Date of Award

Fall 10-1-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering (ENAS)

First Advisor

Hyder, Fahmeed

Abstract

According to the World Health Organization (WHO), cancers are the second-leading cause of death in the United States, next to cardiovascular disease. Although treatments of some solid tumors with high mortality are showing promise, there is one exception: glioblastoma multiforme (GBM). Even with advanced therapies, median survival rate for GBM patients is dismal because most are not diagnosed early enough. A hallmark of normal physiology is maintenance of large ion gradients across the cell membrane, mainly for sodium (Na + ) and potassium (K + ) ions. Under normal conditions, high and low Na + in extracellular (Na + ) and intracellular (Na + ) milieu, respectively (and e i the opposite is true for K + ), produce strong transmembrane and weak transendothelial Na + gradients, which contribute to the cell membrane potential (+ < ) and blood-brain-barrier (BBB) integrity, respectively. The Na + /K + -ATPase in the cell membrane plays a crucial role in transporting Na + and K + against their respective electrochemical gradients by consuming ATP. A universal cancer hallmark is reduced oxidation due to downregulation of Na + /K + -ATPase, a consequence of inefficient metabolism which aids tumor survival. Electrolyte balance in the body is crucial for proper functioning of processes like action potential propagation, muscle movement, and maintaining cell volume, but electrolyte imbalances can lead to pathophysiologies like cancer. Translational magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) methods are an integral part of diagnosing and tracking cancer. Clinical MRI is largely based on detection of the 1 H nuclei in water molecules in soft tissues, where intrinsic 1 H-MRI contrasts provide anatomical separation between healthy tissue and lesion. But paramagnetic lanthanide(III) ions (Ln 3+ ), specifically gadolinium (Gd 3+ ), conjugated with a chelating molecule consisting of electron donors, provide superior 1 H-MRI contrast as the agent (e.g., Dotarem) extravasates into the lesion through leaky blood vessels to enhance the lesion’s appearance. Other nuclei are rarely considered for clinical applications, but these so-called “X-nuclei” (e.g., 23 Na, 31 P, or 17 O) can offer illuminating insights into the physiological processes. 23 Na-MRI has the potential to be a helpful screen for early cancer detection. However, normal 23 Na-MRI cannot separate the overlapping signals between Na + from different compartments like the blood vessel (Na + ), extracellular space (Na + ), and intracellular b e space (Na + ). In this thesis, I have developed a rigorous model which can be applied in i vivo to separate these individual signals by introducing small amounts of a paramagnetic contrast agent based on Ln 3+ metal ions. The model predicts that the induced 23 Na chemical shift and line broadening are monotonically increasing functions of both the agent’s concentration and negative charge, which was validated on a set of nine agents. This established model was then considered for in vivo applications to compartmentalize the 23 Na-MRSI signals in rat models. Since these agents extravasate from blood vessels, but are too negatively charged to enter cells, this method is able to separate and readout the 23 Na signals from Na + , Na + , and Na + with high fidelity by inducing chemical shift differences. b e i Examination of several GBM models in rodent brain, shows that tumors redistribute Na + from the extracellular milieu to dramatically weaken the transmembrane Na + gradient (compared to normal tissue) and concomitantly strengthen the transendothelial Na + gradient. This is a significant finding because the lower level of Na + imply that the e membrane of cancer cells is depolarized (i.e., and thus are they are non-excitable). Others have shown that high + < is common to cells in a proliferative state. Since even immune cells can sense the level of Na + , it is evident the role of compartmental Na + in the tumor e niche will be important to study in vivo. I also report novel findings regarding variations in induced 23 Na line broadening and electrical activity between tumors and healthy tissue which have considerable oncologic significance. Despite the clinical popularity of 1 1 H-MRI, H-MRSI, and general imaging-based approaches, this project demonstrates the vast potential of 23 Na spectroscopic methods to allow novel explorations of the tumor habitat for early diagnosis and tracking treatments.

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