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
Type : text
Degree Program: Chemistry

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