Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
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Item PREPARATION OF A NANOSUSPENSION OF THE PHOTOSENSITIZER VERTEPORFIN FOR PHOTODYNAMIC AND LIGHT-INDEPENDENT THERAPY IN GLIOBLASTOMA(2024) Quinlan, John Andrew; Huang, Huang-Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Photodynamic therapy (PDT) using verteporfin (VP) has treated ocular disease for over 20 years, but recent interest in VP’s light-independent properties has reignited interest in the drug, particularly in glioblastoma (GBM) (NCT04590664). Separate efforts to apply PDT to GBM using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) have also garnered attention (NCT03048240), but, unfortunately, clinical trials using 5-ALA-induced PpIX-PDT have yet to yield a survival benefit. Previous studies have shown VP to be a superior PDT agent than 5-ALA-induced PpIX. Our lab has shown that 690 nm light activates VP up to 2 cm into the brain, while 635 nm light only activates PpIX at depths <1 cm into the brain. Additionally, VP is a more effective photosensitizer than PpIX because it has a higher singlet oxygen yield and is active in the vasculature as well as target tumor cells. However, the hydrophobicity of VP limits effective delivery of the drug to the brain for treatment of GBM.In this context, this thesis aims to re-evaluate the delivery method for VP. VP traditionally requires lipids for delivery as Visudyne. Recent shortages of Visudyne and potential drawbacks of liposomal carriers motivated our development of a carrier-free nanosuspension of VP, termed NanoVP. Previous work has shown that cellular uptake of VP is greater when delivered as NanoVP rather than liposomal VP, resulting in improved cell killing after light activation. This thesis builds on this previous work by (1) evaluating synthesis and storage parameters for NanoVP, (2) determining the pharmacokinetics, biodistribution, and brain bioavailability of NanoVP, and (3) evaluating the potential efficacy of NanoVP as a PDT and a chemotherapy agent, and by supporting development of a zebrafish model of the blood-brain barrier (BBB) for mechanistic studies of improved drug delivery to the brain.Item Mathematical modeling of drug resistance and cancer stem cells dynamics(2010) Tomasetti, Cristian; Levy, Doron; Dolgopyat, Dmitry; Applied Mathematics and Scientific Computation; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In this dissertation we consider the dynamics of drug resistance in cancer and the related issue of the dynamics of cancer stem cells. Our focus is only on resistance which is caused by random genetic point mutations. A very simple system of ordinary differential equations allows us to obtain results that are comparable to those found in the literature with one important difference. We show that the amount of resistance that is generated before the beginning of the treatment, and which is present at some given time afterward, always depends on the turnover rate, no matter how many drugs are used. Previous work in the literature indicated no dependence on the turnover rate in the single drug case while a strong dependence in the multi-drug case. We develop a new methodology in order to derive an estimate of the probability of developing resistance to drugs by the time a tumor is diagnosed and the expected number of drug-resistant cells found at detection if resistance is present at detection. Our modeling methodology may be seen as more general than previous approaches, in the sense that at least for the wild-type population we make assumptions only on their averaged behavior (no Markov property for example). Importantly, the heterogeneity of the cancer population is taken into account. Moreover, in the case of chronic myeloid leukemia (CML), which is a cancer of the white blood cells, we are able to infer the preferred mode of division of the hematopoietic cancer stem cells, predicting a large shift from asymmetric division to symmetric renewal. We extend our results by relaxing the assumption on the average growth of the tumor, thus going beyond the standard exponential case, and showing that our results may be a good approximation also for much more general forms of tumor growth models. Finally, after reviewing the basic modeling assumptions and main results found in the mathematical modeling literature on chronic myeloid leukemia (CML), we formulate a new hypothesis on the effects that the drug Imatinib has on leukemic stem cells. Based on this hypothesis, we obtain new insights on the dynamics of the development of drug resistance in CML.Item SOLUTION ISOELECTRIC FOCUSING AND ITS APPLICATION IN COMPARATIVE PROTEOMIC STUDIES OF NUCLEAR PROTEINS(2005-05-27) An, Yanming; Fenselau, Catherine C; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In proteomic research, experimental and computational approaches are combined to provide global analysis of the entire proteomes of cells and tissues. The identification and quantification of multiple proteins, which constitute a specific biological system, are important for understanding complex problems in biology. The coupling of highly efficient separations and mass spectrometry instrumentation is evolving rapidly and is being widely applied to problems ranging from biological function to drug development. Development of rapid and high-resolution separation technology is an important field in proteomics. In this study, a solution isoelectric focusing apparatus was modified and built into a two-dimensional separation method for peptides. Newly commercialized isoelectric membranes, which carry immobilized ampholytes, were integrated to establish the pH boundaries in this apparatus. High-performance liquid chromatography was employed as the second dimension, integrated with mass spectrometry. An insoluble nuclear protein fraction was used for optimization and evaluation of this method. The insoluble nuclear proteins were recovered from the nuclei of human MCF-7 human cancer cells and cleaved enzymatically. The resulting peptides were analyzed by the two-dimensional separation method, which coupled solution isoelectric focusing with reversed-phase liquid chromatography interfaced with mass spectrometry. A total of 281 peptides corresponding to 167 proteins were identified by this experiment. The high sample capacity and concentration effect of isoelectric focusing make it possible to detect relatively low abundance proteins in a complex mixture. This two-dimensional separation method dramatically improves peptide detection and identification compared with a single dimension LC-MS analysis. This method has been demonstrated to provide efficient and reproducible separation of both protein and peptides. The two-dimensional separation method was combined with proteolytic isotopic labeling for comparative analysis of protein expression in different cells. Abundances of nuclear proteins from three different drug resistant MCF-7 cancer cell lines were compared to those from the drug susceptible parent cell line using this combined strategy. The abundances of 19 proteins were found to be significantly changed. Their functions are considered in relation to potential mechanisms of in drug resistance.