selective image contrast enhancement on a molecular level. This thesis describes the synthesis, visualization, and optimization of several MR contrast agents prepared on varying scaffolds that display cell membrane permeability or elicit enhanced image contrast over current clinical imaging probes. Section 1 (Chapters 2 and 3) describes the synthesis, cell culture, and optimization of six contrast agents that possess the capability to cross cell membranes in sufficient quantity for detection via MR imaging. Four agents are based on the conjugation of a Gd(III) chelator with an 8-amino acid polyarginine oligomer or an amphipathic stilbene molecule, 4-amino-4'-(N,N-dimethylamino) stilbene. However, transport of these contrast agents was determined to be bidirectional, allowing them to efflux rapidly from cultured cells. Therefore, a disulfide linkage was incorporated between the transduction moiety (polyarginine 8-mer) and the Gd(III) chelate (either DOTA or DTPA) to create thiol sensitive derivatives of the cell-permeable contrast agents. These second generation imaging agents successfully displayed prolonged cellular retention via synchrotron radiation X-ray fluorescence (SR-XRF) and MR imaging. Section 2 (Chapters 4 and 5) describes the synthesis of MR contrast agents with elevated relaxivities and versatile scaffolds for potential conjugation of cell-penetrating moieties. These novel contrast agents hold particular promise for the development of multifunctional imaging probes by exploiting metal-based nanoparticles (TiO2) and ring-opening metathesis polymerization (ROMP). Each scaffold allows for attachment of multiple Gd(III) imaging agents via increased surface area (TiO2 nanoparticles) or polymerizable functionalities (ROMP-accessibility) while maintaining additional synthetic handles for fluorophore or cell-penetrating moiety conjugation.

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  • 08/31/2018
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