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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)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.
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(2023)ThesisHollow fibre (HF) membrane modules implemented in submerged membrane bioreactors (MBR) and pressurised applications have been widely accepted for both wastewater treatment and polishing wastewater treatment plant (WWTP) effluents. Further innovations in membrane technologies and wastewater treatment market competitiveness, however, are restricted by high manufacturing and operational costs, where a trade-off exists between membrane system design and filtration performance. In the current work, the effects of HF lengths, physical characteristics and system fouling mitigation techniques were investigated to further optimize filtration performance. The following experimental approaches were considered, (1) small-scale filtration experiments with various HF membrane lengths and fibre dimensions, (2) the development of theoretical filtration models and the assessment of filtration simulations, and (3) pilot-scale filtration performance of prototype large-scale membrane modules in wastewater. Two mathematical models for constant TMP filtration using dead-end HF membranes were developed using firstly the Darcy friction factor, and secondly, the Hagen–Poiseuille model. The models allowed for the overall theoretical lumen pressure drop values, local flux distributions and overall filtration performance to be extensively studied. Laboratory-scale filtration experiments using HF membranes of different lengths (0.5 – 2.0 m) were undertaken with the objective of demonstrating the influence of lumen pressure drop in overall filtration performance. Though greater permeate volumes were obtained when using modules prepared with longer HF membranes, such systems experienced greater lumen pressure loss. These losses reduced the operating TMPs effectiveness, resulting in greater non-uniformity in local fluxes across the length of the HF membranes. The magnitude of losses and degree of non-uniformity in such longer systems were extensively studied, allowing for the identification of effective loss reduction techniques, such as the incorporation of HF membranes with larger inner diameters (ID) in the membrane modules. Pilot scale investigations were undertaken to evaluate the influence of HF length on overall performance in real wastewater feeds. Prototype full-scale modules were prepared with HF membrane of different lengths (1.6 – 2.0 m) and ID. Longer modules demonstrated greater filtration performance as the influence of increased lumen pressure drop due to longer fibre lengths was effectively offset by the enhanced fibre dimensions. Overall, the results presented in this study reveal that a significant interplay exists between module design (including length, packing density, slack, and fibre size), filtration process design (feedwater quality, biomass concentration, aeration rate, aeration/shear efficiency) and the critical flux (of threshold flux) conditions. In conclusion, the incorporation of longer length HF membranes in pressurised and submerged MBR modules has been proven to be a promising innovation which offers enhanced filtration capabilities.