Gold Nanoparticle-Aided Radiation Therapy (GNRT) is a new paradigm in radiation therapy which seeks to make a tumor more susceptible to radiation damage by modifying its photon interaction properties with an infusion of a high-atomic-number substance. The purpose of this study was to quantify the energy deposition due to secondary electrons from gold nanoparticles on a micrometer scale and to calculate the corresponding microscopic dose enhancement factor during GNRT. The Monte Carlo code EGSnrc was modified to obtain the spectra of secondary electrons from atoms of gold and molecules of water under photon irradiation of a tumor infused with 0.7 wt. % gold. Six different photon sources were used: 125I, 103Pd, 169Yb, 192Ir, 50kVp, and 6MV x-rays. Treating the scored electron spectra as point sources within an infinite medium of water, the event-by-event Monte Carlo code NOREC was used to quantify the radial dose distribution, giving rise to gold and water electron dose point kernels. These kernels were applied to a scanning electron microscope (SEM) image of a gold nanoparticle distribution in tissue. The dose at each point was then calculated, enabling the determination of the microscopic dose enhancement at each point. For the lower energy sources 125I, 103Pd, 169Yb, and 50 kVp, the secondary electron fluence was increased by as much as two orders of magnitude, leading to a one-to-two order of magnitude increase in the electron dose point kernel over radial distances up to 50 um. The dose was enhanced by 100% within 5 um of the nanoparticles, and by 5% as far away as 30 um. This study demonstrates a remarkable microscopic dose enhancement due to gold nanoparticles and low energy photon sources. Given that the dose enhancement exceeds 100% within very short distances from the nanoparticles, the maximum radiobiological benefit may be derived from active targeting strategies that concentrate nanoparticles in close proximity to the cancer cell and/or its nucleus.

Controlling catalyst morphology and composition are required to make meaningful structure-activity/stability relationships for the design of future catalysts. Herein, we have employed strategies of presynthesis and infusion or electroless deposition to achieve exquisite control over catalyst composite morphology. The oxygen reduction (ORR) and the oxygen evolution reactions (OER) were chosen as model systems, as their slow kinetics is a major limiting factor preventing the commercialization of fuel cells and rechargeable metal air batteries. In acid, bimetallic (Pt-Cu, Pd-Pt) and monometallic (Pt) catalysts were presynthesized in the presence of capping ligands. Well alloyed Pt-Cu nanoparticles (3-5 nm) adsorbed on graphitic mesoporous carbon (GMC) displayed an ORR activity >4x that of commercial Pt. For both presynthesized Pt and Pt-Cu nanocrystals on GMC, no activity loss was also observed during degradation cycling due to strong metal-support interactions and the oxidation resistance of graphitic carbon. Similar strong metal-support interactions were achieved on non-graphitic carbon for Pd3Pt2 (<4 nm) nanoparticles due to disorder in the metal surface This led to enhanced mass activity 1.8x versus pure Pt, as well as improved stability. For basic electrolytes, we developed an electroless co-deposition scheme to deposit Ag (3 nm) next to MnOx nanodomains on carbon. We achieved a mass activity for Ag-MnOx/VC, 3x beyond the linear combination of pure component activities due to ensemble effects, where Ag and MnOx domains catalyze different ORR steps, and ligand effects from the unique electronic interaction at the Ag-MnOx interface. Activity synergy was also shown for Ag-Pd alloys (~5 nm), achieving up to 5x activity on a Pd basis, resulting from the unique alloy surface of single Pd atoms surrounded by Ag. Lastly, we combined arrested growth of amorphous nanoparticles with thin film freezing to create a high surface area, pure phase perovskite aggregate of nanoparticles after calcination. Sintering was mitigated during the high temperature calcination required to form the perovskite crystals. The high surface areas and phase purity led to OER mass activities ~2.5x higher than the benchmark IrO2 catalyst. / text

The efficiency of one fluid displacing another in permeable media depends greatly on the pore-scale dynamics at the main wetting front. Experiments have shown that the frontal dynamics can result in two different flow regimes: a stable and an unstable front. In stable displacements, any perturbation of the front will diminish with time and the effect of variation in permeability will be lessened. In contrast, in unstable displacements any perturbation of the front will grow with time and any variation in permeability will be magnified. In this dissertation, the stability of two different displacement processes are contemplated; a) vertical infiltration of dense liquid into dry sand from above and b) horizontal displacement of nanoparticle suspension with high pressure liquid CO₂. Significant insights are obtained by measuring the in-situ flow patterns in real time with a light transmission method and CT scanning. Vertical infiltration of dense fluid into dry sands from above is often observed to be unstable and produce gravity driven fingers. The formation of gravity fingers can have large consequences on the sweep efficiency of a displacement. Infiltration experiments showed that gravity driven fingers have a unique saturation profile known as saturation overshoot with a higher saturation at the finger tips than the saturation at the finger tail. Despite the vast number of theoretical and experimental investigations, conditions under which the front is unstable, remain unclear. To determine what controls the saturation overshoot and how it relates to the dynamics at the initial wetting front, saturation overshoot was measured as a function of flux for seven different liquids. These liquids gave a range of molecular weights, viscosities, and vapor pressures. It is found that for each fluid there is a flux (called overshoot flux) below which saturation overshoot ceases and the front is diffuse. The magnitude of the overshoot flux depends inversely on the invading fluid's viscosity and shows little or no dependence on the invading fluid's surface tension, vapor pressure, or miscibility with water. Since the saturation overshoot is not described by the continuum multi-phase flow models, the experimental results are used to develop a semi-continuum model that bridges the continuum-scale and pore-scale physics. The proposed model predicts the observed dependence of overshoot on media permeability and invading fluid properties. At the planned depth for CO₂ injection, either as an enhanced oil recovery technique or for CO₂ storage, CO₂ is typically less dense and less viscous than the in-situ fluid. Therefore, CO₂ injection is unstable and produces viscous fingers. This can greatly reduce the efficiency of a CO₂ flood or CO₂ storage capacity of an aquifer. To remedy this behavior, surface treated nanoparticles were used to reduce the mobility of injected CO₂. Displacement experiments were performed at low pressure with a CO₂ analogue (n-octane) fluid and at high pressure with liquid CO₂. Saturation distributions and pressure drops were measured in real time with the CT scanner when high pressure liquid CO₂ or n-octane was used to displace brine in different cores with and without suspended nanoparticles. In the presence of nanoparticles, the displacement front is more spatially uniform with a later breakthrough compared to the same experiment with no suspended nanoparticles. These observations suggest that nanoparticle stabilized foam, which forms during the displacement, acts to suppress the instability. It is argued that the generation of droplets occurs at the leading front of all drainage displacements. In the presence of nanoparticles, these droplets are preserved when nanoparticle adhere at the fluid-fluid interface. The new mechanism for foam generation described here, provides an interesting alternative for mobility control in CO₂ floods. Moreover, the same mechanism can potentially a) increase the CO₂ storage capacity of an aquifer, b) enhance the CO₂ capillary trapping, and c) provide an engineered barrier to CO₂ leakage from a storage sites, thereby alleviating the risk of contaminating the overlying fresh groundwater resources for CO₂ storage projects. / text

Polycationic nanoparticles were synthesized with an activators regenerated by electron transfer for atom transfer radical polymerization-based (ARGET ATRP-based) emulsion in water method and investigated for their utility as biomaterials for drug delivery. The polycationic nanoparticles were composed of 2-(diethylamino)ethyl methacrylate (DEAEMA) for pH-responsiveness, poly(ethylene glycol) methyl ether methacrylate (PEGMA) for improved biocompatibility, tert-butyl methacrylate (tBMA) to impart hydrophobicity, and a tetraethylene glycol dimethacrylate (TEGDMA) cross-linking agent for enhanced colloidal stability. Dynamic light scattering demonstrated pH-responsive swelling, and cell-based assays demonstrated pH-dependent membrane disruption. The polycationic nanoparticles demonstrated low toxicity to cells. The polycationic nanoparticles were evaluated for use as drug delivery biomaterials by investigating the interactions with the drug and cells. Delivery remains a major challenge for translating small interfering RNA (siRNA) to the clinic, and overcoming the delivery challenge requires effective siRNA delivery vehicles. The polycationic nanoparticles demonstrated efficient siRNA loading. Evidence of siRNA-induced knockdown in cells was observed following transfection with the polycationic nanoparticle/siRNA complexes. Imaging techniques confirmed enhanced siRNA internalization using the polycationic nanoparticle/siRNA complexes compared to naked siRNA. An array of polycationic nanoparticles synthesized using ARGET ATRP or UV-initiated polymerization methods was characterized to examine the effect of polymerization method on material properties and the connection to molecular structure. An improved understanding of molecular structure, and its connection to polymerization method and material characteristics, may aid the design of advanced materials. The ARGET ATRP polycationic nanoparticles demonstrated increased nanoscale homogeneity compared to the UV-initiated polymerization polycationic nanoparticles; increased nanoscale heterogeneity in the UV-initiated polymerization polycationic nanoparticles was associated with broader transitions. The polycationic nanoparticles promoted cellular uptake of siRNA and induced knockdown, thus demonstrating potential as siRNA delivery vehicles. The ARGET ATRP method provides an alternative route to creating polycationic nanoparticles with improved nanoscale homogeneity. / text

Magnetic and plasmonic properties combined in a single nanostructure provide a synergy that is advantageous in a number of biomedical applications, such as contrast enhancement in multimodal imaging, simultaneous capture and detection of circulating tumor cells, and photothermal therapy of cancer. These applications have stimulated significant interest in development of magneto-plasmonic nanoparticles with optical absorbance in the near-infrared region and a strong magnetic moment. In this dissertation, we addressed this need to create a novel immunotargeted magneto-plasmonic nanoparticle platform. The nanostructures were synthetized by self-assembly of primary 6 nm iron oxide core-gold shell particles, resulting in densely packed spherical nanoclusters. The close proximity of the primary particles in the nanoclusters generates a greatly improved response to an external magnetic field and strong near-infrared plasmon resonances. A procedure for antibody conjugation and PEGylation to the hybrid nanoparticles was developed for biomedical applications which require molecular and biocompatible targeting. Furthermore, we presented two biomedical applications based on the immunotargeted hybrid nanoparticle platform, including circulating tumor cell (CTC) detection and cell-based immunotherapy of cancer. In the CTC detection assays, rare cancer cells were specifically targeted by antibody-conjugated nanoparticles and efficiently separated from normal blood cells by a magnetic force in a microfluidic chamber. The experiments in whole blood showed capture efficiency greater than 90% for a variety of cancers. We also explored photoacoustic imaging to detect nanoparticle-labeled CTCs in whole blood. The results showed excellent sensitivity to delineate the distribution of hybrid nanoparticles on the cancer cells. Thus, these works paves the way for a novel CTC detection approach which utilizes immunotargeted magneto-plasmonic nanoclusters for a simultaneous magnetic capture and photoacoustic detection of CTCs. In another application, we introduced a novel approach to label cytotoxic T cells using the magnetic nanoparticles with an expectation to enhance T cell recruitment in tumor under external magnetic stimulus. A series of in vitro experiments demonstrated highly controllable manipulation of labeled T cells. Thus, these results highlight the promise of using our nanoparticle platform as a multifunctional probe to manipulate and track immune cells in vivo and further improve the efficacy of cell-based cancer immunotherapy. / text

N-Thiolated B-lactams represent a novel family of antibacterial agents, whose in vitro activity is confined largely to Staphylococcus species, including multidrug-resistant forms of S. aureus. N-Thiolated B-lactams have recently been shown to possess intriguing biological activities which are addressed in Chapter II. Current development of nanoparticles as a new drug delivery vehicle is described in Chapter III. Chapter IV and V described the current research in our laboratories focusing on the synthesis and characterization of emulsified polyacrylate/polyacrylamide nanoparticle antibacterials for drug delivery of water-insoluble antibiotics. These nanoparticles can be prepared in aqueous media directly from acrylate/acrylamide monomers through free radical microemulsion polymerization. These emulsions contain antibiotic-conjugated polyacrylate nanospheres measuring 30-60 nm in diameter and have enhanced antibacterial activity against drug resistant S. aureus (MRSA) through what we believe is a novel mechanism.

<p>Cancer is currently the second leading cause of death in the United States. Although many treatment options exist, some of the most common, including radiotherapy and chemotherapy, are restricted by dose-limiting toxicities. In addition, the largest hurdle for translating novel biological therapies such as siRNA into the clinic is lack of an efficient delivery mechanism to get the therapeutic into malignant cells. This work aims to improve this situation by engineering a minimally invasive controlled release system that specifically delivers therapeutics to the site of malignant tissue. This platform consists of two novel material components: a thermally responsive poly[N-isopropylacrylamide-co-acrylamide] (NIPAAm-co-AAm) hydrogel and gold-silica nanoshells. Therapeutic molecules are encapsulated within a poly(NIPAAm-co-AAm) hydrogel carrier, leading to increased serum stability, circulation time, and decreased exposure to off-site tissues. Additionally, gold-silica nanoshells embedded within this hydrogel will be used to optically trigger therapeutic release from the carrier. This hydrogel-nanoshell composite material was designed to be swollen under physiologic conditions (37 oC), and expel large amounts of water and absorbed molecules at higher temperatures (40-45 oC). This phase transition can be optically triggered by embedded gold-silica nanoshells, which rapidly transfer near-infrared (NIR) light energy into heat due to the surface plasmon resonance phenomena. NIR light can deeply penetrate biological tissue with little attenuation or damage to tissue, and upon exposure to such light a rapid temperature increase, hydrogel collapse, and drug expulsion will occur. Ultimately, these drug-loaded hydrogel-nanoshell composite particles would be injected intravenously, passively accumulate in tumor tissue due to the enhanced permeability and retention (EPR) effect, and then can be externally triggered to release their therapeutic payload by exposure to an external NIR laser. This dissertation describes the synthesis, characterization, and validation of such a controlled therapeutic delivery platform.</p><p>Initial validation of poly(NIPAAm-co-AAm)-gold nanoshell composites to act as a material in site-specific cancer therapeutic delivery was accomplished using bulk hydrogel-nanoparticle composite disks. The composite material underwent a phase transition from a hydrated to a collapsed state following exposure to NIR light, indicating the ability of the NIR absorption by the nanoshells to sufficiently drive this transition. The composite material was loaded with either doxorubicin or a DNA duplex (a model nucleic acid therapeutic), two cancer therapeutics with differing physical and chemical properties. Release of both therapeutics was dramatically enhanced by NIR light exposure, causing 2-5 fold increase in drug release. Drug delivery profiles were influenced by both the molecular size of the drug as well as its chemical properties. </p><p>Towards translation of this material into in vivo applications, the hydrogel-nanoshell composite material was synthesized as injectable-sized particles. Such particles retained the same thermal properties as the bulk material, collapsing in size from ~330 nm to ~270 nm upon NIR exposure. Furthermore, these particles were loaded with the chemotherapeutic doxorubicin and NIR exposure triggered a burst release of the drug payload over only 3 min. In vitro, this platform provided increased delivery of doxorubicin to colon carcinoma cells compared to free-drug controls, indicating the irradiated nanoshells may increase cell membrane permeability and increase cellular uptake of the drug. This phenomena was further explored to enhance cellular uptake of siRNA, a large anionic therapeutic which cannot diffuse into cells easily. </p><p>This work advances the development of an injectable, optically-triggered delivery platform. With continued optimization and in vivo validation, this approach may offer an novel treatment option for cancer management.</p> / Dissertation

An outstanding challenge in modern medicine is the safe and efficient delivery of drugs. One approach to improve drug delivery yield and increase specificity towards diseased cells, is to employ a drug carrier to facilitate transport. Promising steps towards developing such a carrier have been taken by the nascent field of nanomedicine: nanometer-sized particles designed to evade premature excretion, non-specific absorption, and the body’s immune response, can reduce undesired drug loss, while also increasing specific drug uptake into diseased cells through targeting surface modifications. However, progress is limited by incomplete knowledge of the ‘ideal’ nanoparticle design as well as a lack of appropriate high resolution construction methods for its implementation. DNA origami, a modular, nanometer-precise assembly method that would enable the rapid testing of particle properties as well as massively parallel fabrication, could provide an avenue to address these needs. In this thesis, I employed the DNA origami method to investigate how nanoscale shape and ligand functionalization affect nanoparticle uptake into cultured endothelial cells. In the first part, I evaluated the uptake yield of a series of eight shapes that ranged from 7.5 nm to 400 nm in their individual dimensions. The best performing shape of that study, a 15 × 100 nm DNA origami nanocylinder, was internalized 18-fold better than a dsDNA control of the same molecular weight. In a follow up study, I decorated this nanocylinder with integrin-targeting cyclic RGD peptides. This surface functionalization increased cellular uptake another 13-fold. In addition, uptake yield and the ratio of internalized versus surface-bound particles depended on the number of ligands present on the nanoparticle surface. This work represents a significant first step towards attaining the ability to design and implement an 'ideal' nanoparticle drug carrier. In the future, the DNA origami method can be used as a platform technology to further expand our understanding of transport properties of drug carriers and achieve safer and more efficient drug delivery.

This thesis describes the development of hyperpolarized silicon particles as a new type of magnetic resonance imaging (MRI) agent. Silicon particles are inexpensive, non-toxic, biodegradable, targetable, and have unique physical properties that lead to extremely long nuclear polarization times. The \(^{29}Si\) nuclei are hyperpolarized by low temperature dynamic nuclear polarization using naturally occurring defects at the particle surface and directly imaged using \(^{29}Si\) MRI. The imaging window achievable is several orders of magnitude longer than other hyperpolarized imaging agents. The technique requires no additional imaging agent to be incorporated into the silicon, and so toxicity complications are reduced. The construction of a system for low temperature dynamic nuclear polarization and a NMR spectrometer for studying the nuclear polarization dynamics in silicon particles is described. Room temperature nuclear spin relaxation \((T_1)\) times are investigated for a variety of silicon particles spanning five orders of magnitude in mean diameter, from 10nm nanoparticles to mm-scale granules. The nuclear \(T_1\) times of all Si particles are found to be long, ranging from many minutes to several hours at room temperature. \(T_1\) is found to be a function of particle size, dopant concentration, synthesis method and crystallinity. A core-shell model to describe the electron and nuclear spin dynamics in the particles is developed. The decay in nuclear hyperpolarization is studied as a function of ambient magnetic field and temperature, demonstrating that the long spin relaxation times persist despite changing environmental conditions. A new technique is reported for enhancing the dynamic nuclear polarization in silicon particles using modulated microwave irradiation. A theoretical model for understanding this enhanced polarization process is developed. As well as providing an efficient mechanism for polarizing the \(^{29}Si\) nuclei within the particle, the surface defects are also found to be efficient at polarizing \(^1H\) nuclei in frozen solutions surrounding the particles. Several in-vivo applications of hyperpolarized \(^{29}Si\) MRI are demonstrated, including gastrointestinal imaging, intravenous imaging and mapping blood flow in a tumor. The spin relaxation rates are found to be unaffected by surface functionalization, the particles tumbling in solution, or the in-vivo environment. / Engineering and Applied Sciences

The ability of surface-treated silica nanoparticles to stabilize oil/water emulsions presents us with many interesting avenues of study. The goal of this research is to assess the ability of a dispersion of specially surface-treated nanoparticles to stabilize an oil/water emulsion of prescribed internal structure created by flow within a fracture. We hypothesize that for a set of conditions (nanoparticle concentration, salinity, aqueous to organic phase ratio) a critical shear rate exists. That is, for flow rates that exceed this critical shear rate, an emulsion can be created. Flow experiments were conducted within fractured Boise sandstone and cement cylinders. The Boise sandstone core (D = 1 in and L = 12 in) was cut down its length and propped open to a specific aperture with beads. The fracture was saturated with dodecane then displaced with nanoparticle dispersion, and vice versa while pressure drop across the fracture was recorded. Class H cement cylinders (D = 1 in and L = 3 in) were allowed to set, then failed in compression to create a rough-walled fracture along their length. These fractured cement cylinders were then sealed and encased in epoxy to isolate the fractures. CT scans of the encased fractures were used to determine the aperture width, which is utilized when calculating the shear rate inside of the fracture maintained during an experiment. A dispersion of surface-modified silica nanoparticles and decane were coinjected into both the Boise sandstone and cement fractures and the pressure drop was measured across the fractures at a variety of shear rates. The effluent of each experiment was collected in sample tubes. Observation of the effluent and pressure drop data both support our hypothesis of emulsion generation being possible once a critical shear rate has been reached. Alteration of the injected phase ratio and increased residence time of the two phases inside of a fracture both affect the amount of emulsification occurring within the fractures. Increasing the residence time of both phases within a fracture allows for more opportunities for emulsification to occur, resulting in a greater amount of emulsion to be generated. Injection of high or low volumetric ratios of nanoparticle dispersion to organic phase results in little amounts of emulsion generation; however, between the nanoparticle dispersion to organic phase ratios of 0.25:1 and 2:1 significant amounts of emulsion are generated. / text