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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

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
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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

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
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Description
Many therapeutics administered for some of the most devastating illnesses can be toxic and result in unwanted side effects. Recent developments have been made in an alternative treatment method, called gene therapy. Gene therapy has potential to rectify the genetic defects that cause a broad range of diseases. Many diseases,

Many therapeutics administered for some of the most devastating illnesses can be toxic and result in unwanted side effects. Recent developments have been made in an alternative treatment method, called gene therapy. Gene therapy has potential to rectify the genetic defects that cause a broad range of diseases. Many diseases, such as cancer, cystic fibrosis, and acquired immunodeficiency (AIDS) already have gene therapy protocols that are currently in clinical trials. Finding a non-toxic and efficient gene transfer method has been a challenge. Viral vectors are effective at transgene delivery however potential for insertion mutagenesis and activation of immune responses raises concern. For this reason, non-viral vectors have been investigated as a safer alternative to viral-mediated gene delivery. Non-viral vectors are also easy to prepare and scalable, but are limited by low transgene delivery efficacies and high cytotoxicity at effective therapeutic dosages. Thus, there is a need for a non-toxic non-viral vector with high transgene efficacies. In addition to the hurdles in finding a material for gene delivery, large-scale production of pharmaceutical grade DNA for gene therapy is needed. Current methods can be labor intensive, time consuming, and use toxic chemicals. For this reason, an efficient and safe method to collect DNA is needed. One material that is currently being explored is the hydrogel. Hydrogels are a useful subclass of biomaterials, with a wide variety of applications. This class of biomaterials can carry up to a thousand times their weight in water, and are biocompatible. At smaller dimensions, referred to as micro- and nanogels, they are very useful for many biomedical applications because of their size and ability to swell. Based on a previously synthesized hydrogel, and due to the advantages of smaller dimension in biomedical applications, we have synthesized aminoglycoside antibiotic based nanogels and microgels. Microgels and nanogels were synthesized following a ring opening polymerization of epoxide-containing crosslinkers and polyamine-containing monomers. The nanogels were screened for their cytocompatibilities and transfection efficacies, and were compared to polyethylenimine (PEI), a current standard for polymer-mediated transgene delivery. Nanogels demonstrated minimal to no toxicity to the cell line used in the study even at high concentrations. Due to the emerging need for large-scale production of DNA, microgels were evaluated for their binding capacity to plasmid DNA. Future work with the aminoglycoside antibiotic-based nanogels and microgels developed in this study will involve optimization of nanogels and microgels to facilitate in better transgene delivery and plasmid DNA binding, respectively.
ContributorsMallik, Amrita Amy (Author) / Rege, Kaushal (Thesis advisor) / Dai, Lennore (Committee member) / Nielsen, David (Committee member) / Arizona State University (Publisher)
Created2014
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Description
Gold nanoparticles have emerged as promising nanomaterials for biosensing, imaging, photothermal treatment and therapeutic delivery for several diseases, including cancer. We have generated poly(amino ether)-functionalized gold nanorods (PAE-GNRs) using a layer-by-layer deposition approach. Sub-toxic concentrations of PAE-GNRs were employed to deliver plasmid DNA to prostate cancer cells in vitro. PAE-GNRs

Gold nanoparticles have emerged as promising nanomaterials for biosensing, imaging, photothermal treatment and therapeutic delivery for several diseases, including cancer. We have generated poly(amino ether)-functionalized gold nanorods (PAE-GNRs) using a layer-by-layer deposition approach. Sub-toxic concentrations of PAE-GNRs were employed to deliver plasmid DNA to prostate cancer cells in vitro. PAE-GNRs generated using 1,4C-1,4Bis, a cationic polymer from our laboratory demonstrated significantly higher transgene expression and exhibited lower cytotoxicities when compared to similar assemblies generated using 25 kDa poly(ethylene imine) (PEI25k-GNRs), a current standard for polymer-mediated gene delivery. Additionally, sub-toxic concentrations of 1,4C-1,4Bis-GNR nanoassemblies were employed to deliver expression vectors that express shRNA ('shRNA plasmid') against firefly luciferase gene in order to knock down expression of the protein constitutively expressed in prostate cancer cells. The roles of poly(amino ether) chemistry and zeta-potential in determining transgene expression efficacies of PAE-GNR assemblies were investigated. The theranostic potential of 1,4C-1,4Bis-GNR nanoassemblies was demonstrated using live cell two-photon induced luminescence bioimaging. The PAE class of polymers was also investigated for the one pot synthesis of both gold and silver nanoparticles using a small library poly(amino ethers) derived from linear-like polyamines. Efficient nanoparticle synthesis dependent on concentration of polymers as well as polymer chemical composition is demonstrated. Additionally, the application of poly(amino ether)-gold nanoparticles for transgene delivery is demonstrated in 22Rv1 and MB49 cancer cell lines. Base polymer, 1,4C-1,4Bis and 1,4C-1,4Bis templated and modified gold nanoparticles were compared for transgene delivery efficacies. Differences in morphology and physiochemical properties were investigated as they relate to differences in transgene delivery efficacy. There were found to be minimal differences suggestion that 1,4C-1,4Bis efficacy is not lost following use for nanoparticle modification. These results indicate that poly(amino ether)-gold nanoassemblies are a promising theranostic platform for delivery of therapeutic payloads capable of simultaneous gene silencing and bioimaging.
ContributorsRamos, James (Author) / Rege, Kaushal (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Caplan, Michael (Committee member) / Vernon, Brent (Committee member) / Garcia, Antonio (Committee member) / Arizona State University (Publisher)
Created2014
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Description
This research reports on the investigation into the synthesis and stabilization of

iron oxide nanoparticles for theranostic applications using amine-epoxide polymers. Although theranostic agents such as magnetic nanoparticles have been designed and developed for a few decades, there is still more work that needs to be done with the type of

This research reports on the investigation into the synthesis and stabilization of

iron oxide nanoparticles for theranostic applications using amine-epoxide polymers. Although theranostic agents such as magnetic nanoparticles have been designed and developed for a few decades, there is still more work that needs to be done with the type of materials that can be used to stabilize or functionalize these particles if they are to be used for applications such as drug delivery, imaging and hyperthermia. For in-vivo applications, it is crucial that organic coatings enclose the nanoparticles in order to prevent aggregation and facilitate efficient removal from the body as well as protect the body from toxic material.

The objective of this thesis is to design polymer coated magnetite nanoparticles with polymers that are biocompatible and can stabilize the iron oxide nanoparticle to help create mono-dispersed particles in solution. It is desirable to also have these nanoparticles possess high magnetic susceptibility in response to an applied magnetic field. The co- precipitation method was selected because it is probably the simplest and most efficient chemical pathway to obtain magnetic nanoparticles.

In literature, cationic polymers such as Polyethylenimine (PEI), which is the industry standard, have been used to stabilize IONPs because they can be used in magnetofections to deliver DNA or RNA. PEI however is known to interact very strongly with proteins and is cytotoxic, so as mentioned previously the Iron Oxide nanoparticles

i

(IONPs) synthesized in this study were stabilized with amine-epoxide polymers because of the limitations of PEI.

Four different amine-epoxide polymers which have good water solubility, biodegradability and less toxic than PEI were synthesized and used in the synthesis and stabilization of the magnetic nanoparticles and compared to PEI templated IONPs. These polymer-templated magnetic nanoparticles were also characterized by size, surface charge, Iron oxide content (ICP analysis) and superconducting quantum interference devices (SQUID) analysis to determine the magnetization values. TEM images were also used to determine the shape and size of the nanoparticles. All this was done in an effort to choose two or three leads that could be used in future work for magnetofections or drug delivery research.
ContributorsTamakloe, Beatrice (Author) / Rege, Kaushal (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Chang, John (Committee member) / Arizona State University (Publisher)
Created2014
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Description
Biological membranes are critical to cell sustainability by selectively permeating polar molecules into the intracellular space and providing protection to the interior organelles. Biomimetic membranes (model cell membranes) are often used to fundamentally study the lipid bilayer backbone structure of the biological membrane. Lipid bilayer membranes are often supported using

Biological membranes are critical to cell sustainability by selectively permeating polar molecules into the intracellular space and providing protection to the interior organelles. Biomimetic membranes (model cell membranes) are often used to fundamentally study the lipid bilayer backbone structure of the biological membrane. Lipid bilayer membranes are often supported using inorganic materials in an effort to improve membrane stability and for application to novel biosensing platforms. Published literature has shown that a variety of dense inorganic materials with various surface properties have been investigated for the study of biomimetic membranes. However, literature does not adequately address the effect of porous materials or supports with varying macroscopic geometries on lipid bilayer membrane behavior. The objective of this dissertation is to present a fundamental study on the synthesis of lipid bilayer membranes supported by novel inorganic supports in an effort to expand the number of available supports for biosensing technology. There are two fundamental areas covered including: (1) synthesis of lipid bilayer membranes on porous inorganic materials and (2) synthesis and characterization of cylindrically supported lipid bilayer membranes. The lipid bilayer membrane formation behavior on various porous supports was studied via direct mass adsorption using a quartz crystal microbalance. Experimental results demonstrate significantly different membrane formation behaviors on the porous inorganic supports. A lipid bilayer membrane structure was formed only on SiO2 based surfaces (dense SiO2 and silicalite, basic conditions) and gamma-alumina (acidic conditions). Vesicle monolayer adsorption was observed on gamma-alumina (basic conditions), and yttria stabilized zirconia (YSZ) of varying roughness. Parameters such as buffer pH, surface chemistry and surface roughness were found to have a significant impact on the vesicle adsorption kinetics. Experimental and modeling work was conducted to study formation and characterization of cylindrically supported lipid bilayer membranes. A novel sensing technique (long-period fiber grating refractometry) was utilized to measure the formation mechanism of lipid bilayer membranes on an optical fiber. It was found that the membrane formation kinetics on the fiber was similar to its planar SiO2 counterpart. Fluorescence measurements verified membrane transport behavior and found that characterization artifacts affected the measured transport behavior.
ContributorsEggen, Carrie (Author) / Lin, Jerry Y.S. (Thesis advisor) / Dai, Lenore (Committee member) / Rege, Kaushal (Committee member) / Thornton, Trevor (Committee member) / Vogt, Bryan (Committee member) / Arizona State University (Publisher)
Created2011
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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

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
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Description
The effects of specific histone deacetylase inhibitors (HDACi) on transgene expression in combination with a novel polymer as a delivery vehicle are investigated in this research. Polymer vectors, although safer than viruses, are notorious for low levels of gene expression. In this investigation, the use of an emerging chemotherapeutic anti-cancer

The effects of specific histone deacetylase inhibitors (HDACi) on transgene expression in combination with a novel polymer as a delivery vehicle are investigated in this research. Polymer vectors, although safer than viruses, are notorious for low levels of gene expression. In this investigation, the use of an emerging chemotherapeutic anti-cancer drug molecule, HDACi, was used to enhance the polymer-mediated gene expression. HDACi are capable of inhibiting deacetylation activities of histones and other non-histone proteins in the cytoplasm and nucleus, as well as increase transcriptional activities necessary for gene expression. In a prior study, a parallel synthesis and screening of polymers yielded a lead cationic polymer with high DNA-binding properties, and even more attractive, high transgene expressions. Previous studies showed the use of this polymer in conjunction with cytoplasmic HDACi significantly enhanced gene expression in PC3-PSMA prostate cancer cells. This led to the basis for the investigation presented in this thesis, but to use nuclear HDACi to potentially achieve similar results. The HDACi, HDACi_A, was a previously discovered lead drug that had potential to significantly enhance luciferase expression in PC3-PSMA cells. The results of this study found that the 20:1 polymer:plasmid DNA weight ratio was effective with 1 uM and 2 uM HDACI_A concentrations, showing up to a 9-fold enhancement. This enhancement suggested that HDACi_A was effectively aiding transfection. While not an astounding enhancement, it is still interesting enough to investigate further. Cell viabilities need to be determined to supplement the results.
ContributorsLehrman, Jennifer (Author) / Rege, Kaushal (Thesis advisor) / Caplan, Michael (Committee member) / Pizziconi, Vincent (Committee member) / Arizona State University (Publisher)
Created2012
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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

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
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Description
Environmentally responsive microgels have drawn significant attention due to their intrinsic ability to change volume in response to various external stimuli such as pH, temperature, osmotic pressure, or electric and magnetic fields. The extent of particle swelling is controlled by the nature of the polymer-solvent interaction. This thesis focuses on

Environmentally responsive microgels have drawn significant attention due to their intrinsic ability to change volume in response to various external stimuli such as pH, temperature, osmotic pressure, or electric and magnetic fields. The extent of particle swelling is controlled by the nature of the polymer-solvent interaction. This thesis focuses on design and synthesis of environmentally responsive microgels and their composites, and encompasses methods of utilizing microgel systems in applications as vehicles for the adsorption, retention, and targeted delivery of chemical species. Furthermore, self-assembled microgel particles at ionic liquid (IL)-water interfaces demonstrate responsive colloidal lattice morphology. The thesis first reports on the fundamental aspects of synthesis, functionalization, and characteristic properties of multifunctional environmentally responsive microgels derived from poly(N-isopropylacrylamide) (PNIPAm) and other functional co-monomers. In particular, the uptake and release of active chemical species such as rheology modifiers into and from these ionic microgels is demonstrated. Moreover, a facile tunable method for the formation of organic-inorganic composites with Fe3O4 nanoparticles adsorbed and embedded within ionic microgel particles is explored. Additionally, the development of zwitterionic microgels (ZI-MG) is presented. These aqueous ZI-MG dispersions exhibit reversible parabolic swelling as a function of pH and display a minimum hydrodynamic diameter at a tunable isoelectric point (IEP). This study also elucidates the controlled uptake and release of surfactants from these particle systems. The extent of surfactant loading and the ensuing relative swelling/deswelling behaviors within the polymer networks are explained in terms of their binding interactions. The latter part of this thesis highlights the versatility of fluorescently labeled microgel particles as stabilizers for IL-water droplets. When the prepared particles form monolayers and equilibrate at the liquid-liquid interface, the colloidal lattice organization may re-order itself depending on the surface charge of these particles. Finally, it is shown that the spontaneously formed and densely packed layers of microgel particles can be employed for extraction applications, as the interface remains permeable to small active species.
ContributorsChen, Haobo (Author) / Dai, Lenore L (Committee member) / Chen, Kangping (Committee member) / Forzani, Erica (Committee member) / Lind, Mary Laura (Committee member) / Mu, Bin (Committee member) / Arizona State University (Publisher)
Created2015