Fundamental studies and applications for the development of novel MRI contrast agents: Hyperpolarized xenon-129 and superparamagnetic iron oxide nanoparticles

Author

Laura L. Walkup, Southern Illinois University CarbondaleFollow

Date of Award

5-1-2014

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Goodson, Boyd

Abstract

Since its discovery in the mid-1950s, the phenomenon of nuclear magnetic resonance (NMR) has been recognized as a powerful, nondestructive analytical technique capable of probing the structure and dynamics of many systems-- ranging in size from simple organic molecules, through large biomolecular complexes, and even the tissues of the human body by use of magnetic resonance imaging (MRI). Indeed, MRI is perhaps the most well-known application of MR, and in the clinic, MRI is growing in popularity as an alternative to other imaging modalities such as computerized tomography (CT), positron emission tomography (PET), and x-ray, all of which rely on ionizing forms of radiation to generate images. Both NMR and MRI operate on the same physical principles as discussed in Chapter 1: the manipulation of populations of nuclear spins in different energy states using radiofrequency (rf) pulses. This dissertation work focuses on the development of two different types of MRI contrast agents: hyperpolarized 129Xe gas and superparamagnetic iron oxide nanoparticles (SPIONs). The largest `Achilles' Heel' of MR techniques is their inherent lack of detection sensitivity due to the exceedingly small magnitude of the nuclear spins, giving rise to small thermal polarizations. Chapter 2 reviews strategies for improving the MR spin polarization, and the following chapter focuses on the physics of one such strategy-- spin-exchange optical pumping (SEOP), which is used to prepare highly spin-polarized noble gases (e.g., 3He and 129Xe). SEOP is a two-step process whereby first, the electronic spins of an alkali metal vapor become polarized via the absorption of circularly-polarized resonant laser light, and second, the electronic spin polarization is transferred from the alkali metal atoms to the nuclear spins of the noble gas atoms via collisions; Chapter 4 discussed the experimental considerations and implementation of SEOP. Hyperpolarized noble gases prepared via SEOP have a wide variety of MR applications, reviewed in Chapter 5, including use in pulmonary MRI where the hyperpolarized noble gas provides contrast in the lung-space. The development of hyperpolarized 129Xe as contrast for pulmonary MRI has suffered on two fronts: firstly, due to the physics of SEOP, generating large volumes of highly spin-polarized gas is challenging, and secondly, the commercial devices used to perform SEOP and prepare the hyperpolarized gas, so-called `hyperpolarizers', are expensive and proprietary, which has limited access to the technology to researchers and clinics. Chapter 7 discusses the design and construction of a fully automated, clinical-scale, `open-source' 129Xe hyperpolarizer with the purpose of developing an accessible, lower cost, mostly `off-the-shelf' alternative to commercial polarizers. The hyperpolarizer operates at high Xe densities and provides high polarizations (i.e., ~90%, ~57%, ~50%, and ~30% at Xe partial pressures of ~300, ~500, ~760, and ~1570 torr, respectively) and currently is housed at Brigham and Women's Hospital where it has received full FDA/IRB approval and is involved in in vivo pulmonary imaging studies. Preliminary developments and results from a second-generation 129Xe hyperpolarizer are discussed in Chapter 8 which includes improvements in the optical design, gas handling manifold, and SEOP oven. The `open-source' hyperpolarizer design allow for greater access to hyperpolarized gas technology, and in time, as more laboratories adopt the design and expand upon it, a community of scientists and clinicians using hyperpolarized gas will grow and facilitate the sharing of ideas. The final SEOP-related chapter discusses fundamental studies of N2 temperatures during SEOP conducted in situ with Raman spectroscopy which shed light on the thermalization of energy during SEOP and the interrelation between key experimental SEOP parameters. The second aspect of MRI contrast discussed is the use of SPIONs as environmentally- sensitive contrast agents, and the synthesis and applications of SPIONs are reviewed in Chapter 6. Among other features, SPIONs offer high biological tolerability and flexible surface chemistry to allow for functionalization which can be exploited to yield differential MR response in different chemical environments. One general biological parameter of interest is tissue pH where local reductions in pH are associated with a variety of conditions including inflammation and cancers, and Chapter 10 focuses on the development of melamine dendron-functionalized SPIONs as pH-sensitive MRI contrast agents. Also discussed is a model for understanding how SPION clustering affects MR response. Such contrast agents could be developed as molecular imaging agents capable of mapping tumor pH in vivo.