Doctor of Philosophy, Case Western Reserve University, 2023, Biomedical Engineering

Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent and aggressive disease. Although patient outcomes have exhibited modest improvement in recent years, both incidence and death from HNSCC has increased in the United States and other developed countries. Of the utmost importance for HNSCC patients is enhancing diagnostic methods, which can improve patient outcomes by facilitating more directed, precise, and efficient treatment regimens. Magnetic resonance imaging (MRI) presents a critical diagnostic tool for localizing and assessing HNSCC lesions, but current contrast agents are not targeted and rely on passive tumor mechanics to produce enhancement. Extradomain B fibronectin (EDB-FN) is a unique extracellular target that exhibits low expression in normal tissues, yet is significantly upregulated in HNSCC. Furthermore, EDB-FN expression levels are associated with aggressive tumor characteristics, making it an attractive target for non-invasive diagnostic techniques. This research focuses on the development and application of molecular imaging techniques for MRI by targeting EDB-FN in HNSCC. Because EDB-FN has been explored in a relatively small subset of cancers in independent studies, we first sought to demonstrate the pan-cancer utility of EDB-FN as an extracellular target by probing large public RNA-seq databases for EDB-FN expression. Our results posit EDB-FN as a widely applicable extracellular target, having strong correlations with diagnostic criteria associated with tumor progression and aggressiveness, as well as patient prognosis. Importantly, we demonstrated EDB-FN upregulation in HNSCC in association with lymph node status, a diagnostic criterion strongly correlated with tumor aggressiveness and patient prognosis. The ZD2 peptide was previously developed as a small targeting ligand specific to EDB-FN that can be conjugated to imaging agents to enable molecular imaging. Here, we applied and evaluated the use of a ZD2-targeted MRI con (open full item for complete abstract)

Committee: Zheng-Rong Lu (Advisor); James Basilion (Committee Member); Agata Exner (Committee Member); Dan Ma (Committee Chair) Subjects: Biomedical Engineering

Doctor of Philosophy, Case Western Reserve University, 2022, Biomedical Engineering

The goal of this work is to create software platforms for evaluation of two imaging agents. One is for a fibrin-fibronectin targeting probe CREKA-Gd applied to detect breast cancer metastases in whole mouse body, and the other one is for a protease-activated probe 6qcNIR designed for better visualization of the surgical margins of keratinocyte carcinomas. Both platforms include imaging protocols and analysis software to evaluate these promising molecular approaches at the cellular level. For evaluation of CREKA-Gd, 3D cryo-imaging that sections and images a whole mouse and provides microscopic fluorescent and color images was utilized to generate ground truth for GFP-labeled metastases. Convolutional neural network (CNN)-based algorithms were utilized for segmenting GFP-labeled breast cancer metastases and organs of interest to quantify the metastases distribution. Metastases segmentation software included three steps: candidate segmentation, CNN-based candidate classification, semi-automatic correction, reducing human intervention time from >12 hours to ~2 hours. The algorithm was successfully applied for segmenting pancreatic metastases, demonstrating generalizability. For multi-organ segmentation, 2D U-Net and 3D U-Net were compared. With 63 mice for training, 2D U-Net had the best performance with median Dice score >0.9 for all organs except bladder. Deep learning organ segmentation achieved human segmentation accuracy, reduced inter-observer differences, and cut manual intervention time from ~2 hours to 25 minutes for editing. Fluorescent imaging using 6qcNIR allowed 100% tumor margin assessment by generating en face images that correlate with histology and may be used to overcome the limitations of conventional bread-loaf histology. For evaluation of 6qcNIR, imaging was done with an inverted, flying-spot fluorescence scanner that reduces scattering. We developed a “puzzle-fit” software to correlate the fluorescent images with histology with spatial accu (open full item for complete abstract)

Committee: David Wilson (Advisor); Pallavi Tiwari (Committee Chair); Weihong Guo (Committee Member); James Basilion (Committee Member); Zheng-Rong Lu (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2021, Biomedical Engineering

Cardiovascular heart disease (CVD) is the leading cause of mortality in the U.S. and worldwide. Over the past several decades, the healthcare costs associated with CVD have steadily risen to more than 200 billion dollars per year and are expected to rise further with the aging population. Cardiovascular MRI (CMR) is a well-established imaging technique that provides the most comprehensive evaluation of the cardiovascular system. CMR is considered the gold standard for evaluating ventricular function and myocardial viability. Despite the growing evidence of its advantages over other imaging modalities and its potential as a “one-stop-shop” diagnostic tool, the role of CMR in clinical cardiology remains limited. One major impediment to its wider usage is the inefficient acquisition that makes CMR exams excessively long, often lasting for more than an hour; this diminishes its efficiency and cost-effectiveness relative to other imaging modalities. The current paradigm offers either a prolonged segmented acquisition that requires regular cardiac rhythm and multiple breath-holds or a fallback option of real-time, free-breathing acquisition with degraded spatial and temporal resolutions. Recently, 3D imaging has gained significant interest due to its volumetric coverage and isotropic resolution. In particular, 4D flow imaging has emerged as a powerful tool that provides temporally and spatially resolved velocity maps of the blood in the heart and great vessels. A major technical limitation of 4D flow imaging is the long acquisition, which makes the images susceptible to motion artifacts. In this work, we present a framework that provides a whole-heart coverage and enables a rapid, quantitative assessment of hemodynamics. In addition, the method employs self-gating and thus extracts and compensates the physiological motions from the information in the MRI data itself, obviating the need to utilize electrocardiogram or respiratory gating. Novel extensions of the method, whe (open full item for complete abstract)

Committee: Rizwan Ahmad (Advisor); Rengasayee Veeraraghavan (Committee Member); Orlando Simonetti (Committee Member); Jun Liu (Committee Member) Subjects: Biomedical Engineering; Medical Imaging

Doctor of Philosophy, Case Western Reserve University, 2021, Biomedical Engineering

Issues with limited intratumoral drug penetration and heterogeneous drug distribution continue to impede the therapeutic efficacy of nanomedicine-based delivery systems, especially in metastatic disease. Ultrasound (US)-mediated drug delivery has emerged as one of the most effective means of overcoming these challenges. An enhancement of vascular permeability and on demand drug release can be triggered by physical US effects including cavitation, acoustic streaming, or hyperthermia caused by pressure variation of acoustic wave. Microbubbles (MBs) have been widely used as a drug-carrier for cancer theranostics. However, their clinical application in drug delivery is limited by their large size (1-8 um). Alternatively, submicron echogenic bubbles or nanobubbles (NBs) with size of 100-500 nm, can promote extravasation by taking an advantage of the enhanced permeability and retention (EPR) effect, resulting in higher drug accumulation in tumors and improved efficacy. The overall goal of the research described in this dissertation is to develop a more effective US-mediated drug delivery system to improve treatment efficacy for patients diagnosed with early or advanced ovarian cancer. An optimal NB formulation with a highly stable NB and high drug loading was developed and characterized in vitro. An effective strategy to improve drug loading efficiency into the bubbles using deprotonation technique was used. Delivery efficiency and therapeutic efficacy of these NBs were evaluated in cell culture model of human cancer cells. Improved in vitro therapeutic efficacy of these drug-loaded NBs in human ovarian cancer cells (OVCAR3) was observed. To further understand the in vitro and in vivo behavior and stability of these NBs, the influence of size and concentration of the NBs were investigated. Lastly, the optimized NB formulation and delivery parameters were used to treat orthotopic rat liver tumors which was selected as an aggressive cancer model. Accumulation of drug and NB (open full item for complete abstract)

Committee: Anirban Sen Gupta (Committee Chair); James Basilion (Committee Member); Jeffrey Capadona (Committee Member); Agata Exner (Advisor) Subjects: Biomedical Engineering; Biomedical Research; Nanotechnology

Doctor of Philosophy, The Ohio State University, 2017, Chemistry

In cancer therapy, one of the most important factors in positive outcomes is early detection of the primary tumors and any metastases. Detection of primary tumors is often effected via positron emission tomography (PET) imaging using 18-fluorodeoxyglucose (FDG) as a contrast agent. Its natural target results from the upregulation of glucose-based metabolism in tumor tissue. While this method has gained widespread use, it does suffer from some drawbacks. It requires an injection of a radiological agent and has a limited spatial resolution (~1cm) that can prevent detection of metastatic tumors. To improve on both of these issues magnetic resonance imaging (MRI) can be used. This technique has a better resolution (<1mm) and while still requiring a contrast agent, it is not radiological. This higher resolution could allow for the in vivo visualization of metastases. MRI is not without drawbacks though. Its primary issues are the requirement of achieving high local concentrations (>30 µM) selectively in tumor tissue. This project looks at designing a self-assembling vehicle that exploits the natural hallmarks of cancer to passively target and accumulate an MRI contrast agent locally in a tumor tissue. Passive targeting is the preferred route, over a biomarker or receptor, as these are not prevalent enough to create the concentrations required and because they are incredibly heterogeneous from one cancer to another. The hallmarks being investigated include the acidic pH of the extracellular space of a tumor and larger vasculature pore size. Due to increased aerobic and anaerobic glycolysis, reduced oxidative phosphorylation and active pumping of lactate and protons into the extra cellular space, the pH around a tumor is significantly lowered, as far down as a pH of 6.5. We have designed nanomaterials that change self-assembled morphologies with pH. They begin as peptide amphiphile (PA) monomers and upon introduction in a solution (artificial or natural, lik (open full item for complete abstract)

Committee: Joshua Goldberger (Advisor); Dmitri Kudrayshov (Committee Member); Steffen Lindert (Committee Member) Subjects: Chemistry

PHD, Kent State University, 2017, College of Arts and Sciences / Department of Chemistry

The objectives of this dissertation work are twofold. The first of the two is to evaluate the anti-cancer properties of a series of copper based NP systems rationally designed and synthesized via aqueous route utilizing simple salt metathesis reactions in the presence of biocompatible polymer. The acquired resistance of cancer cells to conventional molecular drugs such as cisplatin and doxorubicin presents simultaneously both opportunities and challenges to chemists to develop novel and more effective anti-cancer agents. While many known NPs, both inorganic and organic/polymeric are reported for drug delivery applications, the inherent capability of the copper based NPs as anti-cancer agents is relatively less explored. Further, there is lack of systematic study to evaluate the behavior of these NPs under the conditions pertaining to physiological and tumor intracellular and extracellular milieu. The utility of the proposed NPs in my dissertation is based on the hypothesis that copper-based NPs elevate the production of ROS to unsustainable levels in cancer cells through surface copper mediated Fenton-like chemistry that generates free radicals thereby inducing the cancer cell death. The second objective is to explore the same NP systems for diagnostic purposes at a much lower concentration window as potential imaging agents for positron emission tomography (PET). The nuclide Cu-64 is a positron-emitting radioisotope and owing to its favorable decay characteristics is being extensively studied for its application in PET imaging. This area is predominantly comprised of copper-64 chelate complexes based on macrocyclic ligands. Hitherto, the main focus of many such studies is devoted to the development of suitable macrocyclic chelators, more recently as bifunctional chelators, to impart kinetic and thermodynamic stability to the metal-chelate complexes. Numerous studies have shown that these copper chelate complexes suffer from copper exchange with biomolecules in viv (open full item for complete abstract)

Committee: Songping Huang PhD (Advisor); Scott Bunge PhD (Committee Member); Mietek Jaroniec PhD (Committee Member); Gail Fraizer PhD (Committee Member); Torsten Hegmann PhD (Committee Member) Subjects: Chemistry; Nanoscience

PhD, University of Cincinnati, 2015, Engineering and Applied Science: Biomedical Engineering

Cardiovascular disease (CVD) is the leading cause of death worldwide, and the economic impact of CVD is expected to increase substantially in future decades as disability rates due to ischemic heart disease and stroke rise. More effective diagnostic tools and therapies are necessary to limit the growing burden of CVD, particularly those which manifest in clotting within the arteries of the heart or brain. Echogenic liposomes (ELIP) are nanoparticle theragnostic agents being developed to target and treat cardiovascular disease. ELIP contain a small amount of gas and can function as an injectable ultrasound contrast agent (UCA) to improve visualization of the heart or diseased arteries. Previous investigations have shown that it is possible to load ELIP with bioactive gases, and that pulsed ultrasound exposure can result in the loss of echogenicity from ELIP. The purpose of this study was to determine if pulsed ultrasound exposure can also be used for controlled release of gas from ELIP. Determining the relationship between microbubble activity and acoustically-induced gas release will help to develop a method utilizing ELIP as therapeutic agents for delivery of gas to tissue. In Chapters 2 and 3, acoustic methods were used to characterize a series of novel formulations of ELIP with different shell components and gas content. Estimates of the shell properties of ELIP, as well as two commercially available UCAs, Definity® and MicroMarker®, were obtained using a linearized viscoelastic acoustic scattering model. Overall, ELIP are characterized by higher shell elasticity and shell damping coefficient than the commercially available agents. Replacing air with the high molecular weight gas octafluoropropane and addition of polyethylene glycol into the shell formulation resulted in longer stability and improved high-frequency response, making these ELIP formulations particularly suitable for intravascular ultrasound applications. In addition, ELIP encapsulating octaf (open full item for complete abstract)

Committee: Christy Holland Ph.D. (Committee Chair); Todd Abruzzo Ph.D. (Committee Member); Nico de Jong Ph.D. (Committee Member); Shaoling Huang Ph.D. (Committee Member); T. Douglas Mast Ph.D. (Committee Member) Subjects: Biomedical Research

PHD, Kent State University, 2015, College of Arts and Sciences / Department of Chemistry

The combination of nanotechnology with medicinal chemistry has developed into a burgeoning research area. Nanomaterials (NMs) could be seamlessly interfaced with various facets in biology, biochemistry, medicinal chemistry and environmental chemistry that may not be available to the same material in the bulk scale. This dissertation research has focused on the development of nanoparticulate coordination polymers for diagnostic and therapeutic applications. Modern imaging techniques include X-ray computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET). We have successfully developed several types of nanoparticulate diagnostics and therapeutics that have some potential usefulness in biomedicine. Synthesis and characterization of nanoparticulate based PET (Positron emission tomography)/SPECT (Single photon emission computed tomography) are discussed in chapter 3. For the preparation of 68Ga-radiopharmaceuticals, fast formation kinetics are required owing to the short half-life of 68Ga. Our accelerated synthesis involving the aqueous solution and efficient-easy purification of PB NPs would be highly desirable. In addition, easy preparation and fast purification allow physicians to gain considerable time for imaging even with relatively low concentration of radiopharmaceuticals. We demonstrate for the first time the use of Ga(III) doped colloidal solutions of Prussian blue (PB) as a novel radioactive Ga(III) delivering agent. The PET/SPECT imaging modalities provide information on molecular processes using radiolabeled imaging agents; on the other hand PET and SPECT gives limited anatomical details and spatial resolution as a major disadvantage, regardless of their high-sensitivity in tracking in vivo biomarkers. Also we have described for the first time a novel nanoparticulate solid-state compound that contains both Gd(III) (f7, S=7/2) and Ga(III) as dopants in the network s (open full item for complete abstract)

Committee: Songping Huang Dr (Advisor); Scott. D Bunge Dr (Committee Member); Mietek Jaroniec Dr (Committee Member); Gail.C Fraizer Dr (Committee Member); Torsten Hegmann Dr (Committee Member) Subjects: Chemistry

MS, University of Cincinnati, 2015, Engineering and Applied Science: Biomedical Engineering

Ultrasound-enhanced thrombolysis (UET) is under development as an adjuvant to thrombolytic administration for the treatment of ischemic stroke. Initial studies have demonstrated the efficacy of UET in the presence of ultrasound contrast agents (UCAs), stabilized microbubbles that can be injected into the bloodstream. These studies demonstrated ultrasound-enhanced thrombolysis when acoustic emissions characteristic of stable cavitation, ultraharmonics (UH) and the subharmonic (SH), were present. The current study was performed to determine the threshold for cavitation activity in an in- vitro human clot model in flow exposed to an UCA and 120-kHz pulsed or continuous wave ultrasound. Two UCAs were used to nucleate cavitation, Definity® and echogenic liposomes (ELIP). Definity® is a commercially available UCA, and ELIP are potential theragnostic agents for the treatment of stroke, with the potential to encapsulate and release drugs, such as the thrombolytic drug recombinant tissue-plasminogen activator (rt-PA), upon exposure to ultrasound. UH and broadband (BB) cavitation thresholds occurred at the same acoustic pressure (0.3 ± 0.1 MPa, peak-to-peak) for both UCAs, and were mostly independent of the ultrasound duty cycle.

Committee: Christy Holland Ph.D. (Committee Chair); T. Douglas Mast Ph.D. (Committee Member); Marepalli Rao Ph.D. (Committee Member) Subjects: Biomedical Research

MS, Kent State University, 2014, College of Arts and Sciences / Department of Chemistry

Gallium is a main group element. After platinum, gallium was a second metal found has anticancer properties in early 1970s. Gallium is non-toxic and redox inactive. Because of similar ionic radii, electronegativity, ionization potential and electron affinity, gallium ions could be looked as a mimic of ferric ions. Thus, gallium ions are able to interference iron metabolism, especially intracellular process. Ferric ion is a cofactor of ribonucleotide reductase of DNA replication, once ferric ion is replaced by gallium ion, ribonucleotide reductase would be inhibited. This would greatly affect cell division. Due to anticancer properties, gallium compounds are developed as anticancer agent to treat solid tumor. The first generation of gallium anticancer agent was gallium nitrate as an oral drug. However, there are some problems of gallium nitrate. Gallium nitrate is a metal salts which has low efficiency and bio-availability in cancer treatment. Patents needed to take large doses of gallium nitrate to produce desired results. On one hand, free gallium ions may form hydroxide in biological pH. And it could be cleared by kidney in few hours easily. Large dose of gallium nitrate may cause some damage to kidney. On the other hand, tumor cells start to build up drug resistance by either shutting down or turning off transferrin receptor activity or excreting gallium ions through ion pump. To solve these problems, scientists are investigating gallium complexes as small molecules or nanoparticles for drug delivery. We developed gallium ferricyanide nanoparticles and gallium lawsonate nanoparticles as potential anticancer agents to treat solid tumor. Gallium ferricyanide is an analog of Prussian blue which found in 1706 by an artists' color maker, Heinrich Diesbach. It was used as a pigment in painting for a long time. It was known that Prussian blue is non-toxic. It could use to treat thallium poisoning and as cesium removal. Gallium ferricyanide nanoparticle was investiga (open full item for complete abstract)

Committee: Songping Huang (Advisor); Scott Bunge (Committee Member); Mietek Jaroniec (Committee Member) Subjects: Chemistry

PhD, University of Cincinnati, 2007, Arts and Sciences : Chemistry

Novel Eu3+-containing macrocyclic complexes were synthesized and studied as anion sensing probe molecules. Several of these macrocycles exhibited unique luminescence responses to hydrogen-bond accepting anions (fluoride, acetate, and dihydrogen phosphate) in DMSO, even in the presence of a chloride ion background. The first series of compounds highlighted a high-yielding synthetic route for highly functional macrocycles that incorporate a Eu3+ chelate, aromatic antennae, thiourea groups as anion-binding units, and a variable linker that tunes the size and rigidity of the pocket. These macrocycles exhibited Eu3+ luminescence where emission intensity (λexc = 272 nm, λem = 614 nm) was correlated to the linker length. Anion-induced changes in emission intensity were dependent on the basicity of the anion, and emission enhancements were observed up to 77% upon titration with fluoride in one case. Through luminescence lifetime studies of the Eu3+ macrocycles and the study of a newly synthesized series of organic model compounds, it was determined that the luminescence response to anions was the result of interaction with the thiourea moieties and no evidence was observed for anion coordination to Eu3+. Additionally, two second-generation macrocycles were synthesized, incorporating an amine unit for stronger binding affinity. One of these macrocycles, featuring a pendant naphthalene antenna, responded to several anions in aqueous solution by means of a luminescence decrease of up to 30%. This general macrocyclic design shows promise for the development of Eu3+-based anion sensors that function in competitive solvents. In continuing work with lanthanide complexes, a new targeted Gd3+-based magnetic resonance imaging contrast agent was designed and synthesized for specific binding to the dopamine receptor protein. A relaxivity of 7.1 mM-1s-1 was measured for this complex at 400 mHz and 310 K. A Eu3+ analogue was also synthesized and structurally characterized. Luminescence (open full item for complete abstract)

Committee: Theresa Reineke (Advisor) Subjects: Chemistry, Inorganic

Master of Science, The Ohio State University, 2011, Chemistry

Cancer is a disease that affects millions of people each year, with early detection often enabling the most effective treatment. A characteristic shared amongst tumors is an acidic extracellular matrix, resulting from the constant glycolytic cycle required to produce energy for uncontrolled replication. The Enhanced Permeablity and Retention (EPR) effect describes the ability of macromolecules to enter tumor tissue through “leaky” vasculature and temporarily evade clearance from the body. Combining these ideas, it may be possible to increase tumor detection through an active and passive targeting approach with creative molecular design. Biomaterials have been developed for use in many biological applications such as tissue engineering, cellular signaling, and tumor imaging. Specifically, peptide amphiphiles are a class of biocompatible molecules comprised of amino acids and lipids known to self-assemble into ordered structures including spherical micelles, cylindrical micelles, and ribbons. The work presented herein describes the development of a self-assembling peptide amphiphile (PA), capable of dynamically transitioning into nanofibers in a pH range corresponding to the extracellular vasculature of tumor tissue (pH 6.4-7.4). We have explored the role of molecular design on the pH dependent self-assembly behavior through a combination of techniques: circular dichroism (CD), transmission electron microscopy (TEM), cryo-TEM, critical aggregation concentration (CAC) measurements, and pKa titrations. This work has produced a series of self-assembling PA molecules that assemble into nanofibers when the pH is reduced from 7.4 to 6.6, in isotonic salt solutions simulating the acidic extracellular environment of cancer cells. This transition is rapid and reversible, indicating the system to be under thermodynamic equilibrium. By fine-tuning the attractive hydrophobic and hydrogen bonding forces with repulsive electrostatic forces, the single molecule to nanofiber trans (open full item for complete abstract)

Committee: Joshua Goldberger PhD (Advisor); Michael Tweedle PhD (Advisor); Magliery Thomas (Committee Member) Subjects: Chemistry

Doctor of Philosophy, The Ohio State University, 2008, Biomedical Engineering

Magnetic Resonance Imaging (MRI) has been established as a primary imaging module in clinical practices. The usefulness of MR contrast agents to improve visualization of MR imaging is firmly established. Extracellular gadolinium(Gd)-based contrast agents are the most widely used MR contrast media. The Gd-based contrast agent is intravenously injected, follows the pathway of blood circulation, enters into extravascular space, and then diffuses back into the vasculature, thereby acting as a probe to visualize microcirculatory properties. Functional dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) uses T1-weighted acquisition to observe the uptake of contrast agents. The use of DCE-MRI has become increasingly widespread for quantifying and visualizing microvascular characteristics such as microvessel density and vascular permeability. Pharmacokinetic analysis of DCE-MRI can assess pathophysiological permeability changes in cancerous tissues with abnormal angiogenesis. Different kinetic models of DCE-MRI were used, including a modified two-compartment pharmacokinetic model based on more realistic model assumptions. Using all of these pharmacokinetic models to investigate the predictors of imaging biomarkers were performed at 1.5T, 3T and 7T MRI systems. Total 45 patients with metastasis thyroid carcinomas were enrolled in a clinical trial study using a RAF/VEGF-R inhibitor drug. DCE-MRI was performed in a baseline scan and followup scans after every eight weeks during therapy. DCE-MRI pharmacokinetic results were correlated with biomarkers, such as serum calcitonin and RESICT measurement. The study showed DCE-MRI appeared to be a valuable diagnostic adjunct for monitoring the microvascular properties of malignant tumors during anti-angiogenic therapy. Therapy monitoring using DCE-MRI provides the capability for evaluating the biologic therapeutic responses by a clinically readily available approach. This also indicates that this approach appears feasible (open full item for complete abstract)

Committee: Michael V. Knopp (Advisor); Petra Schmalbrock (Committee Member); Bradley Clymer (Committee Member) Subjects: Radiology

Doctor of Philosophy, The Ohio State University, 2005, Biomedical Engineering

This study was structured to challenge the hypothesis that nano-sized particulates could be molecularly targeted and bound to the prognostic and predictive HER-2/neu cell membrane receptor to elicit detectable changes in ultrasound response from human breast cancer cells. This study first utilized an agarose tissue phantom model to embed nanoparticles throughout its matrix to simulate cell conjugation of contrast agents to evaluate the sensitivity of the ultrasound modality. SKBR-3 human cancer cells were then enlisted to test the efficacy of the particle conjugation strategy used in this study and ultimately, to provide conclusive remarks regarding the validity of the stated hypothesis. A characterization-mode ultrasound (CMUS) system was used to apply a continuum mechanics based, two-step inversion algorithm to reconstruct the mechanical material properties of agarose tissue phantoms with the sensitivity to statistically distinguish particle concentration data from samples containing 4.56 x 1013 particles/sample, 4.56 x 1012 particles/sample, 4.56 x 1011 particles/sample, and 0.00 particles/sample. This ability to statistically differentiate particle concentrations by measured density was then maintained throughout the CMUS testing of SKBR-3 cells treated with molecularly targeted conjugated iron oxide nanoparticles. The statistical analysis of these ultrasound results supported the ability to differentiate between 3+ HER-2/neu positive SKBR-3 cells that have been successfully tagged with Herceptin conjugated iron oxide particles to those that have not demonstrated particle binding. Furthermore, the secondary objectives of this study were also completed. C-scan images suggest that molecularly targeted iron oxide particles were successfully bound to the surface of 3+ HER-2/neu positive breast cancer tissue. Insufficient data was collected to decisively establish conclusive evidence regarding the ability to quantify HER-2/neu expression upon human tissue; however, t (open full item for complete abstract)

Committee: Mauro Ferrari (Advisor) Subjects: Engineering, Biomedical

Doctor of Philosophy, Case Western Reserve University, 2008, Biomedical Engineering

Molecular imaging has become one of the most significant developments in MRI in the last decade with dramatic impacts for disease diagnosis and therapy. A novel MRI contrast strategy named PARAmagnetic Chemical Exchange Saturation Transfer(PARACEST) can exploit the NMR chemical shift to selectively detect molecular biomarkers, while retaining the sensitivity and spatial resolution of MRI. The development of this novel approach for cancer biomarker detection is described in the following chapters. Chapter 1: Background information is presented about the relevance of biomarker detection by molecular imaging and MRI molecular imaging. The mechanisms of MRI contrast agent including T 1contrast agents, T 2/T 2* contrast agents and CEST/PARACEST contrast agents are introduced. The PARACEST contrast mechanism is then emphasized for the potential biomedical applications. Chapter 2: A new irreversible nitric oxide (NO) responsive PARACEST MRI contrast agent, Yb-DO3oAA, has been designed, synthesized and characterized. The PARACEST effects have been investigated with respect to pH, temperature, and concentration for the in vivoapplicability. The ability to detect NO has been demonstrated in vitro. Chapter 3: A new MRI method has been developed for assessing in vivo pH by using a PARACEST MRI contrast agent Yb-DO3AoAA. A ratiometric approach has been employed based on the two intra-molecular PARACEST signals. Our study has demonstrated that this method can be used for measuring extracellular pH within in vivo animal models without the need for a second “control” agent. Chapter 4: New MRI pulse sequences have been developed to address the poor temporal resolution challenges for the in vivoapplications of PARACEST agents. Different strategies have been developed for the applications in different in vivo environments. These new MRI methods have been developed for high field small animal studies and tested both within in vitroand in vivomodels. Chapter 5: The major drawbacks and t (open full item for complete abstract)

Committee: Mark Pagel (Advisor) Subjects: Engineering, Biomedical