2018 UMKC Dissertations - Access Restricted to UMKC
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Item Peptide-Based Platform For Cancer Therapeutics And Drug Transportation Across Blood-Brain Barrier(University of Missouri -- Kansas City, 2018) Barve, Ashutosh; Cheng, Kun (Professor)Prostate cancer is the most common male malignancy and remains the second-leading cause of death due to cancer in American men. While surgery and radiation are effective in prostate cancer therapy at early stages, the majority of the patients ultimately relapse and develop advanced prostate cancer. Conventional chemotherapy is one of the most widely used techniques to combat prostate cancer, along with surgery, radiation therapy, and cryotherapy. However, chemotherapy itself has many limitations, such as lack of specificity, high toxicity to normal cells, inadequate availability to the tumor tissue, drug resistance, and the complicated microenvironment in tumor tissues. As a result, there is a great need to develop targeted delivery systems for chemotherapy agents for prostate cancer therapy. One objective of this dissertation is to develop peptide-based platforms for two chemotherapy agents, TGX-D1 and cabazitaxel. Despite efforts and advancements in the field of neuroscience, drug delivery to the brain and CNS remains a major challenge. Neurological diseases/disorders, infections, and brain cancers are becoming more predominant but effective drug therapies remain elusive. The blood-brain barrier (BBB) is a physical, chemical and metabolic barrier that restricts and controls the movement of substances from the blood circulation to the brain extracellular fluid or brain cells. Because of this barrier, approximately 98% of small-molecule drugs and 100% of large-molecule drugs, including recombinant proteins, monoclonal antibodies, and nucleic acids, cannot cross the BBB. The second objective of this dissertation is to identify a peptide sequence that can cross the BBB and deliver drug molecules, without affecting the integrity of the BBB. This work will be completed using the phage display technique. In chapter 1 and 2, we introduced and discussed the background of prostate cancer and the utilization of prostate cancer relevant antigens and enzyme for targeted drug delivery. We also discussed the role of the BBB as a major hurdle in drug delivery to the brain, and the identification of peptide ligands using phage display. In chapter 3, an enzyme-responsive peptide drug conjugate was developed for TGX-D1, a promising PI3K inhibitor for prostate cancer therapy. LNCaP-specific KYL peptide was used as the targeting ligand and the prostate-specific antigen (PSA) cleavable peptide (SSKYQSL) was used as the enzyme-responsive linker. SSKYQSL is cleaved by recombinant human PSA at 10-250 μg/mL. By contrast, the linker is stable in the serum of prostate cancer patients with high PSA levels (> 500 ng/mL), indicating that this linker can survive the systemic circulation in prostate cancer patients but be cleaved in the tumor microenvironment. Cellular uptake of the peptide drug conjugate in prostate cancer cells is improved by about nine times. Biodistribution studies reveal significant tumor accumulation of the peptide drug conjugate in nude mice bearing C4-2 tumor xenografts. Meanwhile, distribution of the conjugate in other major tissues is the same as the parent drug, indicating a high specificity of the conjugate to prostate cancers in vivo. In chapter 4, we developed a biodegradable, enzyme-responsive, and targeted polymer micelle for cabazitaxel. The micelle was spontaneously formed from two amphiphilic block copolymers. The first block copolymer consists of PEG, an enzyme-responsive peptide, and cholesterol; whereas the second block copolymer consists of a targeting ligand (DUPA), PEG and cholesterol. The enzyme-responsive peptide is cleavable in the presence of MMP-2, which is overexpressed in prostate cancer cells. DUPA is a small molecule-based targeting ligand, which binds to prostate-specific membrane antigen (PSMA) with a high affinity. The micelle showed a low critical micelle concentration (CMC), high drug loading, and high entrapment efficiency. The release of cabazitaxel from the micelle is dependent on the cleavage of the enzyme-responsive peptide by MMP-2. Also, the micelle showed dramatically higher cellular uptake in prostate cancer cells compared to free cabazitaxel. Importantly, the polymeric micelle demonstrated better inhibition of tumor growth in mice bearing prostate cancer xenografts compared to free cabazitaxel. Taken together, these findings suggest that the enzyme-responsive PSMA-targeted cabazitaxel micelle is a potent and promising drug delivery system for advanced prostate cancer therapy. In chapter 5, we developed a novel phage display biopanning procedure to discover shuttle peptides that can cross the BBB. 7-mer and 12-mer peptide phage libraries were used in the study. For the 7-mer phage library, we used a five-round biopanning procedure consisting of two rounds of in vitro screening and three rounds of in vivo screening. We selected more than 100 phage colonies for DNA extraction and sequencing. We successfully discovered 62 novel peptide sequences, of which seven sequences repeated multiple times for a total repetition of 50 times. These sequences were used for in vivo biodistribution studies. We labeled these peptides with a fluorescent dye and injected them into rats via the tail vein. We then euthanized the rats, collected various organs, and checked the fluorescence intensity in each of the organs. For the 12-mer library, we designed a 4-round biopanning procedure. We started with a first round of in vitro selection, followed by in vivo screening, and then repetition of the in vitro and in vivo rounds of screening. We dissected different parts of the brain, including the cerebellum, brain stem, and cerebrum, and enriched phages separately for each part of the brain to enrich peptides that are specific for particular parts of the brain. We successfully discovered more than 150 novel peptide sequences, with more than 50 sequences specific for different parts of the brainItem The Effectiveness of Reading Folk Literature in Improving English Language Learners’ Reading Proficiency in Elementary Grades(University of Missouri -- Kansas City, 2018) Erdogan, Nabat; Wei, Michael, 1968-This mixed-methods study investigates the effectiveness of reading folktales, fairy tales, and fables in improving English learners’ reading proficiency levels in elementary grades and explores students’ experiences with reading folk literature. An experiment involving folk literature-based reading intervention was conducted with 68 second grade English learners for 11 weeks in an urban elementary school. The participants’ pre- and postintervention NWEA reading scores were analyzed using repeated-measures ANOVA. The analysis of the results shows that reading folk literature is as effective as traditional reading texts in improving elementary English learners’ reading skills. The most significant finding from the quantitative phase of the study is that the use of folk literature in an ESL class can increase elementary English learners’ reading scores at least as much as traditional (unpredetermined) reading materials can do. The qualitative phase of the study used documents, observations, and interviews as the primary sources of data. The thematic analysis of the observation data yielded the following themes: (1) well-managed and structured lessons, (2) vocabulary instruction, (3) fluency, phonics, and phonemic awareness instruction, (4) reading comprehension instruction, and (5) oral language instruction. It was concluded that the components of reading instruction observed in the folk-literature intervention class matched the six components of effective reading instruction for ELLs suggested by the National Literacy Panel (2000). The interview data were analyzed to construct six narrative case studies as well as to derive themes from the participant responses. Three overarching themes emerged as a result of the interview data analysis: (1) text selection, (2) vocabulary teaching, and (3) visual support. The interviews revealed that the consideration of these three components while teaching reading to English learners is of critical importance. The themes that emerged from the qualitative data analyses provide guidelines for effective reading instruction for elementary English learners as well as native English speaking students struggling with literacy skills in English. Overall, the research increases the body of knowledge about effective reading instruction for struggling readers in general, and for English learners in particular. The research findings support previous research on essential components of effective reading instruction.Item Evaluation of Cement-Based Reactive Media for Contaminant Remediation(University of Missouri -- Kansas City, 2018) Holmes, Ryan Rodrick; Hart, Megan Leanore, 1976-Water contaminated with heavy metals, arsenic, and other industrial pollutants poses a severe risk to human health. Reactive media present an opportunity to intercept contaminants but have high material or environmental costs. Cement-based media filters (CBFM) present an opportunity to use ubiquitous cement mixed with a recycled material to permanently remove contaminants. By engineering a mechanical and chemical matrix derived from cement, an enhanced filter media can be produced to target and treat a spectrum of contaminants. Mechanisms of removal are adsorption, diffusion, precipitation and coprecipitation. The highly alkaline pore water of the cement drives each mechanism to produce a compounding effect, unique to CBFM and previously unreported. Batch reactor and breakthrough testing were performed using CBFM and showed 30 and 40 times increase from equilibrium to flow-through systems. Ordinary portland cement was used as the control for all systems and was replaced by supplementary cementitious materials (SCMs) to evaluate the impact of substitution on contaminant removal. The control removed over 50% of most contaminants, but when various SCMs were used, removal improved to over 95% and was ion selective. Ion selectivity for the system was accomplished through the unique mineral phases formed during removal and mimicked accelerated natural processes. Scanning electron microscopy and X-ray diffraction were used to analyze precipitates and phase distribution in cement. Heavy metals were removed due to coprecipitation with calcium and then encapsulated by oolitic calcite. Arsenic, boron, sulfate, and chlorides were removed by ettringite phase, stabilized by the ion inclusions. The mineral formations present an advancement to previous systems like activated carbon because the removal mechanisms produce continuous additional removal not limited by the reactive media but rather by the pore volume required for crystal deposition. CBFM achieve high levels of removal using sustainable recycled media and concentrate the contaminants for future valorization. This study shows the successful development of CBFMs for remediation.Item Three Essays on Public Money Creation, Endogenous Bank Credit Creation, and Remaining Empirical Issues: Interest Rates and Inflation(University of Missouri -- Kansas City, 2018) Kim, Hongkil; Eaton, Peter JamesThis dissertation examines the interconnectedness between money/credit creation and its empirical relevance to macroeconomic variables. It takes the position that the amount of money/credit created for GDP-related transactions inevitably influences the business cycle and inflation while the money/credit extension for non-GDP based transactions (mainly for purchasing financial assets) helps explain movements of interest rates, exchange rates, and an asset bubble/crash. With this approach, the main objectives of this dissertation is to demonstrate that 1) excess bank credit creation/depletion for households’ spending is crucial in explaining US inflation, 2) the European Central Bank could successfully contain pressures in struggling sovereign bond markets, relying on its unique power to create its currency (the euro) and 3) interest rate exogeneity is, if not theoretically impossible, difficult to attain due to market psychology and endogenous credit creation. Having recognized effects of money/credit creation on a macroeconomic environment, the dissertation naturally proceeds to suggest policy proposals that guide credit creation and allocation of credit for productive purposes and assign a proper role for public money creation to counter ebb and flow of private credit creation.Item Development of Random Triblock Copolymer Based Nanoparticulate Formulation for Sustained Release of Macromolecules/Biologics in Treatment of Posterior Segment Ocular Diseases(University of Missouri -- Kansas City, 2018) Ngatuni, Mary Joseph; Melchert, Russell B.Random triblock copolymers (RTB) were successfully synthesized by ring opening copolymerization method. RTB copolymers are composed of FDA approved materials such as polyethylene glycol (PEG), glycolide (GA), lactide (LA) and ɛ-caprolactone (CL). RTB copolymers were synthesized and developed for sustained delivery of macromolecules to the posterior segment of the eye. RTB copolymers of different composition and molecular weights were synthesized. The polymers were evaluated for their molecular weight, purity, crystallinity, functionality, cytotoxicity and biocompatibility. No toxicity was observed when ocular cell lines were treated with RTB polymers. Moreover, polymers did not induce inflammatory mediators when treated with macrophage cells. These data confirm lack of in vitro cytotoxicity and production of inflammatory mediators, which suggests RTB copolymers may be good candidates for ocular delivery of macromolecules. In this project, several formulation strategies have been employed to enable sustained delivery of macromolecules by employing nanoparticle approach. In the first approach, synthesized RTB copolymers were further utilized to encapsulate macromolecules with various molecular weights ranging from 237-1 kDa. These macromolecules include catalase, IgG, bovine serum albumin, IgG Fab fragment, lysozyme, insulin and octreotide. Our results observed the effect of macromolecule molecular weight on drug loading and entrapment efficiency. In order to ensure sustained and prolonged release, nanoparticles were suspended in thermosensitive gel which acted as a secondary barrier. The second approach was combining the benefit of two technologies i.e. nanoparticle and liposome to formulate hybrid nanoparticles encapsulating IgG, IgG F(ab)’₂ and IgG Fab fragments. JMP full factorial design was employed in order to understand factors and interactions influencing particle size, entrapment efficiency and drug loading of nanoparticles. Optimized formulation was obtained based on the results from the design. Nanoparticles were prepared according to the optimized formulation and characterized for particle size, PDI, entrapment efficiency and drug loading. In vitro release of macromolecules from hybrid nanoparticles suspended in thermosensitive gel revealed prolonged release of macromolecules. The final approach was the modification of octreotide by ion pairing agents to form hydrophobic ion pairing complexes. The complexes were found to be reversible at physiological pH with high amounts of counter ions. The complexes were further encapsulated inside nanoparticles using RTB copolymer. Encapsulation efficiency and drug loading was found to be higher since the complexes are hydrophobic in nature and partition well into polymer matrix. In vitro release studies indicated prolonged release for extended period. Moreover, acylation of octreotide was observed in smaller quantity, while large amounts of native octreotide were released.