Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer with an average survival time of 15 months. GBM is considered incurable with even the most aggressive multimodal therapies and is characterized by near universal recurrence. Irreversible electroporation (IRE) is a cellular ablation method currently being investigated as a therapy for a variety of cancers. Application of IRE involves insertion of electrodes into tissue to deliver pulsed electric fields (PEFs), which destabilize the cell membrane past the point of recovery, thereby inducing cell death. While this treatment modality has numerous advantages, the lack of selectivity for malignant cells limits its application in the brain where damage to healthy tissue is especially deleterious. In this dissertation we hypothesize that a form of IRE therapy, high-frequency IRE (H-FIRE), may be able to act as a selective targeted therapy for GBM due to its ability to create an electric field inside a cell to interact with altered inner organelles. Through a comprehensive investigation involving experimental testing combined with numerical modeling, we have attained results in strong support of this hypothesis. Using tissue engineered hydrogels as our platform for therapy testing, we demonstrate selective ablation of GBM cells. We develop mathematical models that predict the majority of the electric field produced by H-FIRE pulses reach the inside of the cell. We demonstrate that the increased nuclear to cytoplasm ratio (NCR) of malignant GBM cells compared to healthy brain—evidenced in vivo and in in vitro tissue mimics—is correlated with greater ablation volumes and thus lower electric field thresholds for cell death when treated with H-FIRE. We enhance the selectivity achieved with H-FIRE using a molecularly targeted drug that induces an increase in NCR. We tune the treatment pulse parameters to increase selective malignant cell killing. Finally, we demonstrate the ability of H-FIRE to ablate therapy-resistant GBM cells which are a focus of many next-generation GBM therapies. We believe the evidence presented in this dissertation represents the beginning stages in the development of H-FIRE as a selective therapy to be used for treatment of human brain cancer. / Ph. D. / Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer with an average survival time of 15 months. GBM is considered incurable with even the most aggressive multimodal therapies and is characterized by near universal recurrence. Irreversible electroporation (IRE) is a therapy currently being developed for the treatment of a variety of cancers. Application of IRE involves the delivery of energy directly into the tumor tissue in the form of pulsed electric fields (PEFs). These PEFs destabilize the cell membrane past the point of recovery, thereby inducing cell death. Though this treatment modality has numerous advantages, the lack of selectivity for malignant cells limits its application in the brain where damage to healthy tissue is especially deleterious. In this dissertation we hypothesize that a form of IRE therapy, high-frequency IRE (H-FIRE), may be able to act as a selective targeted therapy for GBM due to its ability to create electric fields inside cells. Because cancer is characterized by alterations in inner organelles compared to healthy cells, electric fields inside the cell may be able to target these alterations resulting in selective malignant cell killing. Through a comprehensive investigation involving experimental testing combined with numerical modeling, we have attained results in strong support of this hypothesis. We have successfully demonstrated selective ablation of malignant GBM cells. We have shown that the increased nuclear to cytoplasm ratio (NCR) of malignant GBM cells compared to healthy brain—evidenced in vivo and in in vitro tissue mimics—is correlated with greater ablation volumes and thus lower electric field thresholds for cell death when treated with H-FIRE. We have enhanced the selectivity v achieved with H-FIRE using a molecularly targeted drug that induces an increase in NCR. We have tuned the treatment parameters to increase selective malignant cell killing. Finally, we have demonstrated the ability of H-FIRE to ablate therapy-resistant GBM cells which are a focus of many next-generation GBM therapies. We believe the evidence presented in this dissertation represents the beginning stages in the development of H-FIRE as a selective therapy to be used for treatment of human brain cancer.

Glioblastoma Multiforme (GBM) is a highly aggressive and prevalent brain tumor with an average 5-year survival rate of approximately 6.9%. Its complex pathophysiology, characterized by the capacity to invade surrounding tissues beyond the visible tumor margin, intratumor heterogeneity, hypoxic core, and the presence of the blood-brain barrier (BBB) that restricts the penetration of large therapeutic agents, all pose formidable challenges for effective therapeutic intervention. The standard of care for GBM has thus far exhibited limited success, and patients often face a poor prognosis. Electroporation-based therapies, such as irreversible electroporation (IRE), have emerged as promising alternatives to conventional treatments. By utilizing high amplitude pulsed electric fields, IRE is able to permeabilize cells, disrupt the BBB, and induce non thermal ablation of soft tissues. However, IRE is oftentimes accompanied by undesirable secondary effects such as muscle contractions, complex anesthetic protocols, and susceptibility to electrical heterogeneities, which have impeded its clinical translation. To address these limitations, high-frequency IRE (H-FIRE) was developed. H-FIRE employs short bursts of bipolar pulses, similar in duration to the cell charging time constant, enabling the desired tissue ablation while minimizing nerve excitation and muscle contractions. Additionally, H-FIRE reduces susceptibility to electrical heterogeneities, allowing for more predictable treatment volumes, thus enhancing the feasibility of clinical translation. This dissertation investigates H-FIRE for targeting malignant gliomas while looking into improved efficacy when administering the therapy in conjunction with other treatment forms and technologies. Specifically, the presented work focuses on several key areas: (1) determining the effect of pulsing protocol and geometric configuration selection on the biological outcomes from electroporation; (2) using a tumor bearing rodent glioma model to evaluate the effects of H-FIRE as a standalone therapy and as a combinatorial therapy with liposomal doxorubicin; (3) investigating the effects of waveform shape on biological outcomes; (4) utilizing real-time Fourier Analysis SpecTroscopy (FAST) to accurately model rises in temperature during treatment; and (5) modifying real-time FAST methods to determine treatment endpoints for safe and effective ablation volumes. / Doctor of Philosophy / Glioblastoma Multiforme (GBM) is one of the deadliest tumors, with an overall five-year survival rate of approximately 6.9%. Unfortunately, it also holds the position of being the most prevalent malignant brain tumor, constituting nearly 50.1% of all primary malignant brain tumor diagnoses. Despite its widespread occurrence, there has been limited success in improving survival rates. The tumor's infiltrative nature and its location behind the blood-brain barrier (BBB), which often screens out large drug molecules like chemotherapeutics, contribute significantly to these unfavorable treatment outcomes. This dissertation explores the potential of high-frequency irreversible electroporation (H-FIRE) as a solution to these challenges. H-FIRE employs bursts of pulsed electric fields to induce nanoscale defects in the cell membrane. The response to these defects may involve temporary pores that facilitate the uptake of therapeutic molecules into the cell, or larger and longer lasting pores that disrupt cell homeostasis, ultimately leading to cell death. Furthermore, this pulsed field therapy has shown success in enabling molecules to bypass the BBB. Thus, this dissertation aims to elucidate the various biophysical phenomena associated with H-FIRE, shedding light on how to manipulate treatment protocols to maximize BBB disruption and enhance therapy when used in conjunction with combinatorial agents. Additionally, this work aims to further develop technologies to provide real-time feedback, ensuring the safe and effective delivery of the treatment. Through these efforts, this dissertation aspires to offer valuable insights into optimizing H-FIRE for the treatment of malignant gliomas and advancing the understanding of combinatorial therapies in this specific context.

The electric field-induced reduction of heat transfer from a rod-stabilized diffusion flame and a step-stabilized premixed flame was investigated. The fuel examined was propane. Inlet velocity for the diffusion mode was a nominal value of 3.4 m/s with nominal air/fuel ratios of 420, 320, and 270. Inlet velocities ranged from 4.5 to 9.9 m/s for the premixed mode with equivalence ratios of 0.65 to 1.03. Maximum applied voltages for the diffusion and premixed modes were 8.0 and 6.6 kVDC, respectively. The field was applied in a direction perpendicular to the flow. Heat transfer amelioration was quantified using records of temperature versus downstream distance from the stabilizer acquired for the external surface of the heatloaded electrode which was exposed to the ambient environment. In addition, shadowgraphs and photographs were used to observe any alteration of flame position or of the bulk flowfield. These observations were used to investigate mechanisms potentially responsible for heat transfer reduction. The rod-stabilized diffusion mode displayed some field-induced reduction in heat transfer. Both bulk flow alteration and reduction in radiation (associated with soot) were concluded to be responsible. Flame impingement on the heat-loaded electrode was reduced by a field-induced increase in flow along the surface. Flame luminosity was reduced by the electric field (presumably due to a field-induced modification of soot production and/or destruction). This caused a reduction in radiative heat transfer. No heat-transfer amelioration was noted for the premixed step-stabilized mode. This was attributed primarily to a geometry not accommodating to field-induced heat transfer reduction. Higher velocities and a lower presence of soot than the diffusion mode and problems associated with flame impingement on both electrodes (reduces maximum voltages and distorts field), also contributed to the negative result. Limited displacement of the luminous portion of the reaction zone was noted. / Master of Science

This work investigates the use of irreversible electroporation (IRE) for tissue engineering applications and as a cancer ablation therapy. IRE uses short, high-intensity electric pulses to create pores in a cell's membrane and disrupt its stability. At a certain energy level, damage to the cell becomes too great and it leads to cell death. The particular mechanisms that drive this response are still not completely understood. Thus, further characterization of this behavior for cell death induced by pulsed electric fields (PEFs) will advance the understanding of these types of therapies and encourage their use to treat unresectable tumors that can benefit from the non-thermal mechanism of action which spares critical blood vessels and nerves in the surrounding area. We evaluate the response to PEFs by different cell types through experimental testing combined with computer simulations of these treatments. We show that IRE can be used to kill a specific type of bacteria that produce cellulose which can be used as an implantable material to repair damaged tissues. By killing these bacteria at particular times and locations during their cellulose production, we can create conduits in the overall structure of this material for the transport of oxygen and nutrients to the cells within the area after implantation. The use of tissue models also plays a key role in the investigation of various cancer treatments by providing a controlled environment which can mimic the state of cells within a tumor. We use tumor models comprised of a mix of collagen and cancer cells to evaluate their response to IRE based on the parameters that induce cell death and the time it takes for this process to occur. The treatment of prostate and pancreatic cancer cells with standard monopolar (only positive polarity) IRE pulses resulted in different time points for a full lesion (area of cell death) to develop for each cell type. These results indicate the presence of secondary processes within a cell that induce further cell death in the border of the lesion and cause the lesion to increase in size several hours after treatment. The use of high-frequency irreversible electroporation (H-FIRE)--comprised of short bursts of high-intensity, bipolar (both positive and negative polarity) pulses--can selectively treat cancer cells while keeping healthy cells in the neighboring areas alive. We show that H-FIRE pulses can target tumor-initiating cells (TICs) and late-stage, malignant cancer cells over non-malignant cells using a mouse ovarian cancer model representative of different stages of disease progression. To further explore the mechanisms that drive this difference in response to IRE and H-FIRE, we used more complex tumor models. Spheroids are a type of 3D cell culture model characterized by the aggregation of one or more types of cells within a single compact structure; when embedded in collagen gels, these provide cell-to-cell contact and cell-to-matrix adhesion by interactions of cells with the collagen fibers (closely mimicking the tumor microenvironment). The parameters for successful ablation with IRE and H-FIRE can be further optimized with the use of these models and the underlying mechanisms driving the response to PEFs at the cellular level can be revealed. / Ph. D. / This work investigates the use of irreversible electroporation (IRE) for tissue engineering applications and as a cancer ablation therapy. IRE uses short, high-intensity electric pulses to create pores in a cell’s membrane and disrupt its stability. At a certain energy level, damage to the cell becomes too great and it leads to cell death. The particular mechanisms that drive this response are still not completely understood. Thus, further characterization of this behavior for cell death induced by pulsed electric fields (PEFs) will advance the understanding of these types of therapies and encourage their use to treat unresectable tumors that can benefit from the non-thermal mechanism of action which spares critical blood vessels and nerves in the surrounding area. We evaluate the response to PEFs by different cell types through experimental testing combined with computer simulations of these treatments. We show that IRE can be used to kill a specific type of bacteria that produce cellulose which can be used as an implantable material to repair damaged tissues. By killing these bacteria at particular times and locations during their cellulose production, we can create conduits in the overall structure of this material for the transport of oxygen and nutrients to the cells within the area after implantation. The use of tissue models also plays a key role in the investigation of various cancer treatments by providing a controlled environment which can mimic the state of cells within a tumor. We use tumor models comprised of a mix of collagen and cancer cells to evaluate their response to IRE based on the parameters that induce cell death and the time it takes for this process to occur. The treatment of prostate and pancreatic cancer cells with standard monopolar (only positive polarity) IRE pulses resulted in different time points for a full lesion (area of cell death) to develop for each cell type. These results indicate the presence of secondary processes within a cell that induce further cell death in the border of the lesion and cause the lesion to increase in size several hours after treatment. The use of high-frequency irreversible electroporation (H-FIRE)—comprised of short bursts of high-intensity, bipolar (both positive and negative polarity) pulses—can selectively treat cancer cells while keeping healthy cells in the neighboring areas alive. We show that H-FIRE pulses can target tumor-initiating cells (TICs) and late-stage, malignant cancer cells over non-malignant cells using a mouse ovarian cancer model representative of different stages of disease progression. To further explore the mechanisms that drive this difference in response to IRE and H-FIRE, we used more complex tumor models. Spheroids are a type of 3D cell culture model characterized by the aggregation of one or more types of cells within a single compact structure; when embedded in collagen gels, these provide cell-to-cell contact and cell-to-matrix adhesion by interactions of cells with the collagen fibers (closely mimicking the tumor microenvironment). The parameters for successful ablation with IRE and H-FIRE can be further optimized with the use of these models and the underlying mechanisms driving the response to PEFs at the cellular level can be revealed.

Electric fields influence reactions by stabilization of charge-separated transition states. While this has been a longstanding hypothesis supported computationally, recent experimental confirmations highlight the potential for leveraging electric field effects to drive small molecule reactions far from equilibrium. Herein we report electric-field catalysis of an alkane solvent-derived acylation reaction in the scanning tunneling microscope-break junction (STM-BJ), providing additional support for this hypothesis. Additionally, the design and reactivity of an internally charged zwitterionic ligand are disclosed. Synthetic access of metal ligands bearing opposing charged functional groups permitted the examination of stochiometric metalation and catalytic behavior of electric field-bearing ligands.While traditionally computation has been used to rationalize why a particular catalyst is successful descriptively, it has been rarely used to screen candidates and prescriptively provide optimal catalyst structure. We report a neural network-enabled catalyst screening platform that dramatically reduce the resource intensity for examining a large chemical space. We leverage this platform to examine azolium N-heterocyclic carbene (NHC) precursors to address the lack of compatibility for electron-rich aryl aldehydes in the NHC-catalyzed Stetter reaction. This led to the discovery of a new class of azolium NHC precursor: oxadiazoliums that proved competent in achieving the target reaction addressing current limitations in Stetter catalysis.

Computational chemistry has emerged as a transformative discipline within the chemical sciences. Fueled by advancements in theoretical frameworks and the exponential growth of computational power, it offers unparalleled capabilities for elucidating the intricacies of matter at the atomic and molecular level. Modern chemistry research demonstrates the power of computational tools in revealing material properties and guiding the discovery of novel materials. By employing varies of theoretical methods, in this thesis, we present our research focused on catalytic reactions and optical properties of nanomaterials. In Chapter 1, the theory foundations of Density Functional Theory are introduced. Chapter 2 introduces methods for optical properties calculation, including Discrete Dipole Approximation (DDA) method and coupled dipole (CD) method, are reviewed. In Chapter 3, we discuss our research on carbon monoxide reduction to methanol using frustrated Lewis pair (FLP) catalyst. We propose a new FLP catalyst that successfully reduced CO with low activation barrier. Chapter 4 explores the mechanism of [2+2] benzannulation reaction with palladium coordination catalyst. The catalytic reaction pathway is proposed, with the activation energy barrier of each transition state calculated. How ligand participates in the C-H activation and benzannulation steps is also examined. In Chapter 5, we discuss our numerical investigation on enhancement factor of the radiative decay rate of multiple emitters when emitters are placed near a nanosphere. We found that the enhancement factor is affected by the magnitude and the relative phase of the induced dipole.

Thesis (PhD (Physics))--Stellenbosch University, 2008. / The advent of high intensity short pulse lasers has opened the door to investigating buried solid-solid interfaces through the technique of optical second harmonic generation (SHG). This has led to extensive study of technologically important systems such as the Si/SiO2 interface. In this study, SHG is employed to study the interface between highly boron doped p+-type Si and its native oxide layer (SiO2). Previous studies from this laboratory have extensively investigated the photo-induced charge transfer process across the Si/SiO2 interface in the case of undoped natively oxidized Si by means of SHG, with initial SHG measurements being performed on boron doped p+-type Si. The natively oxidized p+-type Si/SiO2 sample was placed on a computer controlled positioning system which allowed for translation of the sample and rotation around the azimuth. The laser system employed was characterized in terms of spectral composition, pulse duration, pulse repetition rate, spatial pro le and pulse energy in order to ensure quantitative measurements. The SHG signal generated from the sample interface was recorded in re ection. Under the applied irradiation conditions, defects are created at the interface by the near infra red (NIR) femtosecond radiation from the laser. These defects are then populated via multi-photon processes by electrons and to a lesser extent holes. The charge transfer across the interface induces an interfacial electric eld. This photo-induced electric eld is in addition to the built-in interfacial electric eld caused by positive ionization of naturally occurring interfacial defects due to the strong doping of the bulk Si. It is this interfacial electric eld, consisting of the built-in doping induced eld and the photo-induced electron and hole elds, that is probed by SHG. The SHG signal is strongly dependent on the magnitude of this interfacial electric eld as the electric eld induced second harmonic (EFISH) signal dominates all other contributions to the observed SHG signal in the case of the Si/SiO2 system. The temporal evolution of the SHG signal is recorded for di erent intensities from virgin as well as the pre-irradiated samples. This yields information about the time scales on which the charge separation occurs as well as the in- uence of existing photo-induced trap sites on the charge separation process, since the strength of the SHG signal is an indirect measure of the interfacial electric eld strength. The angular dependence of the SHG signal (SH rotational anisotropy measurements) for both the initial signal (when the doping induced electric eld dominates) and the saturated signal (when the electron induced electric eld dominates) is measured. Both these measurements show a four fold symmetry but with a relative 45 phase shift between them. This iii is taken as con rmation of the reversal of the interfacial electric eld direction. The initial SHG signal as a function of intensity is also recorded for di erent incident wavelengths. The variation in the non-quadratic dependence of the initial SHG signal on the incident intensity is attributed to a resonant enhancement of two-photon absorption and subsequent screening of the interfacial electric eld by charge carriers. The measurement performed and the results obtained contribute to the understanding of the photo-induced charge separation process across buried solid-solid interfaces, speci cally as it applies to the important Si/SiO2 interface.

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Metal and oxide interactions are of broad scientific and technological interest in areas such as heterogeneous catalysis, microelectronics, composite materials, and corrosion. In the real world, such interactions are often complicated by the presence of interfacial impurities and/or high electric fields that may change the thermodynamic and kinetic behaviors of the metal/oxide interfaces. This research includes: (1) the surface hydroxylation effects on the aluminum oxide interactions with copper adlayers, and (2) effects of high electric fields on the interface of thin aluminum oxide films and Ni3Al substrate. X-ray photoelectron spectroscopy (XPS) studies and first principles calculations have been carried out to compare copper adsorption on heavily hydroxylated a- Al2O3(0001) with dehydroxylated surfaces produced by Argon ion sputtering followed by annealing in oxygen. For a heavily hydroxylated surface with OH coverage of 0.47 monolayer (ML), sputter deposition of copper at 300 K results in a maximum Cu(I) coverage of ~0.35 ML, in agreement with theoretical predictions. Maximum Cu(I) coverage at 300 K decreases with decreasing surface hydroxylation. Exposure of a partially dehydroxylated a-Al2O3(0001) surface to either air or 2 Torr water vapor results in recovery of surface hydroxylation, which in turn increases the maximum Cu(I) coverage. The ability of surface hydroxyl groups to enhance copper binding suggests a reason for contradictory experimental results reported in the literature for copper wetting of aluminum oxide. Scanning tunneling microscopy (STM) was used to study the high electric field effects on thermally grown ultrathin Al2O3 and the interface of Al2O3 and Ni3Al substrate. Under STM induced high electric fields, dielectric breakdown of thin Al2O3 occurs at 12.3 } 1.0 MV/cm. At lower electric fields, small voids that are 2-8 A deep are initiated at the oxide/metal interface and grow wider and deeper into the metal substrate, which eventually leads to either physical collapse or dielectric breakdown of the oxide film on top.