Closomers at a click :
a treatise on the design, synthesis and in vivo MRI of novel click closomers as high performance and efficacious contrast agents
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The advent of Magnetic Resonance Imaging or MRI has truly revolutionized the field of medical diagnostic and imaging. The signal intensity and the overall detail and clarity of an image obtained in an MRI exam is enhanced spectacularly by the administration of a chemical species, called the Contrast Agent. Once injected, the contrast agent rapidly moves within the body, tickling the differential distribution of numerous water protons, in the process generating an image with an enhanced contrast between normal and diseased tissues or organs. The current batch of clinically approved contrast agents are mostly low molecular weight species that suffer from low overall relaxivity, poor tissue selectivity and extremely short intravascular half-lives. In addition, these contrast agents are hampered with inferior contrast enhancement at low concentrations and have been reported to be toxic. I herein report a novel class of Closomer Contrast Agents based on a closo-borane framework with multifold improvements in relaxivity, contrast enhancement and tumor avidity. These monodisperse, nanomolecular and multifunctional molecules are based on the novel and unique twelve-fold functionalization of closoB12(OH)12 2- with a varying range of Gd-chelates such as DTTA and AAZTA. This work also presents an extension of the azide-alkyne click chemistry to the closomer platform that generates an efficient tool for rapid and multifold derivatization of the closomer core. The successful modification of various Gd-chelates such as DTPA, DTTA and AAZTA for conjugation at the B12-core has also been elaborately discussed.
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