Responsive Agents Detecting Biomarkers with Magnetic Resonance Imaging

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Responsive Agents Detecting Biomarkers with Magnetic Resonance Imaging

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Title: Responsive Agents Detecting Biomarkers with Magnetic Resonance Imaging
Author(s):
Zhang, Lei
Advisor: Sherry, A. Dean
Date Created: 2017-08
Format: Dissertation
Keywords: Paramagnetic contrast media
Biochemical markers
Hydrogen-ion concentration
Lactates
Abstract: Paramagnetic chemical exchange saturation transfer (paraCEST) is a novel technique used in magnetic resonance imaging that offers several advantages over the traditional gadolinium T1 agents. In this dissertation, I aimed to investigate new types of paraCEST contrast agents responsive to biologically relevant parameters, such as lactate and pH. In Chapter 1, a description is given detailing the techniques and basic concepts, such as T₁, T_{2ex}, and CEST agents. In Chapter 2, we describe the study of EuDO3A, a well-known lanthanide macrocyclic complex that can be used as a shift reagent for L-lactate, a biologically relevant metabolite overproduced by tumors. Here, we utilized the CEST technique as a means of detecting extracellular L-lactate. The lactate hydroxyl proton shifts from 0.5ppm to 47ppm in the presence of EuDO3A at room temperature. This unique property allows EuDO3A to serve as a shift reagent (SR) for the in vitro imaging of extracellular L-lactate produced by cancer cells. In Chapter 3, we proposed a way that could optimize the lactate SRs and combine better CEST contrast with structural simplicity. We used a revolutionary approach that uses chirality at δ-position centers of the pendant arms in the heptadentate macrocyclic Yb-complexes. This strategy promotes preferential orientation of the conformers in solution and forms selective complexes with lactate in a single conformation. Furthermore, the SRs presented in this chapter can discriminate L- from D-lactate through ¹H NMR and CEST. The approach used might prove useful in the design of metabolite-specific shift reagents for functional MRI. In Chapter 4, we describe the properties of a series of LnDOTAM-amine complexes. Ln-DOTAM-amine complexes prove useful for detecting pH changes in vitro with a bimodal strategy by CEST and T_{2ex} NMR mechanisms. We also proposed a mathematical model to explain the pH sensitivity based on a base-catalyzed amine process. The proton exchange rates were affected by a hydrogen bond network established between bound water protons and outer-sphere amines. Furthermore, since the longitudinal relaxation rates (R₁) remained unchanged through the entire pH range, a concentration independent ratiometric method (r_{2ex}/r₁) can be used for pH imaging by MRI by DyDOTAM-amine complexes. Concluding this dissertation is a chapter providing future perspectives as they pertain to each project and conclusion.
Degree Name: PHD
Degree Level: Doctoral
Persistent Link: http://hdl.handle.net/10735.1/5503
Terms of Use: Copyright ©2017 is held by the author. Digital access to this material is made possible by the Eugene McDermott Library. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Type : text
Degree Program: Chemistry

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