Chemical and Biomolecular Engineering - Theses
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ItemNovel polymeric architectures through controlled/living polymerization, click chemistry and supramolecular interactions( 2013)The properties and functions of polymeric materials are not only dictated by their composition but also their structural arrangement (i.e., architecture or topology). Exploration of polymers with novel molecular architectures has become a practical strategy for developing advanced soft nanomaterials essential to emerging nanotechnologies. Utilizing a combination of modern synthetic chemistries including controlled/living polymerization, click chemistry and supramolecular interactions, this body of research resulted in the development of facile, versatile and highly efficient synthetic pathways for the preparation of a fascinating array of unprecedented macro(supra)molecular architectures. A scaffold approach that provides access to a library of highly functionalized core cross-linked star (CCS) polymers was developed. Novel functional star macromolecular architectures including fluorescent, saccharide and amphiphilic polyester-based CCS polymers were synthesized by grafting a polyalkyne CCS polymer scaffold with the corresponding azido functional compounds through click chemistry. Factors affecting the grafting efficiency (i.e., click efficiency) of the azido compounds onto the CCS scaffolds were identified. This study not only introduces a versatile and efficient synthetic route towards highly functionalized CCS polymers, but also provides a valuable reference source for the high density functionalization of complex 3-D nanostructures. The near-quantitative synthesis of polyester-based CCS polymers was demonstrated through organic catalyst-mediated ring opening polymerization. Using this innovative approach, novel benzyl and alkyne end-functional polyester-based CCS polymers were conveniently synthesized in high yields (90 - 96%) at ambient temperatures. Side-reactions that are responsible for trace amounts of low molecular weight impurities in the resulting polymers were identified. The established high-yielding system, which involves no toxic metal catalysts or additives and operates under mild reaction conditions with fast reaction rates, represents a powerful synthetic tool for building new functional star macromolecular architectures. In addition to CCS polymers, other functional supra(macro)molecular polymers were also explored. Poly(pseudo)rotaxanes with star and bottlebrush supramolecular structures were constructed via self-assembly of the corresponding guest macromolecules with α-cyclodextrin (CD) through inclusion complexation. The α-CD inclusion complexation was found to be a useful functionalization strategy for the polyester-based (i.e., poly(ε-caprolactone)) guest macromolecules through non-covalent interactions. Such modification not only alters the inherent chemical and physical properties of the guest polymeric materials but also, surprisingly, affects their molecular size and conformation. Lastly, the synthesis of a novel stereospecific cyclic polymer was demonstrated through the application of metal-catalysed living radical polymerization and ‘click’ chemistry. With an appropriate ring size, the resultant cyclic polymers are capable of forming an unprecedented ‘polypseudorotaxane-type’ supramolecular structure with the complementary linear stereoregular polymers via stereocomplex helix formation. The ‘polypseudorotaxane-type’ stereocomplex exhibits remarkably different physical properties compared to the conventional triple-helix supramolecules derived from the stereocomplexation of linear stereoregular polymer pairs. These results demonstrate that it is possible to manipulate the microstructures and properties of the supramolecular polymers by changing the shape (or topology) of the assembling components. The polymeric architectures presented in this thesis possess well-defined hierarchical arrangements of building blocks and functionalities, which imparts them with intriguing characteristics. They may therefore constitute advanced soft nanomaterials with great potential to applications in life sciences and materials technologies. It is anticipated that the established synthetic protocols will aid in the research and development of the next-generation of polymeric materials.
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ItemTunable polymer capsules for therapeutic delivery applications( 2013)The area of therapeutic drug and gene delivery has made rapid progress over the last two decades. This interest in the development of drug delivery systems is aimed at protecting the body from the non-specific side effects of drugs and biomolecules; protecting therapeutic compounds from premature degradation and directing them specifically to target sites; and having tunable carrier degradation and cargo release to optimise the therapeutic efficacy. Of the drug delivery systems studied, the Layer-by-Layer (LbL) approach for the assembly of polymer multilayer films and capsules is of particular interest because it is a facile and highly versatile assembly technique that allows for specific properties to be tailored into the assembled materials to fulfill various criteria needed for the successful bioapplication of these systems. This thesis focuses on the development of a biologically compatible polymer capsule system based on the LbL technique and the incorporation of chemical and physical approaches to achieve stable cross-linked capsules, cargo loading and controlled release. Specifically, the work aims to (i) study the film build up and characteristics of cross-linked polymer films and capsules; (ii) develop stable polymer capsules capable of loading a cargo; (iii) demonstrate a modular approach in achieving tunable capsule degradation and cargo release; and (iv) provide some insight into the behaviour of these capsules in in vitro cell studies. This is demonstrated through the fundamental studies of the assembly of a low-fouling poly(N-vinyl pyrrolidone) (PVPON) capsule which uses a cross-linker in film stabilisation. The cross-linker has a reducible disulphide bond that endows the capsules with stimuli-responsive degradable properties. The optimised capsule system is loaded with a model plasmid DNA and used to demonstrate tunable carrier degradation and cargo release behaviour, through the use of the cross-linkers, in simulated cellular reducing environment. The study is extended to the assembly of hybrid systems, which is based on incorporating a charge-shifting polymer poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) and a block copolymer poly(2-(methacryloyloxy)ethyl-phosphorylcholine)-b-poly(2-(diisopropyl-amino)ethyl methacrylate) (PMPC-PDPA), into films and capsules. These hybrid systems are investigated for their properties. Finally, these different capsule systems are investigated for their interaction and internalisation behaviour in in vitro cell studies. The preliminary results offer some insight into the potential use of these highly engineered drug delivery carriers in biomedical applications.
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ItemNovel and reactive surface coatings via plasma polymerisation( 2012)The work in this thesis investigates the plasma polymerisation of bromine-containing monomers with the aim of functionalising a wide variety of material surfaces with a bromine-functionalised plasma polymer film (BrPP) that is both robust and amenable to secondary reactions. The focus of these reactions has centred upon the copper catalysed alkyne-azide cycloaddition (CuAAC) reaction, a paradigm of click chemistry; a modular synthetic concept referring to reactions that are wide in scope and occur with high specificity and efficiency. Systematic studies were carried out in order to optimise the plasma deposition of a BrPP film coating that is both robust and adherent to the surface on a variety of materials when exposed to both aqueous and organic environments. Optimised thin film deposition conditions were obtained with the monomer 1-bromopropane. The BrPP film was characterised by X-ray photoelectron spectroscopy (XPS), Fourier transform infra-red spectroscopy (FTIR), water contact angle and atomic force microscopy (AFM). The 1-bromopropane plasma polymer film was further characterised using a novel technique developed in this thesis whereby the PP film is first deposited onto a sodium chloride crystal followed by delamination with double-sided tape. This allowed the top- and underside (substrate-plasma polymer interface) of the film to be directly analysed by XPS and near edge X-ray absorption fine structure (NEXAFS) spectroscopy. The chemical composition and molecular orientation of the film were different on the topside compared to the underside and this indicated a heterogeneous film structure. The results provided useful insights into the early stages of film formation and chemistry of the 1-bromopropane plasma polymer film. The bromine groups in the 1-bromopropane PP film were substituted by nucleophilic exchange with sodium azide to create surface-bound azide groups (N3PP) suitable for immobilising functional alkynes via the click reaction. The click reaction was verified by XPS and FTIR analysis, which revealed that the reactivity and efficacy of the reaction were influenced by the subtle variations in the BrPP film chemistry across the different substrates. The micropatterning of a fluorescent alkyne via click microcontact printing was also demonstrated. Following recent developments on the photoinitiation of the click reaction, a photolithographical process was developed to click graft and cross-link alkyne-functionalised poly(ethylene glycol) (PEG) onto the N3PP film to fabricate patterned PEG hydrogels. The hydrogels exhibited tuneable thicknesses, resistance to cell attachment and reactivity towards further click reactions. The versatility and functionality of the BrPP film was further demonstrated by the toposelective and robust deposition onto monolayers of silica microparticles. This resulted in the formation of particles with two distinct regions of different chemistries, which are also commonly referred to as Janus particles. The Janus character of the modified particles was verified by azide nucleophilic exchange and subsequent click reactions with fluorescent alkynes. The formation of discrete half shell structures of the BrPP film following dissolution of the silica template provided further evidence of selective film deposition onto the microparticles. Toposelective deposition was also carried out on a monolayer of silica microparticles that were pre-functionalised with multi-layers of layer-by-layer assembled polymer films. This procedure resulted in the formation of polymeric Janus particles and subsequent dissolution of the silica core resulted in the formation of polymeric Janus capsules.
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ItemBiologically compatible thin films by click chemistry( 2010)The assembly of materials by the Layer-by-Layer (LbL) method provides a versatile and flexible method of assembling nanoscale structures with tailored composition, thickness, size, shape and functionality. Many conventional methods of assembling materials such as thin films and hollow polymer capsules fall short in achieving versatile, covalently bound multilayers. Combining click chemistry, a highly efficient and specific set of reactions, with the established LbL technique provides a number of advantages for the preparation of thin films and hollow polymer capsules. The click-LbL approach permits the production of stable, tailored and functionalisable materials through the modular assembly of a variety of building blocks. This thesis focuses on developing biologically compatible thin films and capsules by the click- LbL technique. Specifically, this work aims to: (i) investigate the fundamental factors controlling the growth and characteristics of click-LbL films; (ii) develop stable, biocompatible films; (iii) demonstrate that click chemistry is a facile and flexible means of functionalising multilayer films; and (iv) demonstrate that click-LbL films are capable of performing specific roles within biological systems. This will be demonstrated through a fundamental study on the assembly of thin films and capsules through assembly of alkyne- and azide-functional poly(acrylic acid) building blocks by the click-LbL technique. The technique is then extended to the assembly of covalently bonded films comprised solely of poly(ethylene glycol) (PEG) acrylates that limit the adsorption of serum proteins. By functionalising click-LbL films of PEG with a cell adhesion promoting peptide, these films then demonstrate the specific adhesion and growth of cells onto a surface. Multilayer films are also assembled using temperature-responsive PEG methacrylate copolymers and their ability to resist the adsorption of proteins from human serum is tested. Hollow capsules comprised of poly(N-vinyl pyrrolidone), with demonstrated low-cytotoxicity, are then produced by multilayer assembly onto colloidal silica. These capsules are covalently stabilised through a click-functionalised cross-linking agent, which can be cleaved under reducing conditions, to deconstruct capsules. The demonstrated properties of click-LbL films and capsules presented herein, offer potential for chemical engineering, pharmaceutical and in particular, biological applications.
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ItemMultifunctional, covalently stabilised capsules from biodegradable materials( 2010)One of the most promising and fast-developing areas of nanotechnology is the design of carrier systems for biomedical applications. These particulate delivery vehicles can be engineered with highly defined properties with a range of sizes, shapes and functionalities. Polymeric nanocapsules assembled using the Layer-by-Layer (LbL) technique are widely regarded as promising candidates for the delivery of biologically relevant agents. By choosing to use naturally occurring polyelectrolyte as LbL materials, such as poly(L-Lysine) (PLL) and poly(L-glutamic acid) (PGA, the resulting capsules can be degraded using enzymes that are present in certain environments within the body. In order to produce covalently stabilised multilayer films, PLL and PGA were modified with alkyne and azide moieties, respectively, enabling the formation of a covalent triazole bond between adjoining layers in the presence of copper during LbL assembly (click chemistry reaction). Stable one-component films and capsules were prepared and characterised. Properties such as enzymatic degradation, tuneable pH-responsive swelling, cytotoxicity, permeability and protein adhesion to the capsule surface were investigated. PLL click films were also equipped with targeting moieties as a proof of concept. The concept of stratified LbL assembly was introduced to tailor the degradation kinetics of the biodegradable hybrid capsules. To investigate drug loading, polymer-drug conjugates of PGA and anticancer drugs (doxorubicin or paclitaxel) were synthesised. The modular LbL assembly approach allowed for loading of these conjugates to multilayer films. A high level of control over drug position and dose was achieved and drugs could subsequently be release by enzymatic degradation. The uptake to colorectal cancer cells and the effect of drug-loaded capsules on cell viability was also investigated. In addition, a drug-resistant cell line was established and the capsular delivery method of anticancer-drugs was found to restore sensitivity of the drug-resistant cell line towards these drugs. In a different approach, PGA was modified with dopamine for continuous assembly of biodegradable capsules with defined properties. Overall, this thesis suggests various promising approaches for the assembly of biodegradable, multifunctional and covalently-stabilised capsules with potential application in targeted drug delivery.