School of Chemistry - Theses

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    Gas Phase Chemistry of Iranium Ions with Unsaturated Carbon-Carbon Bonds
    Brydon, Samuel Charles ( 2023-10)
    The study of cyclic iranium ions has developed rapidly over the last few decades as control of stereoselective outcomes during the electrophilic functionalisation of alkenes is mostly determined by the configurational stability of these species. Trace nucleophiles such as solvent, counter-ions, or unreacted alkene may cause decomposition or racemisation of these intermediates as the electrophilicity of both the heteroatom and endocyclic carbons make them susceptible to nucleophilic attack. Mass spectrometry (MS) thus offers an alternative means by which to isolate these charged species and study their bimolecular reactivity in the gas phase. Generation of these ions was achieved by electrospray ionisation of precursors containing a suitably basic group beta to the heteroatom, which upon protonation would fragment either in-source or following collision-induced dissociation of the pseudomolecular ion to give the heterocyclic three-membered ring. The multistage MS capabilities of a modified linear ion trap were utilised to isolate the iranium ion and observe its reactivity with neutral alkenes or alkynes. Changing the chalcogen (Ch) from sulfur to selenium to tellurium had a significant effect on the partitioning between attack at the heteroatom or ring-opening at carbon. Telluriranium ions underwent exclusive pi-ligand exchange with direct transfer of the tellurenium cation to the neutral reagent in a series of identity reactions, whilst all thiiranium ions studied only showed addition products from ring-opening by the neutral species. The reactivity of seleniranium ions towards alkenes partitioned between these two pathways with electron-donating groups on the heteroatom favouring the former, whilst the latter was promoted by electron-withdrawing groups. Computational studies into the pi-ligand exchange reaction revealed a Huckel pseudocoarctate transition state with a disconnection in the orbital array during the bond-breaking and bond-forming step. Extension to the haliranium ions showed kinetics of ion-molecule reactions with both cyclic and linear alkenes proceeding at the collision rate with iodiranium ions reacting dominantly via pi-ligand exchange, but bromiranium ions underwent carbocation-based fragmentation following ring-opening. Conjugation of the double bond to methyl esters suppressed heteroatom attack on iodiranium ions and only gave allylic stabilised oxocarbenium ions. The partitioning between these two reaction channels could be tuned by substituting inductively electron donating methyl groups onto the carbon-carbon double bond or entirely reverted to pi-ligand exchange by disrupting the conjugation with a methylene spacer enabling differentiation between three isomeric unsaturated methyl esters. Stability of the unsaturated irenium ions was examined by natural bond orbital theory to study (anti)aromaticity in these species. This approach revealed the antiaromatic nature of halirenium ions due to repulsion between the lone pairs and filled pi-orbital of the endocyclic double bond, and non-aromatic nature of the chalcogen irenium ions due to introduction of stabilising pi(C=C) - sigma*(Ch-R) hyperconjugative interactions. These species were generated in the gas phase for the first time by ion-molecule reactions of iranium ions with alkynes. The selenirenium ion structure assignment was strongly supported by cross-over experiments showing selenyl transfer to another alkyne, whilst the proposed iodirenium ion showed different reactivity to that of the open beta-iodovinyl cation produced upon reaction with phenylacetylene.
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    Effectively Benchmarking Density Functional Theory Methods for Models of Enzymatically Catalysed Reactions
    Wappett, Dominique Ann ( 2023-09)
    This thesis involves the analysis of the accuracy of quantum chemical methodology when applied to models of enzymatically catalysed reactions. My main aim is to test Density Functional Theory (DFT) methods, as these are regularly used in computational studies of enzyme mechanisms. This process also results in detailed assessment of high level Coupled Cluster approaches, as I seek to calculate reliable reference values against which DFT methods can be tested. Firstly, I assess a range of density functionals on the ENZYMES28 benchmark set, which contains models of five enzymes (four organic and one zinc-dependent), and make recommendations of methods that perform well. In the second project, I establish guidelines for effective benchmarking of enzymatically catalysed reactions---namely, that the level of theory of the reference values and size of the model systems in the test set should be carefully considered, as inadequate choices of both lead to unreliable benchmarking results. Thirdly, I use the insights from the first two projects to develop the MME55 set which represents 10 different metalloenzymes, as there is limited reliable and comprehensive benchmark data for bioinorganic systems. I use MME55 to benchmark DFT methods, and I compare these results to those from the ENZYMES28 set in the first project. While some recommendations are the same, other methods are notably less reliable for models containing transition metals. Finally, I investigate a new approach to improve the accuracy of DLPNO-CCSD(T) to see how it performs for calculating benchmark energies for enzyme models, and subsequently present updated reference values for the organic models from ENZYMES28 that reflect the recent improvements in Coupled Cluster methodology. From these results, I make recommendations of robust DFT methods that can be applied in future computational studies of enzyme mechanisms instead of functionals that are more popular than they are accurate, such as B3LYP. I also suggest methodology for reliable benchmarking that can be applied broadly to many types of test sets.
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    RAFT Polymerization of Acrylates and Acrylamides in Ionic Liquids; An Accelerated and Potentially Sustainable Process
    Santha Kumar, Arunjunai Raja Shankar ( 2023-04)
    Ionic liquids (ILs) are organic salts having asymmetric cations and anions that remain as liquid below 100 C. ILs have emerged as a new class of sustainable solvents for polymerisation processes because of their unique combination of properties such as low vapour pressure, high thermal and chemical stability, high conductivity, wide electrochemical window, ability to dissolve organic and inorganic solutes, low volatile organic content (VOC), and have tuneable solvent properties such as miscibility, melting point, viscosity, and hydrophilicity depending on the constituting cations and anions. The use of ILs as polymerization media not only increases the sustainability of the process but also increases the rate of polymerization. However, the role of IL and its influence on the polymerisation rate are still subject of investigation. This thesis addresses these issues by designing experiments to study the kinetics of RAFT polymerisation in different ILs, IL-organic binary solvents, and using different monomers and RAFT agents. The kinetics study revealed that the [BMIM][PF6] IL enhances the rate of RAFT polymerization of n-butyl methacrylate almost 10 times irrespective of its miscibility with the polymerization system. It is also revealed that only a small amount of IL is enough to increase the rate of polymerization. Deep eutectic solvent (DES), a subclass of ILs, made of choline chloride/urea was studied as a polymerization media for RAFT polymerization of 2-hydroxyethyl methacrylate and its copolymerization with methyl methacrylate. The kinetics of polymerisation was studied using a novel DSC methodology, which allowed the polymerisation to be monitored in real time. The data showed that the DES accelerated polymerisation as fast as bulk polymerisation but with more than 90% monomer conversion. The block copolymerisation yielded a spherical and a vesicular morphology of the copolymers demonstrating polymerisation-induced self-assembly in DES. Photoiniferter RAFT polymerisation is a slow but unique process to produce high chain-end fidelity polymers. [EMIM][EtSO4] IL was studied to accelerate the RAFT polymerization of N,N-dimethyl acrylamide under photoiniferter condition achieving more than 90% monomer conversion in less than 5 h. Synthesis of different polymer architecture such as chain extension and block copolymerization demonstrated the versatility and robustness of the process. A comparison was made with thermal initiated RAFT polymerisation which showed the high chain-end fidelity of photoiniferter RAFT polymerisation process in ILs.
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    Understanding the Impact of Core Polymer Architecture of pH-Responsive Nanoparticles on Intracellular Therapeutic Delivery
    Samara Devage, Umeka Nayanathara ( 2023-07)
    Advances in nanomedicine have enabled the development of stimuli-responsive polymeric nanoparticles with the potential for improving the efficiency of therapeutic delivery for the treatment of various diseases including cancer. pH-responsive nanoparticles that can respond to changes in the pH of intracellular microenvironments have generated particular interest in addressing specific biological barriers associated with intracellular drug delivery. These nanoparticles can be tailored with different functionalities such as charge-shifting polymers or acid-labile linkers, to effectively navigate biological barriers, allowing for site-specific drug delivery with increased drug circulation time and minimum side effects. In chapter 2, we report the design of a novel dual pH-responsive nanoparticle with tunable core architectures, based on either star or linear morphology, aiming to conquer the limitations associated with conventional pH-responsive systems for intracellular therapeutic delivery. Dual pH-responsive behaviour was achieved by combining both charge-shifting polymers and acid-labile linkages. Four-arm star and linear core polymers were designed by reversible addition-fragmentation chain transfer (RAFT) polymerization of charge-shifting monomers, 2-(diisopropylamino) ethyl methacrylate (DPAEMA) and 2-(diethylamino) ethyl methacrylate (DEAEMA) with 1:1 molar ratio, and hydrophobic anticancer drug, doxorubicin (Dox) was covalently conjugated to the polymer backbone via acid-labile hydrazone linkages. Dual pH-responsive nanoparticles with tunable core polymer architectures were engineered using a nanoprecipitation method by combining either star or linear polymer-Dox conjugates with an amphiphilic block copolymer, poly(2-(diethylamino)ethyl methacrylate)-b-poly(ethylene glycol) (PDEAEMA-b-PEG). The nanoparticles exhibited similar physicochemical properties regardless of the core architecture. Furthermore, both nanoparticles demonstrated dual pH-responsive behaviour, disassembling at pH 6.2-6.0 and releasing the drug in response to the acidic pH. The pH of disassembly could also be tuned by adjusting the ratio of DEAEMA and DPAEMA to 2:1 to design nanoparticles with a disassembly pH of approximately 6.6-6.4. This proof-of-concept design revealed the potential of these dual component systems to act as efficient drug delivery vehicles, opening up new opportunities to design more controlled drug delivery systems. In chapter 3, the dual pH-responsive system was optimized to understand the impact of core architecture of dual pH-responsive nanoparticles on intracellular drug release behaviour. The 2:1 system was used to explore the impact of architecture due to the similar pH of disassembly with previous work which had shown good endosomal escape capabilities. These nanoparticles disassembled when the pH was reduced below 6.6, and faster drug release was observed at acidic pH highlighting their potential to act as effective drug delivery vehicle. Interestingly, nanoparticles with linear polymer core displayed higher cellular association and higher toxicity in MCF-7 breast cancer cells (IC50 = 60 ng/mL) compared to nanoparticles containing the star polymer core architecture (IC50 > 1000 ng/mL). Furthermore, Langmuir-Blodgett experiments revealed that nanoparticle with linear polymer core exhibited significantly higher membrane interactions at endosomal pH, in a model endosomal membrane, compared to nanoparticle with star polymer core. These findings highlight that higher endosomal membrane interactions of nanoparticles with linear polymer core may facilitate improved cytosolic delivery of Dox leading to enhanced toxicity. This suggests that core polymer architecture can influence the intracellular drug release behaviour, and thus this study provides important insights into the design of optimized drug delivery systems. Endosomal escape is the major bottleneck for efficient intracellular delivery of therapeutics. Chapter 4 presents the application and optimization of the split luciferase endosomal escape quantification (SLEEQ) assay to investigate the endosomal escape capability of pH-responsive nanoparticles with tunable core compositions, for intracellular delivery of polypeptide cargoes. SLEEQ assay is based on split luciferase reporter system which consists of LgBiT protein, which is expressed in the cytosol and HiBiT peptide, which is attached to part of the nanoparticle core. HiBiT was attached to the nanoparticle core via cleavable disulfide linkage and non-cleavable carbonylacrylic functionalized thioether linkage. Endosomal escape is quantified by measuring the luminescent signal when they meet together in the cytosol. Nanoparticles with linear polymer core containing 2:1 ratio of DEAEMA:DPAEMA demonstrated five-fold higher endosomal escape with cleavable HiBiT-polymer conjugate compared to those with non-cleavable HiBiT-polymer conjugate. These results suggested that the presence of reducing agents, such as glutathione, in endosomal microenvironment directly impacted the higher endosomal escape observed for the nanoparticles with disulfide-linked HiBiT-polymer conjugates, owing to the potential instability of disulfide linkage within the endosomal microenvironment. These findings indicated that application of more stable linkage for conjugating HiBiT to the nanoparticle core would provide a better understanding of the endosomal escape efficiency of nanoparticles using the SLEEQ assay. However, further studies are required to understand the endosomal escape efficiency of nanoparticles with star polymer core. Together, this work highlights that the design of dual pH-responsive nanoparticles based on charge-shifting polymers and acid-labile linkers, and shows that even subtle changes to the nanoparticle core composition or architecture can have a significant impact on their biological interactions. A greater understanding of how nanoparticle structure influences intracellular therapeutic delivery will pave the way for the design of more efficient and effective drug delivery vehicles in the future.
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    Enhancing Nitrogen Fertilisation Efficiency by Developing Novel Nitrification Inhibitors for a Greener Agriculture
    Yildirim, Sibel Cansu ( 2023-05)
    Nitrogen (N) is used as a fertiliser for its essential role in building biomolecules, such as amino acids, porphyrins and nucleic acids, which directly promote plant growth. Better nutrition leads to a better crop yield; this has been a central dogma in agricultural science for more than 150 years. In an agricultural field, where natural resources are depleted due to frequent harvests, soils do not provide naturally sufficient N in a plant-available form (mineral-N, such as nitrate (NO3-) and ammonium (NH4+)). N is, therefore, a limiting nutrient and is added in an enormous amount into the soil as N fertilisers. Whilst the application rate of N fertiliser was 31.8 Tg back in 1970, today, almost 120 Tg of N is introduced into the soil. Unfortunately, there is no direct correlation between N fertilisation rate and crop yield due to a competing N uptake mechanism by soil organisms known as nitrification. Nitrification can lead to N fertiliser losses of up to 80%. By definition, it is a redox cascade from the highest reduced form of N (NH3) to the highest oxidised form of N (NO3-). The eight electrons released in the mechanism provide essential energy for bacteria and archaea equipped with the enzymes to perform this reaction. Agriculture has been facing the challenge of over-fertilising soil to ensure crop yield for over 50 years now. Not only is excessive N fertilisation not economically impactful, but N fertilisation also hosts various environmental problems. Especially in heavily industrialised and densely populated areas, the high N application rate in soils has polluted the atmosphere with ammonia (NH3) and nitrous oxide (N2O), a greenhouse gas (GHG) with a warming potential approximately 300 times higher than carbon dioxide. To control microbial conversion, synthetic nitrification inhibitors (SNIs) are introduced via co-formulation of N fertilisers. SNIs inhibit the microbial enzyme responsible for the N conversion, namely ammonia monooxygenase (AMO) conserved in ammonia oxidising bacteria (AOB) and archaea (AOA) that perform the initial and rate-limiting step of nitrification. Whilst commercial SNIs have been on the market since the 1970s, the nitrogen use efficiency has remained 50% globally, mainly due to their unpredictable and unreliable performances in soil. Interestingly, the inhibition mechanism of commercial NIs has not been fully understood yet. Moreover, the development of new NIs has been a bottleneck in the past. This thesis investigates into the development of a rapid, accessible, and robust nitrification assay to test the efficacy of potential NI within 60 min. This essay employs AOB of the strain Nitrosomonas europaea and Nitrosospira multiformis and test their nitrification activity in the presence of a SNI. The assay summarises the most-suitable parameter for cell growth, cell harvest, inhibitor concentration and substrate concentration, as these protocols do not exist in literature. The second research chapter focuses on determining the mechanism of inhibition of the existing SNIs 3,4-dimethyl-1H-pyrazole (DMP) and dicyandiamide (DCD), which have not been explored previously. This fundamental research is essential to understand current agricultural products and enable the design of novel NIs with more reliable performance. A series of biochemical studies were performed with DMP and DCD using Nitrosomonas europaea (N. europaea) as a model organism to identify the targeted enzyme in the nitrification enzyme cascade, binding affinity, reversibility of binding, Michaelis Menten kinetics, and toxicity. It was found that both NI act as reversible, non-mechanistic inhibitors. Following these findings from the biochemical experiments in the previous chapter, similar experiments were performed for five derivatives of 1,4-disubstituted 1,2,3-triazoles to directly compare them to the commercial SNI. This class of SNI has recently been tested in soil incubation studies by the postdoctoral student Bethany I. Taggert and showed an exceptional NI in comparison to the ‘gold standard’ DMP especially observed at elevated temperatures. Biochemical parameters for this class of compounds have not been determined. Therefore, five candidates 1,4-disubstituted 1,2,3-triazoles with varying functional groups substituents in the 1-position were tested. It was found that the incorporation of functional groups is detrimental to the inhibitory effect, and with increased lipophilicity, an increased inhibitory effect is observed. All inhibitors acted as non-competitive and reversible inhibitor.
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    The Design and Synthesis of Radioactive Metal Complexes for the Diagnosis and Treatment of Disease
    Morgan, Katherine Anne ( 2023-07)
    Personalised medicine is becoming increasingly important in the treatment of various cancers and diseases. Early diagnosis is important for patient outcomes, and radiation therapy offers a molecular treatment option that allows for highly specific targeting of cancer cells in vivo. The overarching theme of the research described in this thesis relates to the design and synthesis of new radiopharmaceuticals designed to better diagnose or treat various malignancies, including renal cancer, Alzheimer’s disease and cancers that are associated with suppression of the immune system, known as immune checkpoint inhibitors. Selective and targeted delivery of the radionuclide to sites of disease is essential. Radionuclide therapy is possible with radionuclides that emit alpha particles. Actinium-225 emits alpha particles with a radioactive half-life of 9.9 days. Targeted delivery of actinium-225 to tumours has the potential to treat tumours. Chapters Two to Five of this thesis describe new approaches to incorporate actinium-225 into targeting molecules. Chapters, Two, Three and Four discuss the design and synthesis of a new bifunctional ligand, H2MacropaSqOEt designed to form stable complexes with actinium-225. Monoclonal antibodies that target Carbonic Anhydrase IX were chemically modified to incorporate the ligand H2MacropaSqOEt. Carbonic Anhydrase IX is an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. These antibody conjugates were radiolabelled with actinium-225, and [225Ac]Ac(MacropaSq-hG250) was evaluated in a murine model of cancer that overexpresses Carbonic Anhydrase IX. The research presented in these three chapters highlight the future potential of targeted alpha therapy with monoclonal antibodies. The work in Chapter Five focused on the concept of antibody-based pre-targeting. The synthesis of [225Ac]Ac(Macropa-Tetrazine) was a preliminary investigation into the possibilities of pre-targeted alpha therapy, and future work will involve exploring the potential of the iEDDA reaction between [225Ac]Ac(Macropa-Tetrazine) and TCO-modified antibodies. Copper-64 is a positron emitting radionuclide with a half-life of 12.7 hours. Copper-64 is used as a diagnostic radionuclide in positron emission tomography. Chapter Six focused on developing a copper-64-based diagnostic imaging agent for Alzheimer’s disease. The aim of this research project was to develop a proof-of-concept strategy to enable antibody-targeted positron emission tomography imaging via the preparation of small copper-containing molecules designed to cross the blood brain barrier and react with specifically modified Amyloid-beta antibodies. Finally, the research presented in Chapter Seven focused on the development of a new peptide-based imaging agent for the diagnosis of PD-L1-positive tumours. This chapter explored the copper-64 radiochemistry and stability of this new peptide complex.
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    From Synthesis to Application: III-V Semiconductor Nanocrystals and Magnetic Nanoparticles
    Wen, Dingchen ( 2023-07)
    Nanoparticles are a class of materials that has fascinated the whole research community due to their vastly different properties to their bulk counterparts, and their size-dependent optical and electronic properties. These colloidal nanoparticles are usually synthesized in a bottom-up solution based method, which is much less expensive and energy intensive compared to the top-down method to make bulk materials, making them ideal for cheap and scalable solution processed devices for various applications from biomedical to energy harvesting. However, limited reaction temperature due to the physical limits of common organic solvents makes it challenging to synthesize materials with high bond energy. The other challenge is controlling the size of the nanoparticles to take advantage of size-dependent properties. III-V semiconductors are a family of semiconductors made of group III and group V elements. The more covalent nature of the bond between the group III and V elements offers them many advantages over the traditional II-VI semiconductors, but also makes them require more energy to be synthesized. In this thesis, a new reaction route using organometallic compounds to make III-V semiconductor nanocrystals in solution is explored in detail. It is shown that InN, GaN and InSb can be synthesized using this approach with size control, and they have also demonstrated to be effective in solution processed photodetectors. Iron oxide magnetic nanoparticles are the most common type of magnetic nanoparticles and are widely used in biomedical applications such as COVID-19 PCR testing. The size and composition (between gamma-Fe2O3 and Fe3O4) of magnetic nanoparticles dictates many aspects of its magnetic properties, such as the form of magnetism and magnetic response to external magnetic fields. Hence it is critical to maintain control of the composition and size for quality control in real world applications. In this thesis, a simple parameter to control the size and composition of iron oxide magnetic nanoparticles is reported. The ordering and alignment of magnetic nanorods in a uniform external magnetic field was also investigated using synchrotron small angle X-ray scattering.
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    Ultrasound-induced Inactivation of Trypsin Inhibitors for Improving their Functionality
    Wu, Yue ( 2023-08)
    Trypsin inhibitors are anti-nutritional proteins that hinder the digestibility of legume proteins in the gastrointestinal tract, therefore, limiting the application of raw legumes and the consumption of legume products. To improve the commercial and nutritional values of legume products, it is vital to inactivate the two trypsin inhibitors, Kunitz inhibitor and Bowman-Birk inhibitor. However, the traditional thermal inactivation process has unsatisfactory inactivation performance due to the high heat and pH stability of trypsin inhibitors. Therefore, some advanced technologies with high-efficiency and energy-saving should be considered to achieve more effective inactivation of soy trypsin inhibitors. In this thesis, both low- and high-frequency ultrasound treatments were applied to inactivate the Kunitz and Bowman-Birk inhibitors, both in the aqueous phase and in emulsions consisting of the aqueous and non-aqueous phases. The mechanism of ultrasound-induced inactivation and ultrasound-assisted interfacial adsorption and inactivation of soy trypsin inhibitors were proposed and the effect of process-relevant parameters on the ultrasound-assisted inactivation was explored. Additionally, the numerical simulation was used to clarify the mass transfer behaviour of ultrasound-assisted soy amino acid adsorption.
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    Self Assembly Nano Particle Simulation and Modelling of Organic Photovoltaic Materials
    Bhasin, Mayank ( 2022-05)
    This work contributes in predicting effects of OPV materials in solar cell active layers through MD simulations. Through general coarse grained simulations, the rate of change of component solubility, demixing tendency, and the difference in interaction energies, were studied for nano-composite self-assemblies. Routes to form uni- form, core-shell, Janus, and eccentric morphologies were established. Using atom- istic simulations it was established that increasing P3HT chain length the stability of the nanocomposite (P3HT:PCBM/ICBA) decreases, whereas increasing PDI stability increases. Also addressed is why two specific members of the entire BXR series (benzodithiophene- X-thiophene-rhodamine) exhibit liquid-crystalline phase and highest PCE in solar cell usage, compared to the other members. These members exhibit optimum aggregation which is necessary for liquid crystalline phase formation.
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    The Development of SelfImmolative Nanoparticles to Enhance Endosomal Escape
    Smith, Samuel Alexander ( 2023-01)
    Biopharmaceutical therapeutics, including mRNA, DNA and protein, are emerging as powerful treatment strategies for many diseases. Nanoparticle delivery systems are a crucial component to the delivery of biopharmaceuticals due to their enhanced protection, site-specific delivery and improved safety. However, the intracellular trafficking of the biopharmaceutical delivery, in particular endosomal escape, remains an area for enhancement. While polymer delivery systems have been engineered to enhance endosomal escape, many polymer systems are non-degradable. The incorporation of controlled degradability into the polymer system enhances therapeutic release, reduces material accumulation and lowers toxicity. One type of material with very precise control over the degradability is self-immolative polymers (SIPs), which undergo an end-to-end depolymerisation cascade triggered by a single bond cleavage event, often at the end cap. However, SIPs have not been extensively explored for the use as nanoparticle delivery systems to enhance endosomal escape. In this thesis nanoparticles composed of SIPs were developed and the particle behavior, the extent of depolymerisation and interaction with cells of these SIP particles was investigated. The onset of the polymer depolymerisation was found to impact interactions with cells, including endosomal escape. A framework to controlling the onset of depolymerisation through controlling the access of stimuli to the SIP polymer end cap was developed. Partial control over the onset of depolymerisation, through protection of the SIP end cap, was shown through modulation of the polymer side chain hydrophobicity and pKa of the non-degradable shell polymer used in the particle formulation. However, the migration of the SIP to the particle surface and out of the particle prevented the specific control over the onset of depolymerisation. More precise control over the onset of depolymerisation was demonstrated though the modulation of the SIP side chain hydrophobicity and pKa. These particles were shown to rapidly and extensively depolymerise at low pH, while they remained stabile at pH 7.4 for up to one week. While all SIP particles showed rapid depolymerisation, one particle in the series was shown to enhance endosomal escape with a moderate endosomal escape efficiency. Lastly, the loading and release of nucleic acids with a SIP was explored. The work highlighted the importance of selecting the optimal nanoparticle formation conditions to produce polyplexes with ideal properties. In addition, the importance of incorporating a DNA binding group on the SIP side chain was found to be imperative to maintaining complexation under physiological conditions, while also effectively releasing the nucleic acids with upon exposure to stimuli.