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- All Subjects: chemical engineering
- All Subjects: Biochemistry
- Genre: Doctoral Dissertation
- Creators: Rege, Kaushal
Description
Cancer is the second leading cause of death in the United States and novel methods of treating advanced malignancies are of high importance. Of these deaths, prostate cancer and breast cancer are the second most fatal carcinomas in men and women respectively, while pancreatic cancer is the fourth most fatal in both men and women. Developing new drugs for the treatment of cancer is both a slow and expensive process. It is estimated that it takes an average of 15 years and an expense of $800 million to bring a single new drug to the market. However, it is also estimated that nearly 40% of that cost could be avoided by finding alternative uses for drugs that have already been approved by the Food and Drug Administration (FDA). The research presented in this document describes the testing, identification, and mechanistic evaluation of novel methods for treating many human carcinomas using drugs previously approved by the FDA. A tissue culture plate-based screening of FDA approved drugs will identify compounds that can be used in combination with the protein TRAIL to induce apoptosis selectively in cancer cells. Identified leads will next be optimized using high-throughput microfluidic devices to determine the most effective treatment conditions. Finally, a rigorous mechanistic analysis will be conducted to understand how the FDA-approved drug mitoxantrone, sensitizes cancer cells to TRAIL-mediated apoptosis.
ContributorsTaylor, David (Author) / Rege, Kaushal (Thesis advisor) / Jayaraman, Arul (Committee member) / Nielsen, David (Committee member) / Kodibagkar, Vikram (Committee member) / Dai, Lenore (Committee member) / Arizona State University (Publisher)
Created2013
Description
Liquid-liquid interfaces serve as ideal 2-D templates on which solid particles can self-assemble into various structures. These self-assembly processes are important in fabrication of micron-sized devices and emulsion formulation. At oil/water interfaces, these structures can range from close-packed aggregates to ordered lattices. By incorporating an ionic liquid (IL) at the interface, new self-assembly phenomena emerge. ILs are ionic compounds that are liquid at room temperature (essentially molten salts at ambient conditions) that have remarkable properties such as negligible volatility and high chemical stability and can be optimized for nearly any application. The nature of IL-fluid interfaces has not yet been studied in depth. Consequently, the corresponding self-assembly phenomena have not yet been explored. We demonstrate how the unique molecular nature of ILs allows for new self-assembly phenomena to take place at their interfaces. These phenomena include droplet bridging (the self-assembly of both particles and emulsion droplets), spontaneous particle transport through the liquid-liquid interface, and various gelation behaviors. In droplet bridging, self-assembled monolayers of particles effectively "glue" emulsion droplets to one another, allowing the droplets to self-assembly into large networks. With particle transport, it is experimentally demonstrated the ILs overcome the strong adhesive nature of the liquid-liquid interface and extract solid particles from the bulk phase without the aid of external forces. These phenomena are quantified and corresponding mechanisms are proposed. The experimental investigations are supported by molecular dynamics (MD) simulations, which allow for a molecular view of the self-assembly process. In particular, we show that particle self-assembly depends primarily on the surface chemistry of the particles and the non-IL fluid at the interface. Free energy calculations show that the attractive forces between nanoparticles and the liquid-liquid interface are unusually long-ranged, due to capillary waves. Furthermore, IL cations can exhibit molecular ordering at the IL-oil interface, resulting in a slight residual charge at this interface. We also explore the transient IL-IL interface, revealing molecular interactions responsible for the unusually slow mixing dynamics between two ILs. This dissertation, therefore, contributes to both experimental and theoretical understanding of particle self-assembly at IL based interfaces.
ContributorsFrost, Denzil (Author) / Dai, Lenore L (Thesis advisor) / Torres, César I (Committee member) / Nielsen, David R (Committee member) / Squires, Kyle D (Committee member) / Rege, Kaushal (Committee member) / Arizona State University (Publisher)
Created2013
Description
Post-combustion carbon capture is a viable option for reducing CO2 greenhouse gas emissions, and one potentially promising technology for this route is adsorption using chemically and physically based sorbents. A number of exceptional CO2 sorbents materials have been prepared including metal organic frameworks, zeolites, and carbon based materials. One particular group of capable materials are amine based solid sorbents that has shown to possess high adsorption capacities and favorable adsorption kinetics. A key variable in the synthesis of an amine based sorbent is the support which acts as the platform for the amine modification. Aerogels, due to their high porosities and surface areas, appear to be a promising support for an amine modified CO2 sorbent. Therefore, in order to develop a commercially viable CO2 sorbent, particulate aerogels manufactured by Cabot Corporation through an economical and proprietary ambient drying process were modified with amines using a variety of functionalization methods. Two methods of physical impregnation of the amino polymer TEPA were performed in order to observe the performance as well as understand the effects of how the TEPA distribution is affected by the method of introduction. Both samples showed excellent adsorption capacities but poor cyclic stability for lack of any covalent attachment. Furthermore the method of TEPA impregnation seems to be independent on how the polymer will be distributed in the pore space of aerogel. The last two methods utilized involved covalently attaching amino silanes to the surface silanols of the aerogel. One method was performed in the liquid phase under anhydrous and hydrous conditions. The materials developed through the hydrous method have much greater adsorption capacities relative to the anhydrous sample as a result of the greater amine content present in the hydrous sample. Water is another source of silylation where additional silanes can attach and polymerize. These samples also possessed stable cyclic stability after 100 adsorption/regeneration cycles. The other method of grafting was performed in the gas phase through ALD. These samples possessed exceptionally high amine efficiencies and levels of N content without damaging the microstructure of the aerogel in contrast to the liquid phase grafted sorbents.
ContributorsLinneen, Nick (Author) / Lin, Jerry (Thesis advisor) / Pfeffer, Robert (Thesis advisor) / Lind, Mary (Committee member) / Rege, Kaushal (Committee member) / Nielsen, David (Committee member) / Anderson, James (Committee member) / Arizona State University (Publisher)
Created2014
Description
Control engineering offers a systematic and efficient approach to optimizing the effectiveness of individually tailored treatment and prevention policies, also known as adaptive or ``just-in-time'' behavioral interventions. These types of interventions represent promising strategies for addressing many significant public health concerns. This dissertation explores the development of decision algorithms for adaptive sequential behavioral interventions using dynamical systems modeling, control engineering principles and formal optimization methods. A novel gestational weight gain (GWG) intervention involving multiple intervention components and featuring a pre-defined, clinically relevant set of sequence rules serves as an excellent example of a sequential behavioral intervention; it is examined in detail in this research.
A comprehensive dynamical systems model for the GWG behavioral interventions is developed, which demonstrates how to integrate a mechanistic energy balance model with dynamical formulations of behavioral models, such as the Theory of Planned Behavior and self-regulation. Self-regulation is further improved with different advanced controller formulations. These model-based controller approaches enable the user to have significant flexibility in describing a participant's self-regulatory behavior through the tuning of controller adjustable parameters. The dynamic simulation model demonstrates proof of concept for how self-regulation and adaptive interventions influence GWG, how intra-individual and inter-individual variability play a critical role in determining intervention outcomes, and the evaluation of decision rules.
Furthermore, a novel intervention decision paradigm using Hybrid Model Predictive Control framework is developed to generate sequential decision policies in the closed-loop. Clinical considerations are systematically taken into account through a user-specified dosage sequence table corresponding to the sequence rules, constraints enforcing the adjustment of one input at a time, and a switching time strategy accounting for the difference in frequency between intervention decision points and sampling intervals. Simulation studies illustrate the potential usefulness of the intervention framework.
The final part of the dissertation presents a model scheduling strategy relying on gain-scheduling to address nonlinearities in the model, and a cascade filter design for dual-rate control system is introduced to address scenarios with variable sampling rates. These extensions are important for addressing real-life scenarios in the GWG intervention.
A comprehensive dynamical systems model for the GWG behavioral interventions is developed, which demonstrates how to integrate a mechanistic energy balance model with dynamical formulations of behavioral models, such as the Theory of Planned Behavior and self-regulation. Self-regulation is further improved with different advanced controller formulations. These model-based controller approaches enable the user to have significant flexibility in describing a participant's self-regulatory behavior through the tuning of controller adjustable parameters. The dynamic simulation model demonstrates proof of concept for how self-regulation and adaptive interventions influence GWG, how intra-individual and inter-individual variability play a critical role in determining intervention outcomes, and the evaluation of decision rules.
Furthermore, a novel intervention decision paradigm using Hybrid Model Predictive Control framework is developed to generate sequential decision policies in the closed-loop. Clinical considerations are systematically taken into account through a user-specified dosage sequence table corresponding to the sequence rules, constraints enforcing the adjustment of one input at a time, and a switching time strategy accounting for the difference in frequency between intervention decision points and sampling intervals. Simulation studies illustrate the potential usefulness of the intervention framework.
The final part of the dissertation presents a model scheduling strategy relying on gain-scheduling to address nonlinearities in the model, and a cascade filter design for dual-rate control system is introduced to address scenarios with variable sampling rates. These extensions are important for addressing real-life scenarios in the GWG intervention.
ContributorsDong, Yuwen (Author) / Rivera, Daniel E (Thesis advisor) / Dai, Lenore (Committee member) / Forzani, Erica (Committee member) / Rege, Kaushal (Committee member) / Si, Jennie (Committee member) / Arizona State University (Publisher)
Created2014
Description
Gene therapy is a promising technology for the treatment of various nonheritable and genetically acquired diseases. It involves delivery of a therapeutic gene into target cells to induce cellular responses against diseases. Successful gene therapy requires an efficient gene delivery vector to deliver genetic materials into target cells. There are two major classes of gene delivery vectors: viral and non-viral vectors. Recently, non-viral vectors such as cationic polymers have attracted more attention than viral vectors because they are versatile and non-immunogenic. However, cationic polymers suffer from poor gene delivery efficiency due to biological barriers. The objective of this research is to develop strategies to overcome the barriers and enhance polymer-mediated transgene expression. This study aimed to (i) develop new polymer vectors for gene delivery, (ii) investigate the intracellular barriers in polymer-mediated gene delivery, and (iii) explore new approaches to overcome the barriers. A cationic polymer library was developed by employing a parallel synthesis and high-throughput screening method. Lead polymers from the library were identified from the library based on relative levels of transgene expression and toxicity in PC3-PSMA prostate cancer cells. However, transgene expression levels were found to depend on intracellular localization of polymer-gene complexes (polyplexes). Transgene expression was higher when polyplexes were dispersed rather than localized in the cytoplasm. Combination treatments using small molecule chemotherapeutic drugs, e.g. histone deacetylase inhibitors (HDACi) or Aurora kinase inhibitor (AKI) increased dispersion of polyplexes in the cytoplasm and significantly enhanced transgene expression. The combination treatment using polymer-mediated delivery of p53 tumor-suppressor gene and AKI increased p53 expression in PC3-PSMA cells, inhibited the cell proliferation by ~80% and induced apoptosis. Polymer-mediated p53 gene delivery in combination with AKI offers a promising treatment strategy for in vivo and clinical studies of cancer gene therapy.
ContributorsBarua, Sutapa (Author) / Rege, Kaushal (Thesis advisor) / Dai, Lenore (Committee member) / Meldrum, Deirdre R. (Committee member) / Sierks, Michael (Committee member) / Voelkel-Johnson, Christina (Committee member) / Arizona State University (Publisher)
Created2011
Description
Emission of CO2 into the atmosphere has become an increasingly concerning issue as we progress into the 21st century Flue gas from coal-burning power plants accounts for 40% of all carbon dioxide emissions. The key to successful separation and sequestration is to separate CO2 directly from flue gas (10-15% CO2, 70% N2), which can range from a few hundred to as high as 1000°C. Conventional microporous membranes (carbons/silicas/zeolites) are capable of separating CO2 from N2 at low temperatures, but cannot achieve separation above 200°C. To overcome the limitations of microporous membranes, a novel ceramic-carbonate dual-phase membrane for high temperature CO2 separation was proposed. The membrane was synthesized from porous La0.6Sr0.4Co0.8Fe0.2O3-d (LSCF) supports and infiltrated with molten carbonate (Li2CO3/Na2CO3/K2CO3). The CO2 permeation mechanism involves a reaction between CO2 (gas phase) and O= (solid phase) to form CO3=, which is then transported through the molten carbonate (liquid phase) to achieve separation. The effects of membrane thickness, temperature and CO2 partial pressure were studied. Decreasing thickness from 3.0 to 0.375 mm led to higher fluxes at 900°C, ranging from 0.186 to 0.322 mL.min-1.cm-2 respectively. CO2 flux increased with temperature from 700 to 900°C. Activation energy for permeation was similar to that for oxygen ion conduction in LSCF. For partial pressures above 0.05 atm, the membrane exhibited a nearly constant flux. From these observations, it was determined that oxygen ion conductivity limits CO2 permeation and that the equilibrium oxygen vacancy concentration in LSCF is dependent on the partial pressure of CO2 in the gas phase. Finally, the dual-phase membrane was used as a membrane reactor. Separation at high temperatures can produce warm, highly concentrated streams of CO2 that could be used as a chemical feedstock for the synthesis of syngas (H2 + CO). Towards this, three different membrane reactor configurations were examined: 1) blank system, 2) LSCF catalyst and 3) 10% Ni/y-alumina catalyst. Performance increased in the order of blank system < LSCF catalyst < Ni/y-alumina catalyst. Favorable conditions for syngas production were high temperature (850°C), low sweep gas flow rate (10 mL.min-1) and high methane concentration (50%) using the Ni/y-alumina catalyst.
ContributorsAnderson, Matthew Brandon (Author) / Lin, Jerry (Thesis advisor) / Alford, Terry (Committee member) / Rege, Kaushal (Committee member) / Anderson, James (Committee member) / Rivera, Daniel (Committee member) / Arizona State University (Publisher)
Created2011
Description
Gold nanoparticles as potential diagnostic, therapeutic and sensing systems have a long history of use in medicine, and have expanded to a variety of applications. Gold nanoparticles are attractive in biological applications due to their unique optical, chemical and biological properties. Particularly, gold nanorods (GNRs) are increasingly used due to superior optical property in the near infrared (NIR) window. Light absorbed by the nanorod can be dissipated as heat efficiently or re-emitted by the particle. However, the limitations for clinical translation of gold nanorods include low yields, poor stability, depth-restricted imaging, and resistance of cancer cells to hyperthermia, are severe. A novel high-throughput synthesis method was employed to significantly increase in yields of solid and porous gold nanorods/wires. Stable functional nanoassemblies and nanomaterials were generated by interfacing gold nanorods with a variety of polymeric and polypeptide-based coatings, resulting in unique properties of polymer-gold nanorod assemblies and composites. Here the use of these modified gold nanorods in a variety of applications including optical sensors, cancer therapeutics, and nanobiomaterials were described.
ContributorsHuang, Huang-Chiao (Author) / Rege, Kaushal (Thesis advisor) / Sierks, Michael (Committee member) / Dai, Lenore (Committee member) / Ramakrishna, B (Committee member) / Vogt, Bryan (Committee member) / Arizona State University (Publisher)
Created2012
Description
Nanoparticles are ubiquitous in various fields due to their unique properties not seen in similar bulk materials. Among them, core-shell composite nanoparticles are an important class of materials which are attractive for their applications in catalysis, sensing, electromagnetic shielding, drug delivery, and environmental remediation. This dissertation focuses on the study of core-shell type of nanoparticles where a polymer serves as the core and inorganic nanoparticles are the shell. This is an interesting class of supramolecular building blocks and can "exhibit unusual, possibly unique, properties which cannot be obtained simply by co-mixing polymer and inorganic particles". The one-step Pickering emulsion polymerization method was successfully developed and applied to synthesize polystyrene-silica core-shell composite particles. Possible mechanisms of the Pickering emulsion polymerization were also explored. The silica nanoparticles were thermodynamically favorable to self-assemble at liquid-liquid interfaces at the initial stage of polymerization and remained at the interface to finally form the shells of the composite particles. More importantly, Pickering emulsion polymerization was employed to synthesize polystyrene/poly(N-isopropylacrylamide) (PNIPAAm)-silica core-shell nanoparticles with N-isopropylacrylamide incorporated into the core as a co-monomer. The composite nanoparticles were temperature sensitive and could be up-taken by human prostate cancer cells and demonstrated effectiveness in drug delivery and cancer therapy. Similarly, by incorporating poly-2-(N,N)-dimethylamino)ethyl methacrylate (PDMA) into the core, pH sensitive core-shell composite nanoparticles were synthesized and applied as effective carriers to release a rheological modifier upon a pH change. Finally, the research focuses on facile approaches to engineer the transition of the temperature-sensitive particles and develop composite core-shell nanoparticles with a metallic shell.
ContributorsSanyal, Sriya (Author) / Dai, Lenore L. (Thesis advisor) / Jiang, Hanqing (Committee member) / Lind, Mary L. (Committee member) / Phelan, Patrick (Committee member) / Rege, Kaushal (Committee member) / Arizona State University (Publisher)
Created2012
Description
This dissertation provides a fundamental understanding of the impact of bulk polymer properties on the nanometer length scale modulus. The elastic modulus of amorphous organic thin films is examined using a surface wrinkling technique. Potential correlations between thin film behavior and intrinsic properties such as flexibility and chain length are explored. Thermal properties, glass transition temperature (Tg) and the coefficient of thermal expansion, are examined along with the moduli of these thin films. It is found that the nanometer length scale behavior of flexible polymers correlates to its bulk Tg and not the polymers intrinsic size. It is also found that decreases in the modulus of ultrathin flexible films is not correlated with the observed Tg decrease in films of the same thickness. Techniques to circumvent reductions from bulk modulus were also demonstrated. However, as chain flexibility is reduced the modulus becomes thickness independent down to 10 nm. Similarly for this series minor reductions in Tg were obtained. To further understand the impact of the intrinsic size and processing conditions; this wrinkling instability was also utilized to determine the modulus of small organic electronic materials at various deposition conditions. Lastly, this wrinkling instability is exploited for development of poly furfuryl alcohol wrinkles. A two-step wrinkling process is developed via an acid catalyzed polymerization of a drop cast solution of furfuryl alcohol and photo acid generator. The ability to control the surface topology and tune the wrinkle wavelength with processing parameters such as substrate temperature and photo acid generator concentration is also demonstrated. Well-ordered linear, circular, and curvilinear patterns are also obtained by selective ultraviolet exposure and polymerization of the furfuryl alcohol film. As a carbon precursor a thorough understanding of this wrinkling instability can have applications in a wide variety of technologies.
ContributorsTorres, Jessica (Author) / Vogt, Bryan D (Thesis advisor) / Stafford, Christopher M (Committee member) / Richert, Ranko (Committee member) / Rege, Kaushal (Committee member) / Dai, Lenore (Committee member) / Arizona State University (Publisher)
Created2011
Description
Chromatin is the dynamic structure of proteins and nucleic acids into which eukaryotic genomes are organized. For those looking to engineer mammalian genomes, chromatin is both an opportunity and an obstacle. While chromatin provides another tool with which to control gene expression, regional density can lead to variability in genome editing efficiency by CRISPR/Cas9 systems. Many groups have attempted to de-silence chromatin to regulate genes and enhance DNA's accessibility to nucleases, but inconsistent results leave outstanding questions. Here, I test different types of activators, to analyze changes in chromatin features that result for chromatin opening, and to identify the critical biochemical features that support artificially generated open, transcriptionally active chromatin.
I designed, built, and tested a panel of synthetic pioneer factors (SPiFs) to open condensed, repressive chromatin with the aims of 1) activating repressed transgenes in mammalian cells and 2) reversing the inhibitory effects of closed chromatin on Cas9-endonuclease activity. Pioneer factors are unique in their ability to bind DNA in closed chromatin. In order to repurpose this natural function, I designed SPiFs from a Gal4 DNA binding domain, which has inherent pioneer functionality, fused with chromatin-modifying peptides with distinct functions.
SPiFs with transcriptional activation as their primary mechanism were able to reverse this repression and induced a stably active state. My work also revealed the active site from proto-oncogene MYB as a novel transgene activator. To determine if MYB could be used generally to restore transgene expression, I fused it to a deactivated Cas9 and targeted a silenced transgene in native heterochromatin. The resulting activator was able to reverse silencing and can be chemically controlled with a small molecule drug.
Other SPiFs in my panel did not increase gene expression. However, pretreatment with several of these expression-neutral SPiFs increased Cas9-mediated editing in closed chromatin, suggesting a crucial difference between chromatin that is accessible and that which contains genes being actively transcribed. Understanding this distinction will be vital to the engineering of stable transgenic cell lines for product production and disease modeling, as well as therapeutic applications such as restoring epigenetic order to misregulated disease cells.
I designed, built, and tested a panel of synthetic pioneer factors (SPiFs) to open condensed, repressive chromatin with the aims of 1) activating repressed transgenes in mammalian cells and 2) reversing the inhibitory effects of closed chromatin on Cas9-endonuclease activity. Pioneer factors are unique in their ability to bind DNA in closed chromatin. In order to repurpose this natural function, I designed SPiFs from a Gal4 DNA binding domain, which has inherent pioneer functionality, fused with chromatin-modifying peptides with distinct functions.
SPiFs with transcriptional activation as their primary mechanism were able to reverse this repression and induced a stably active state. My work also revealed the active site from proto-oncogene MYB as a novel transgene activator. To determine if MYB could be used generally to restore transgene expression, I fused it to a deactivated Cas9 and targeted a silenced transgene in native heterochromatin. The resulting activator was able to reverse silencing and can be chemically controlled with a small molecule drug.
Other SPiFs in my panel did not increase gene expression. However, pretreatment with several of these expression-neutral SPiFs increased Cas9-mediated editing in closed chromatin, suggesting a crucial difference between chromatin that is accessible and that which contains genes being actively transcribed. Understanding this distinction will be vital to the engineering of stable transgenic cell lines for product production and disease modeling, as well as therapeutic applications such as restoring epigenetic order to misregulated disease cells.
ContributorsBarrett, Cassandra M (Author) / Haynes, Karmella A (Thesis advisor) / Rege, Kaushal (Committee member) / Mills, Jeremy (Committee member) / Kiani, Samira (Committee member) / Arizona State University (Publisher)
Created2019