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(2022)ThesisTwo-dimensional transition metal dichalcogenide (TMD) nanocrystals (NCs) exhibit unique optical and electrocatalytic properties. However, the growth of uniform and high-quality NCs of monolayer TMD remains a challenge. Until now, most of them are synthesized via solution-based hydrothermal process or ultrasonic exfoliation method, in which the capping ligands introduced from organic solution often quench the optical and electrocatalytic properties of TMD NCs. Moreover, it is difficult to homogeneously disperse the solution-based TMD NCs on a substrate for device fabrication since the dispersed NCs can easily aggregate. Here, we put forward a novel CVD method to grow closely-spaced TMD NCs and explored the growth mechanism and attempts on the size control. Their applications acting as electrocatalysts and adhesion layer for Au film deposition have been also well displayed. Through the whole chapters of this thesis, the following aspects are highlighted: 1. MoS2 and other TMD nanocrystals have been grown on the c-plane sapphire. The surface oxygen vacancies determine the density of TMD nanocrystals. The MoS2 nanocrystals demonstrate excellent hydrogen evolution reaction and surface-enhanced Raman scattering performance owing to the abundant edges. 2. Deep insights into the growth of MoS2 nanograins have been explored. The surface step edges and lattice structures of the underlying sapphire substrates have a significant influence on the growth behaviors. The step edges could modulate the aggregation of MoS2 nanograins to form unidirectional triangular islands. The Raman spectra of MoS2 demonstrate a linear relationship with the crystal size of MoS2. 3. The orientation of sapphire substrate has an of importance effect on the critical size of MoS2 nanocrystals. The MoS2 nanocrystals have the smallest size on the r-plane sapphire, besides, the MoS2 on r-plane sapphire demonstrates the sintering-resistance feature, which is attributed to the edge-pinning effect when MoS2 edges are anchored on the sapphire surface. 4. The MoS2 nanocrystalline layer was utilized as the adhesion layer for Au film depositing on a sapphire substrate. The Au films on MoS2 displayed superior transmittance and electrical conductivity as well as outstanding thermal stability, which lay in the strong binding of Au film with MoS2 nanocrystalline layer.
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(2022)ThesisAntibodies are increasingly useful therapeutics, and examples include the checkpoint inhibitors pembrolizumab1 and ipilimumab2 in cancer immunotherapy, and anti tau therapies in Alzheimer’s disease and dementia.3,4 However, specific applications requiring cytosolic delivery of the antibody, or transport across the blood-brain barrier pose challenges to antibody therapeutics. These issues may reduce the effectiveness of immunotherapy and restrict it to extracellular targets. Conjugating polymers to proteins and enzymes has been very effective at improving their stability and pharmacokinetics,5–8 and similar approaches have been studied for antibody conjugation.9–12 Finding an effective polymeric delivery system for antibodies can greatly improve immunotherapy. In this work three strategies were explored for the encapsulation and bioconjugation to antibodies. The first approach is the encapsulation via electrostatic interactions between the antibody and a charged block copolymer to form polyion complex (PIC) micelles. Polyphosphonium block copolymers were studied for the first time to encapsulate antibodies, and were compared to their ammonium counterpart. While this approach has the advantage of being reversible, the polymer-antibody electrostatic interactions were too weak for biological applications, and delivery by this means would require a crosslinking strategy. The second approach involves covalent attachment of polymers on the antibody’s surface via a grafting from polymerisation. An oxygen tolerant technique was employed for the screening of a large number of samples in low volumes (<100 μL). Successful grafting was demonstrated by AF4 and gel electrophoresis. Enzyme-linked immunosorbent assay (ELISA) showed retention of up to 40% binding activity relative to the native antibody with a marked improvement in stability. The third strategy introduces a novel acid sensitive linker for the reversible covalent attachment of polymers to the antibody’s surface. This was achieved by using Diels-Alder chemistry to create an activated PEG that forms an amide with a conformational lock similar to citraconic anhydride upon conjugation to the amines on the antibody. The ability of the linker to cleave at pH 5.5 is demonstrated, resulting in almost complete recovery of the original binding activity of the antibody. Overall, the reversible covalent attachment investigated here seems the most promising, and combining the high throughput method with the cleavable linker approach holds great potential for advancing in immunotherapy. References (1) Reck, M. Pembrolizumab as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer. Futur. Med. 2018, 10, 93–105. (2) Gao, J.; Ward, J. F.; Pettaway, C. A.; Shi, L. Z.; Subudhi, S. K.; Vence, L. M.; Zhao, H.; Chen, J.; Chen, H.; Efstathiou, E.; Troncoso, P.; Allison, J. P.; Logothetis, C. J.; Wistuba, I. I.; Sepulveda, M. A.; Sun, J.; Wargo, J.; Blando, J. VISTA Is an Inhibitory Immune Checkpoint That Is Increased after Ipilimumab Therapy in Patients with Prostate Cancer. Nat. Med. 2017, 23 (5), 551–555.. (3) Pedersen, J. T.; Sigurdsson, E. M. Tau Immunotherapy for Alzheimer’s Disease. Trends Mol. Med. 2015, 21 (6), 394–402. (4) Castillo-Carranza, D. L.; Sengupta, U.; Guerrero-Munoz, M. J.; Lasagna-Reeves, C. A.; Gerson, J. E.; Singh, G.; Estes, D. M.; Barrett, A. D. T.; Dineley, K. T.; Jackson, G. R.; Kayed, R. Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes without Affecting Hyperphosphorylated Neurofibrillary Tangles. J. Neurosci. 2014, 34 (12), 4260–4272. (5) Abolmaali, S. S.; Tamaddon, A. M.; Salmanpour, M.; Mohammadi, S.; Dinarvand, R. Block Ionomer Micellar Nanoparticles from Double Hydrophilic Copolymers, Classifications and Promises for Delivery of Cancer Chemotherapeutics. Eur. J. Pharm. Sci. 2017, 104 (January), 393–405. (6) Kurakhmaeva, K. B.; Djindjikhashvili, I. A.; Petrov, V. E.; Balabanyan, V. U.; Voronina, T. A.; Trofimov, S. S.; Kreuter, J.; Gelperina, S.; Begley, D.; Alyautdin, R. N. Brain Targeting of Nerve Growth Factor Using Poly(Butyl Cyanoacrylate) Nanoparticles. J. Drug Target. 2009, 17 (8), 564–574. (7) Jiang, Y.; Fay, J. M.; Poon, C. D.; Vinod, N.; Zhao, Y.; Bullock, K.; Qin, S.; Manickam, D. S.; Yi, X.; Banks, W. A.; Kabanov, A. V. Nanoformulation of Brain-Derived Neurotrophic Factor with Target Receptor-Triggered-Release in the Central Nervous System. Adv. Funct. Mater. 2017, 1703982, 1–11. (8) Klyachko, N. L.; Manickam, D. S.; Brynskikh, A. M.; Uglanova, S. V.; Li, S.; Higginbotham, S. M.; Bronich, T. K.; Batrakova, E. V.; Kabanov, A. V. Cross-Linked Antioxidant Nanozymes for Improved Delivery to CNS. Nanomedicine Nanotechnology, Biol. Med. 2012, 8 (1), 119–129. (9) Bin Liu, Khushboo Singh , Shuai Gong , Mine Canakci, Barbara A. Osborne, and S. T. Protein Antibody Conjugates PACs A Plug‐and‐Play Strategy for Covalent Conjugation and Targeted Intracellular Delivery of Pristine Proteins. Angew. Chemie 2021, 133, 12923–12928. (10) Chan, L. J.; Bulitta, J. B.; Ascher, D. B.; Haynes, J. M.; Mcleod, V. M.; Porter, C. J. H.; Williams, C. C.; Kaminskas, L. M. PEGylation Does Not Signi Fi Cantly Change the Initial Intravenous or Subcutaneous Pharmacokinetics or Lymphatic Exposure of Trastuzumab in Rats but Increases Plasma Clearance after Subcutaneous Administration. Mol. Pharm. 2015, 12, 794–809. (11) Subasic, C. N.; Ardana, A.; Chan, L. J.; Huang, F.; Scoble, J. A.; Butcher, N. J.; Meagher, L.; Chiefari, J.; Kaminskas, L. M.; Williams, C. Poly ( HPMA- Co -NIPAM ) Copolymer as an Alternative to Polyethylene Glycol-Based Pharmacokinetic Modulation of Therapeutic Proteins. Int. J. Pharm. 2021, 608 (September), 121075. (12) Keita Hironaka,a,b Erika Yoshihara, Ahmed Nabil, James J. Lai, A. K. and M. E. Conjugation of Antibody with Temperature-Responsive Polymer via in Situ Click Reaction to Enable Biomarker Enrichment for Increased Diagnostic Sensitivity. Biomater. Sci. 2021, 9, 4870–4879.
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(2022)ThesisDissolved organic carbon is stored and processed in groundwater in three ways. It is stored on minerals by adsorption, it is biologically processed through biodegradation, and it also undergoes a process to return to groundwater called desorption. This biophysiochemical research shows that the groundwater system is therefore a vital part of the global carbon cycle and carbon sink. This research fills a gap in the existing understanding of how to calculate the global carbon budget, as does not yet include the dissolved organic carbon that is stored in groundwater. This thesis exclusively explores processes determining dissolved organic carbon character and concentration in groundwater in different geological environments. This is new, useful knowledge to describe the biophysiochemical process. This research did not examine human interference in adding carbon to groundwater. This research found how dissolved organic carbon is stored and processed in groundwater due to biodegradation and desorption, and how it is adsorbed onto sediment surface. This research explored the characteristics and concentration of Dissolved organic carbon in groundwater by using Liquid Chromatography-Organic Carbon Detection, and other techniques, to examine dissolved organic carbon in terms of its fractions: humic substances, hydrophobic organic carbon, biopolymers, building blocks (BB), low molecular weight neutrals and low molecular weight acids. There were several key findings. First, the results showed that both semi-arid inland low sedimentary organic carbon environments – i.e., Maules Creek and Wellington – were a carbon source; while the high rainfall temperate coastal peatland environment of Anna Bay was a carbon sink. Secondly, another key finding was that dissolved organic carbon was not processed as a whole chemical compound, but it was processed by its fractions where each fraction was processed distinctly. For example, humic substances were only adsorbed/desorbed in groundwater; while low molecular weight neutrals were only consumed by microbes in the biodegradation process in groundwater.
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(2022)ThesisChronic wounds are a major issue in public health. One of the contributing factors in the development of chronic wounds is bacterial infection, which is exacerbated by the presence of multidrug-resistant (MDR) bacteria. One approach to tackle wound infection is the use of non-antibiotic antimicrobials with rapid killing effect without inducing resistance. This thesis aims to investigate the application of antimicrobial polymers and iodine in the development of antimicrobial wound dressing platforms. Firstly, contact-active antimicrobial wound dressings were explored. An inert silk sponge was prepared as the substrate and functionalized with antimicrobial polymers on the surface via layer-by-layer assembly. Electrostatic interactions in the multilayer construct confined the antimicrobial polymers and prevented leaching. The sponge was able to suck bacteria into the porous network and kill them upon contact as evidenced by up to 4 log10 reduction against Gram-negative and Gram-positive bacteria. Additionally, the antimicrobial efficacy was found to be strongly affected by the construction of multilayer assembly. As the contact-active mechanism may reach saturation point on the surface, in the second approach, an antimicrobial platform with a release-killing mechanism was developed. Employing the ability of silk to self-assemble into a thin film, antimicrobial polymers were loaded in the silk matrix. The release of antimicrobial polymers correlated to polymer concentration, silk to polymer ratio, and film configuration. The efficacy of the films was demonstrated by 5 to 7 log10 reduction of planktonic and 3 to 7 log10 reduction of biofilm cells against Pseudomonas aeruginosa and Staphylococcus aureus, including MDR strains. Furthermore, the straightforward coating method was as effective on glass or cotton substrates. The third approach investigated the immobilization of iodine onto wound dressings for a sustained release system. The immobilization was facilitated by polyamide iodophors that were synthesized on the dressing via plasma polymerization of the gaseous amide monomers. The antimicrobial activity correlated strongly to the structure of the polyamide with the short and linear polymer recorded 4 log10 reduction against P. aeruginosa and 7 log10 reduction S. aureus, including a MDR strain. Overall, the immobilization of iodophors on wound dressings demonstrated a potential new approach in reducing bacteria proliferation in wounds.
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(2023)ThesisThis work explores how reversible light-induced pH changes can be increased and applied to control pH-responsive systems with light. Chapter 2 investigates how substitution patterns influence the acidity of merocyanine photoacids in the dark as well as under light irradiation. The parameters which are crucial for increasing light-induced pH changes are defined and applied to synthesized merocyanine photoacids. The light-induced pH changes starting from varying initial pH values are explored and a model is developed to estimate these based on experimentally defined parameters. Transient absorption spectroscopy was used to explore the influence of the protonation state of the merocyanine form (MCH vs MC) on the photoswitching efficiency. A python model is developed to describe the pH- recovery in the dark. Chapter 3 introduces an improved merocyanine photoacid, designed by principles outlined in Chapter 2. The acidity parameters and photoswitching abilities are characterized. The pH switching capacity is investigated and extended into the basic pH range. The light-induced pH switch by the improved photoacid is applied to control the protonation state of an indicator dye. Chapter 4 applies light-induced pH changes to influence the secondary structure of pH-sensitive DNA. The transient formation of these structures is explored. The influence of the initial pH value and a DNA binder on the ratio and kinetics of the system components is investigated. Chapter 5 applies light-induced pH changes to influence the properties of different types of supramolecular polymers. The challenges of applying merocyanine photoacids to generate structural changes of supramolecular polymers by influencing the components protonation state are highlighted. Chapter 6 presents brief conclusions and a future outlook for this research field.
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(2023)ThesisEpidemic thunderstorm asthma (ETSA) outbreaks are triggered by airborne pollen allergens combined with thunderstorm activity. ETSA can affect anyone, as observed in the world’s largest ETSA event in Australia. Allergens from rye grass pollen affect the respiratory airways and the fundamental physicochemical causes, biochemical interactions, and the role of the thunderstorm in ETSA have been the source of much speculation. In this thesis, the physicochemical interactions of thunderstorm-derived reactive oxygen nitrogen species (RONS) and pollen-derived molecules are examined. It is hypothesised that RONS from the plasma-activated water (PAW) react with the airborne pollen allergens, exerting physicochemical changes to enhance allergenicity and subsequently causing ETSA. Simple biomimetic models are demonstrated, examining the key biointerfacial interactions and the influences of the conditions of plasma formation, pH, and temperature, employing advanced interface-sensitive techniques including QCM-D and neutron reflectometry. Firstly, cellulose-mucin interactions were analysed, mimicking the interactions between the walls of inhaled pollen (intine) and mucosa of the respiratory tract (mucin). Interaction with plasma-treated cellulose surfaces led to adsorption and conformational alterations to mucin, potentially indicating changes to the permeability of the mucosa. Secondly, the effect of PAW on the interactions between a model-allergen plant protein and lipid monolayers mimicking alveolar surfactant was studied. The protein took up RONS and PAW-treated protein showed stronger adsorption to the lipid monolayers, implying PAW-treatment enhances transport of the protein into lung tissue. Lastly, the effect of PAW on allergen penetration into epithelial bilayers was elucidated. Solid-supported model lipid bilayers were allowed to interact with model allergen and rye grass derived proteins to deduce the structural integrity of the membrane. PAW-treatment increased adsorption of the proteins to the lipid bilayers, and enabled the penetration into the membrane, corroborating the enhanced allergenicity of PAW-treated allergens. Overall, PAW was seen to enhance three relevant nonspecific biointerfacial interactions; these physicochemical studies complement extant in vitro cell studies in an effort to enable the development of effective monitoring platforms, diagnostics, and therapeutic interventions for the prevention and treatment of ETSA.
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(2023)ThesisTumbling ball milling is a critical comminution process in materials and mineral processing industries. It is an energy intensive process with low energy efficiency. It is important that ball mills and the milling process are properly designed and operated. To achieve this, models at different scales are needed to provide accurate prediction of mill performance under various conditions. This study aimed to develop a combined discrete element method (DEM) and machine learning (ML) modelling framework to link mill design, operation parameters with particle flow and mill efficiency. A scale-up model was developed based on DEM simulations to link mill size ratio, rotation rate, and filling level with power draw and grinding rate. Then, an ML model using the Support Vector Machine (SVM) algorithm was developed to predict the angle of repose (AoR) and collision energy based on various operation conditions. The ML model was trained by the data generated from the DEM simulations and able to predict the AoR and collision energy. In the process monitoring, an artificial neural network (ANN) was firstly proposed to predict internal particle flow properties of a rotating mill based on acoustic emission (AE) signal generated using the DEM. Main features of AE signals and power draw were fed into the ANN to predict flow properties such as particle size distributions, collision energy distribution and filling levels. Further, a convolution neural network (CNN) was used to replace the ANN to extract more efficient features of AE signals non-linearly based on different local frequency ranges in a ball milling process partially filled with steel balls and grinding particles. Last, a physics-informed ML model was developed based on continuous convolution neural network (CCNN) to learn particle contact mechanisms provided by DEM data at different rotation speeds. The ML model coupled with DEM simulation can accelerate DEM simulation to accurately predict particle flow in a long time series. In summary, this work has demonstrated that combining physics-based numerical models DEM to ML models not only improves the efficiency and accuracy of predictions of complicated processes but also provides more insight to the process and makes predictions more transparent.
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(2023)ThesisClean chemical fuels such as molecular hydrogen are promising eco-friendly alternatives to CO2-emitting fossil fuels ; hydrogen can be generated using solar-driven photoelectrochemical water splitting with an efficient semiconductor photoelectrode. However, to optimize the process and reduce costs, exploring new materials and photoelectrode structures, as well as understanding their fundamental characteristics and impact on energy conversion, is crucial. Sulfide-based semiconductors such as CuS and ZnS have gained interest due to their earth abundance, non-toxicity, and suitable band gaps, but have limitations such as rapid recombination of photoexcited charge carriers and susceptibility to (photo)corrosion for CuS, and a wide band gap for ZnS. This thesis explores various approaches, such as varying synthesis conditions for the deposition of CuS thin films, forming CuS-ZnS mixtures, and doping, to improve the performance of both semiconductors. Firstly, CuxS thin films were synthesized using pulsed laser deposition. The deposition conditions such as substrate temperature and background gas pressure were varied to analyze their impact on structural and optoelectronic properties. Substrate temperature had a more significant effect on film growth than background gas pressure, and the highest temperature used (500°C) yielded the best performance with a reduced band gap and higher photocurrent density. However, poor stability was observed. To enhance the stability and overall performance of CuS, mixed films of CuS-ZnS were synthesized; they showed better optoelectronic properties and enhanced photoelectrode performance compared to films of CuS and ZnS on their own. Computational studies using DFT were also used to investigate the CuS-ZnS mixtures, which confirmed the enhanced charge separation as well as reduced band gaps compared to bulk CuS and ZnS. Altering the thickness of the ZnS layer also affected both stability and band gap, attributed to changes in interfacial bond lengths and atomic charges. From DFT calculations, it was found that doping CuS with transition metal and alkaline earth metal dopants affects the bonding behavior and can switch CuS between plasmonic and typical fluorescent semiconductor behavior. Overall, the thesis highlights the importance of exploring new materials and photoelectrode structures and understanding their fundamental characteristics to optimize the process of solar-driven water splitting and reduce costs.
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(2023)ThesisProteins and enzymes are highly versatile materials that are involved in essentially every biological process, making them valuable tools and targets in the field of medicine. This thesis explores two distinct aspects of their applications: Part I focuses on the formation of responsive nanoparticles for drug delivery, while Part II delves into the development of small molecular inhibitors and their use in a novel protease assay. Each part will start with a separate literature review, to give the reader a brief background about the topic. Their biocompatibility, non-toxicity, and ability to specifically interact with cellular receptors make proteins and enzymes promising materials in the design of nanoparticles for drug-delivery applications. In many cases, a covalent modification of the protein is required to drive the formation of nanoparticles which can inadvertently change the properties of the underlying protein. One possibility to overcome this problem is to make the covalent modification reversible by the introduction of responsive linker molecules, which additionally allows targeting. Therefore, Part I of this thesis will explore nanoparticles that degrade in response to specific environmental cues, such as reducing agents, UV-light, or hypoxia. The first chapter is a comprehensive review of the literature on different protein-nanoparticle and the use of responsive linker systems in drug delivery applications. Chapter 2 of the thesis will present the synthesis of PEGylated enzyme nanoparticles designed for delivering catalytically active enzymes into cells. The results obtained will demonstrate the triggered disassembly of the nanoparticles and the subsequent release of catalytically active enzymes, leading to cellular toxicity. Moving on to Chapters 3 and 4, reductive-responsive nanoparticles composed of bovine serum albumin (BSA) and a hypoxia-responsive polymer will be featured as an intracellular drug delivery vehicle for nucleic acids. In Part II of the thesis, the focus is shifted to the design of small molecule inhibitors for acetylcholinesterase (AChE) and their use in the development of a novel protease assay. AChE has important implications in the treatment of Alzheimer's and other diseases. After a short literature review in Chapter 5 discussing the enzyme and past development of its inhibitors, Chapter 6 shows the journey in the design of potent, primary amine-containing inhibitors of AChE based on several known scaffolds. The increased polarity of the molecules hinders their ability to cross the blood-brain barrier, suggesting a potential application in the treatment of functional dyspepsia. Lastly, Chapter 7 deals with the development of a new proteases assay based on the inhibitors synthesized in the previous chapter. Proteases play a crucial role in many biological processes and are thus important medical markers for various diseases. The effect of the potency of the inhibitors after covalent modification with short peptides was evaluated and a mathematical model developed to predict the sensitivity of the assay.
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(2024)ThesisReceptor clustering is one of the most common mechanisms for controlling cell fate in nature, and strategies capable of directing this behaviour hold significant therapeutic potential. One prominent example is the TRAIL protein (TNF-related apoptosis inducing ligand), which selectively induces apoptosis in cancer cells by clustering death receptors DR4 and DR5. Although a potent chemotherapeutic, its clinical use has been hampered by its short circulation half-life. In this thesis, multivalent polymer scaffolds capable of presenting DR4/5 binding peptide ligands were developed as synthetic TRAIL mimics. In any synthetic protein mimic, directing the conformational structure to precisely control the spacing and orientation of multiple ligands is a major challenge. The two scaffolds in this thesis applied different strategies to achieve this. The first scaffold was a core-crosslinked micelle system with surface functionality for attachment of DR5 binding peptides. Micelles featuring varying peptide densities were synthesized and carefully characterized. These micelles successfully induce apoptosis in a colon cancer cell line (COLO205) via DR5 clustering. Micelles with a peptide density of 15% (roughly 1 peptide / 45 nm2) displayed the strongest activity with an IC50 value of 0.8 μM (relative to peptide), suggesting a statistical network of monomeric ligands may suffice to drive DR4/5 signalling. However, significantly improved activity could be achieved using star polymers with a hydrophobic core. Structural characterization by DOSY-NMR and surface plasmon resonance revealed that the improved activity came from the polymer folding in solution, which positioned the peptides in a well-defined manner on the periphery of the star, enhancing their accessibility to DR5. By varying the chemistry of the inner block, a new lead structure of 3-arm PBzA40-b-PDMA40-WDCL was identified in library screening with IC50 values in the low nanomolar range to COLO205. These leads show toxicities approaching that of the native TRAIL protein, but from a material that would be expected to show upwards of 20 h circulation half-lives in vivo.