Chemical and Biomolecular Engineering - Theses
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ItemIn vivo behaviour of polymer-based nanoengineered materials( 2016)Nanoengineered materials are attracting a great deal of interest as the basis for therapeutic delivery systems, due to their potential to prolong circulation half-lives, circumvent solubility problems and reduce toxicity through efficient targeting. The versatility of polymers and polymer-based materials makes them logical candidates in this area, where the ability to tailor particular functionalities is key to producing materials which have a place in the clinic. Specifically, capsules assembled using the layer-by-layer (LbL) technique offer unique control over material composition, size, shape and functionality. Additionally cylindrical polymer brushes (CPBs) offer unique properties, being single molecules which can offer particle-like dimensions through highly tuneable chemistry. Understanding the behaviour of such systems in vivo is critical to progressing materials beyond the laboratory. Achieving significant blood residence time is important for the ultimate bioavailability of potential encapsulated therapeutics. This thesis looks at the in vivo behaviour of both LbL assembled polymer capsules and cylindrical polymer brushes. Specifically this work aims to (i) investigate the behaviour of click-LbL capsule systems in vivo; (ii) extend the understanding of LbL capsule protein fouling behaviour, relating in vitro to in vivo findings; (iii) investigate the behaviour of cylindrical polymer brush materials in vivo. This will be demonstrated through the assembly of a range of click-LbL capsule systems including poly(methacrylic acid) (PMA), poly(N-vinyl pyrrolidone) (PVPON), and poly(2-diisopropylaminoethyl methacrylate) (PDPA), followed by tritium labelling and analysis using a rat model to establish capsule pharmacokinetics and biodistribution. The understanding of LbL capsule behaviour in vivo is then extended by applying poly(ethylene glycol) (PEG) functionalisation approaches to PVPON film and capsule modification. Capsules are functionalised using single PEG chains as well as densely grafted PEG CPBs. Methods used to assess film interaction with serum proteins in vitro are evaluated in light of in vivo performance. This leads to an in vivo study of CPBs to support their viability as drug delivery vehicles in their own right. CPB pharmacokinetics and biodistribution are shown to be dependent on both brush length and stiffness, with promising half-lives in the range reported for some stealth liposome systems. The fundamental in vivo data reported for both LbL capsules and CPBs are expected to form a valuable foundation for the further development of both systems.
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ItemRapid, facile and automated polymer assembly techniques for the preparation of layer-by-layer capsules( 2014)Layer-by-layer (LbL) assembled films and capsules have shown potential application in diverse fields such as energy and drug delivery, because they can be prepared from various polymers and loaded with numerous materials. Although film deposition on planar substrates can be rapid and facile using techniques such as spray-coating or spin-coating, the layering of particles generally requires longer and more involved protocols. LbL assembly on particles typically uses random diffusion as the adsorption driving force, which can lead to the risk of aggregation during layering and washing. To overcome the inherent challenges surrounding polymer deposition on particulate matter, immobilization techniques for suspending the template particles were developed. Immobilizing the template particles has allowed for rapid, facile, and automated layering methods to be applied to particles of varying sizes and compositions. Large particles were suspended in a liquid-based fluidized bed for layering, while smaller particles required immobilization in a porous hydrogel before facile layering was possible. The use of a fluidized bed allowed for the large scale production of polymer microcapsules at a rate roughly ten times faster than conventional methods. However, this technique was generally limited to particles above 5 micrometers. For the hydrogel immobilized particles, a naturally derived polysaccharide, agarose, was used as an immobilizing agent. Electrophoresis, convection and diffusion were then used to deposit polymers on immobilized particles and form capsules ranging from below 100 nanometers to above 1 micrometer. These driving forces allow for the use of different polymer combinations, can be used to load various types of cargo, and can be used to form polymer replica particles. Each driving force has unique benefits, and all three driving forces are either already automated, or potentially automatable. The speed, ease, scope and scale with which these capsules can now be produced should benefit research and development directed towards the application of LbL capsules.
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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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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.