UMD Theses and Dissertations
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Item ENGINEERING TARGETED LIGHT ACTIVATABLE NANOPLATFORMS TO MANAGE RECURRENT CANCERS(2024) Pang, Sumiao; Huang, Huang Chiao HH; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cancer recurrence poses a significant challenge in various malignancies that adverselyaffect long-term survival and quality of life. Glioblastoma (GBM) and ovarian cancer exhibit particularly high recurrence rates. For GBM, tumor recurrence is nearly universal (90%) within 10 months post initial treatment due to its invasive characteristics, limited delivery of therapeutic agents, and persistent drug resistance, resulting in a 5-year survival rate of <10%. While standard chemotherapy and surgery can temporarily alleviate symptoms for both diseases, there has been no significant improvement in long-term disease management or survival extension over several decades. Therefore, it is critical to develop targeted therapies that integrates well with current standards of care strategies. Photomedicine is a promising treatment modality, and the two main phototherapies are photodynamic therapy (PDT) which involves photosensitizer administration followed by light activation resulting in non-thermal chemical damage and photothermal therapy (PTT) which involves exogenous or endogenous sensitizing agents followed by light activation resulting in thermal damage. Clinical applications of both modalities have shown its feasibility and safety; however, they face challenges due to (i) limited cancer selectivity, (ii) heterogenous treatment response, and (iii) low monotherapy treatment efficacy. Leveraging strategic therapeutic targets to advance the current sensitizing agents for targeted delivery is a potential solution to overcome these limitations. The overall objective of this dissertation is to advance and evaluate targeted light-activatable nanoplatforms for phototherapy delivery with considerations for the current clinical workflow of GBM and advanced ovarian cancer. This is achieved through the following goals, (1) engineering a novel Fn14 receptor-directed gold nanorods (DART-GNRs) to assess selectivity and PTT efficacy for GBM, and (2) evaluate safety and long-term efficacy of targeted light-activatable multi-agent nanoplatform (tLAMP) to deliver targeted PDT for peritoneal carcinomatosis. First, this work establishes a reproducible synthesis protocol for DART-GNRs, characterizes its photothermal properties, and demonstrate high selectivity towards the Fn14 receptor of cancer cells. Second half of this dissertation established and investigated a two-fiber tissue optical property (TOP) monitoring method for liquid phantoms and for peritoneal carcinomatosis mouse model to enable safer light dosimetry during PDT, established an irinotecan active loading method to reproducibly synthesize tLAMP, and determined tLAMP tumor nodule penetration depth for enhanced targeted PDT combination therapy with adjuvant chemotherapy to enhance long-term survival for ovarian cancer.Item DEVELOPMENT OF GLYCOSAMINOGLYCAN MIMICKING NANOGEL TECHNOLOGIES FOR CONTROLLED RELEASE OF THERAPEUTICS TO TREAT RETINAL DISEASES IN DIFFERENT AGE GROUPS(2024) Kim, Sangyoon; Lowe, Tao L.; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Retinal diseases, such as diabetic retinopathy, glaucoma, macular degeneration, and retinoblastoma, affect around 13 million people worldwide, with projections indicating a rise to 20 million by 2030. These conditions lead to irreversible vision loss and significant impairment in both adults and children, with an annual economic burden of $139 billion in the United States alone. Aging significantly increases the risk of certain retinal conditions, and with improvements in healthcare leading to increased life expectancy, these conditions are becoming more prevalent due to the natural aging process and associated physiological changes in the eye. Current treatments are either destructive or have low efficacy and are not optimized for the younger population. While therapeutics including small molecular drugs, proteins and antibodies show promise in treating these diseases by reducing inflammation and neuronal apoptosis, their effectiveness is hindered by short half-lives and inability to cross the blood-retinal barrier (BRB). Nanoparticles offer a potential solution by improving drug delivery across biological barriers, yet no nanoparticles have been developed to effectively transport intact proteins or small molecules across the BRB to the retina without toxicity, slow clearance and stability. Therefore, there is an unmet need to evaluate the physical and physiological property changes of the eye along development and develop nanoparticle systems that can control and sustain the release of therapeutics across the blood retinal barrier (BRB) to treat the retinal diseases. In this project, the thickness, rheological property, permeability and morphological property changes of ocular barriers including sclera, cornea and vitreous humor in the developing eye from preterm to adult were evaluated using porcine ex vivo model. Two glycosaminoglycan mimicking nanogel systems, poly(NIPAAm-co-DEXcaprolactoneHEMA) nanogels with and without positive or negative charges and β-cyclodextrin based poly(β-amino ester) (CD-p-AE) nanogels were developed for sustained release of intact proteins including insulin and anti-TNFα, and small hydrophobic drugs, respectively across the ex vivo porcine sclera and in vitro BRB models: human fetal retinal pigment epithelial (hfRPE), adult retinal pigment epithelial (ARPE-19) and human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Completion of this project will have a significant impact on developing novel personalized nanotherapeutics to treat retinal diseases in different age groups.Item DESIGN OF HYBRID POLYMER- INORGANIC NANOASSEMBLIES FOR BIOMEDICAL APPLICATIONS(2018) Yang, Kuikun; Nie, Zhihong; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Assembly of inorganic nanoparticles (NPs) can give rise to novel collective properties due to the coupling between adjacent subunits, which are not accessible from individual nanoparticles. Among them, hybrid polymer-inorganic nanoassemblies (HPINs) are particularly attractive by combining the complementary strengths of inorganic NPs and polymers. This dissertation describes the design of HPINs with elaborately tailored physicochemical properties and the applications of HPINs in tumor diagnosis and therapy. First, we introduced the design principles and representative morphologies of HPINs. Size, shape, surface charge and coatings are crucial properties to be considered before the design of HPINs. Among various types of HPINs, we focused on the hybrid vesicles assembled from polymer-tethered inorganic NPs due to their synergistic properties that surpass their constituent components. We also summarized recent advances in the development of HPINs as attractive platforms for cancer imaging and therapy. Second, we developed an enzyme-free signal amplification technique, based on gold vesicles encapsulated with Pd−Ir NPs as peroxidase mimics, for colorimetric assay of disease biomarkers with significantly enhanced sensitivity. Third, we introduced a universal approach to attach amphiphilic block copolymers onto oleic acid or/and oleylamine capped NPs to trigger their assembly. Various NPs including Fe3O4, Cu9S5, MnO and upconversion NPs were assembled into hollow vesicles with novel physicochemical properties for a variety of biomedical applications. Finally, we described the fabrication of nanosized magneto-vesicles comprising tunable layers of densely packed superparamagnetic iron oxide nanoparticles (SPIONs) in membranes via cooperative assembly of polymer-tethered SPIONs and free poly(styrene)-b-poly(acrylic acid). Due to the high packing density of SPIONs, the magneto-vesicles showed enhanced signal in magnetic resonance imaging as well as improved efficiency in magnetic-guided drug delivery both in vitro and in vivo.Item DESIGN AND HIERARCHICAL ASSEMBLY OF AMPHIPHILIC SUPRACOLLOIDS THAT MIMIC BIMOLECULAR COMPOUNDS(2018) Zhang, Shaoyi; Nie, Zhihong; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Self-assembly of nanoparticles (NPs) into desired structures with precisely controlled NP organization is crucial to the property discovery and application of inorganic NPs. Despite tremendous efforts made in the past decades, little progress has been achieved in controlled hierarchical assembly of NPs. My dissertation is focused on the multi-level assembly of inorganic NPs into various hierarchical structures by tethering NPs with functional block copolymers (BCPs). First, one versatile strategy was developed to design monodisperse amphiphilic supracolloids with defined valence and chemical patches by co-assembly of binary disparate hybrid building blocks composed of BCP-functionalized NPs. The binary BCP is composed of a hydrophilic/hydrophobic block and a Lewis base-containing/Lewis acid-containing block. The resulting supracolloids consist of two different types of inorganic NPs precisely arranged in space, which mimics the geometric shape and valence of bimolecular compounds containing two elements. By varying the size, chemical composition and feeding ratio of NPs, as well as the length of BCP combinations, supracolloids with different valences, compositions and localized chemical patches (which are determined by the BCP tethers) were produced in high yield. Second, the amphiphilic supracolloids were demonstrated to assemble into a range of two-dimensional (2D) hierarchical structures at the liquid/liquid interface. Depending on the quality of solvent, amphiphilic dimers were found to assemble into petal-like structures with different numbers of dimers. Moreover, amphiphilic trimers underwent side-by-side or end-to-end association to form ribbon or chain structures, depending on the arrangement of hydrophilic and hydrophobic domains (chemical patches). Third, the effect of polymer length of BCP tethers within supracolloids was systematically studied on the ribbon formation of trimer-like supracolloids with hydrophobic center and hydrophilic ends. It was found that longer hydrophobic block and shorter hydrophilic BCP tethers facilitate the formation of ribbon. The results were summarized in a product diagram. Finally, the pH effect on the assembly of amphiphilic supracolloidal trimers was investigated. A transition of assembly morphologies from ribbons to chains was observed, with changing pH of the water phase. This can be attributed to the change on the amphiphilicity of supracolloidal trimers upon the addition of acid or base.Item Functionally Coated Faceted Aluminum Nanocrystals: Aerosol Synthesis and Reactivity(2013) Kaplowitz, Daniel Alan; Zachariah, Michael R; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The demand for large scale manufacture of nanoaluminum for use in propellant applications has motivated research into development of an aerosol production scheme. In addition, the reactive nature of aluminum in the presence of oxygen has inspired investigation into functionally coating bare nanoaluminum prior to exposure to the atmosphere. Faceted aluminum crystals are fabricated in the aerosol phase via thermal pyrolysis of triisobutylaluminum, a low temperature gas-phase synthesis route, and combustion tests of oxygen passivated product in thermite combination show an increase in energy release compared to commercial nanoaluminum. Three different coatings on this bare nanoaluminum are developed: a decoration of Ni/Ni2O3 particles by thermal decomposition of Ni(CO)4, a homogeneous layer of Fe3O4 by thermal decomposition of Fe(CO)5, and a monolayer of perfluoropentanoic acid via bridge bonding between aluminum and carboxylate groups. X-ray photoelectron spectroscopy analysis indicates that the metal oxide coatings have facilitated formation of an expanded aluminum oxide layer during an air bleed, but perfluoropentanoic acid has successfully passivated aluminum. The protection from significant oxide formation for the perfluoropentanoic acid coating is evident in a 16% increase in active fuel content by thermogravimetric analysis compared to the untreated case. Subsequent temperature jump fine wire combustion tests show decreased ignition temperatures for all three coatings. Combustion chamber tests in thermite combinations display poor pressure output for the Ni/Ni2O3 coated case, but reasonable response for the Fe3O4 product. Flame ignition of perfluoropentanoic acid coated product is shown to produce AlF3 by chemical analysis of char, indicating the passivation coating also functions in direct oxidizer delivery.Item Investigation into the Potential Toxicity of Zero-Valent Iron Nanoparticles to a Trichloroethylene-Degrading Groundwater Microbial Community(2013) Zabetakis, Kara Margaret; Torrents, Alba; Yarwood, Stephanie A; Marine-Estuarine-Environmental Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The microbiological impact of zero-valent iron remediation of groundwater was investigated by exposing a trichloroethylene-degrading anaerobic microbial community to bare and coated iron nanoparticles. Changes in population numbers and metabolic activity were analyzed using qPCR and were compared to those of a blank, negative, and positive control to assess for microbial toxicity. Additionally, these results were compared to those of samples exposed to an equal concentration of iron filings in an attempt to discern the source of toxicity. Statistical analysis revealed that the three iron treatments were equally toxic to total Bacteria and Archaea populations, as compared with the controls. Therefore, toxicity appears to result either from the release of iron ions and the generation of reactive oxygen species, or from alteration of the redox system and the disruption of microbial metabolisms. There does not appear to be a unique nanoparticle-based toxicity.Item Magnetic Drug Targeting: Developing the Basics(2013) Nacev, Aleksandar Nelson; Shapiro, Benjamin; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Focusing medicine to disease locations is a needed ability to treat a variety of pathologies. During chemotherapy, for example, typically less than 0.1% of the drugs are taken up by tumor cells, with the remaining 99.9% going into healthy tissue. Physicians often select the dosage by how much a patient can physically withstand rather than by how much is needed to kill all the tumor cells. The ability to actively position medicine, to physically direct and focus it to specific locations in the body, would allow better treatment of not only cancer but many other diseases. Magnetic drug targeting (MDT) harnesses therapeutics attached to magnetizable particles, directing them to disease locations using magnetic fields. Particles injected into the vasculature will circulate throughout the body as the applied magnetic field is used to attempt confinement at target locations. The goal is to use the reservoir of particles in the general circulation and target a specific location by pulling the nanoparticles using magnetic forces. This dissertation adds three main advancements to development of magnetic drug targeting. Chapter 2 develops a comprehensive ferrofluid transport model within any blood vessel and surrounding tissue under an applied magnetic field. Chapter 3 creates a ferrofluid mobility model to predict ferrofluid and drug concentrations within physiologically relevant tissue architectures established from human autopsy samples. Chapter 4 optimizes the applied magnetic fields within the particle mobility models to predict the best treatment scenarios for two classes of chemotherapies for treating future patients with hepatic metastatic breast cancer microtumors.Item QUANTIFYING PARTICLE PROPERTIES FROM ION-MOBILITY MEASUREMENTS(2012) Li, Mingdong; Zachariah, Michael R.; Chemical Physics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Nanoparticles have received considerable interest due to the wide variety of potential applications in biomedical, optical, and electronic fields. However, our capabilities for quantitatively charactering these materials, for example in number concentration or shape are limited. The objective of this work is to develop experimentally verified theories to quantify particle properties from aerosol based ion-mobility measurement. The use of aerosol tools is predicated on the idea that these methods offer the best chance for quantification, due to a better understanding of the physics of ion transport in the gas phase. Nevertheless this does not preclude us from using these techniques to characterize particles in liquids as will be show in the first part of this work which resolves problems associated with generating an aerosol from colloidal suspensions. In this dissertation I resolve the problem of artificial "droplet induced aggregation" during electrospray which can corrupt the eventual determination of particle size. I develop an experimentally verified statistical based model, to determine and correct this undesired artifact. Furthermore, I have found that this nominally undesired artifact can be used in a beneficial way that allows one to determine the absolute number concentration of nanoparticles in solution, without the need for calibration particles. Mobility is one of the most important and fundamental properties of a particle. However most particle characterization approaches interpret the results of mobility measurement in the context of spherical particle transport. I have undertaken to systematically explore the mobility properties of non-spherical particles. In this dissertation I develop a theory to quantify the effect of orientation on the mobility and the dynamic shape factor of charged axially symmetric particles in an electric field. The experimental results of well-defined doublets of NIST traceable size standard 127nm, 150nm, 200nm and 240nm PSL spheres are shown to be in excellent agreement with the expected values based on my theory. More general new theories of the mobility of nonspherical particles are also proposed and compared with current theories. I also propose a new instrument, a pulsed differential mobility analyzer (PDMA), to obtain shape information by measuring the electrical mobility under different electric fields.Item Functional Nanostructure Synthesis and Properties(2012) Liu, Qing; Zachariah, Michael R; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The dissertation addressed challenges in the nanostructure synthesis, applied the materials to engineering fields, such as lithium battery material, fluorescent and magnetic drug deliveries; and developed new characterization methods to better understand particle properties and formation mechanisms.Item COPPER OXIDE NANOARCHITECTURES FOR PHOTOELECTROCHEMICAL HYDROGEN GENERATION(2012) Chiang, Chia-Ying; Ehrman, Sheryl H; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Hydrogen is a high-quality energy carrier, similar to electricity, which can be used with high efficiency and near-zero emissions at the point of use. The most promising means of producing hydrogen using a renewable energy source and potentially reducing the generation of greenhouse gases production is through solar-hydrogen photoelectrochemical (PEC) water decomposition. In order to utilize the solar irradiation, small band gap material is essential. In this dissertation, I focus on the earth abundant, non-toxic and direct transit copper oxide (CuO) with band gap around 1.3-1.8 eV. In a PEC cell, the photo-excited charge carriers need to be separated as soon as they form in order to have a high photocurrent density. Thus, four approaches are studied: (1) decrease particle size to decrease the electron-hole recombination in the particles, (2) increase surface area to increase the active sites and decrease the distance for electrons travel to the surface to react with water (3) increase conductivity to decrease the resistance of the electrode, and (4) shorten charge carrier transport distance to decrease the chance of recombination of charge carriers. In the first part of this study, I describe the aerosol route, flame spray pyrolysis, for making CuO nanoparticles. By controlling the precursor concentration and flame conditions, the particle size can be tuned. Also, the simulation results of particle growth, based on collision/sintering theory with sintering by solid state diffusion, are in good agreement with the experimental results. Furthermore, the flame spray pyrolysis made CuO nanoparticles were spin coated on conducting ITO glass substrates for the PEC study. Here, the relatively uniform CuO nanoparticles showed much better photocurrent density compared to the commercial CuO nanoparticles with a broad size distribution. This demonstrates the importance of the size of material for PEC application. The second approach I introduced is to increase surface area to increase the active sites. Instead of changing the CuO suspension concentration to make films with different porosity, I present a new route for forming porous structures by spin coating the powder including CuO and its intermediate product, Cu2(NO3)(OH)3. During the post annealing process, the intermediate product transforms into CuO and leaves voids in the film, thus producing a porous film and increasing the active surface area for the water splitting reaction. In the third approach, lithium was incorporated as a dopant to increase conductivity and decrease the resistance of the electrode. With the lithium added, the conductivity increased by two orders of magnitude and thus highly decreased the film resistance and increased the photocurrent density. The final part of this dissertation focuses on three dimensional current collectors, used to decrease the charge carrier transport distance and thus decrease the chance of recombination. Here, the genetically modified tobacco mosaic virus (TMV1cys) served as a template for the three dimensional structure, made by sputter deposition of CuO. By varying the virus concentration, the distance between the current collectors can be tuned to optimize the charge carrier transport distance, light reflection as well as the CuO thickness for efficient absorption of solar energy.