Studies of the cationic polymerisation of vinylic and energetic cyclic ether monomers

The cationic polymerisation of various monomers, including cyclic ethers bearing energetic nitrate ester (-ON02) groups, substituted styrenes and isobutylene has been investigated. The main reaction studied has been the ring-opening polymerisation of 3- (nitratomethyl)-3-methyl oxetane (NIMMO) using the alcohol/BF3.0Et2 binary initiator system. A series of di-, tri- and tetrafunctional telechelic polymers has been synthesised. In order to optimise the system, achieve controlled molecular weight polymers and understand the mechanism of polymerisation the effects of certain parameters on the molecular weight distribution, as determined by Size Exclusion Chromatography, have been examined. This shows the molecular weight achieved depends on a combination of factors including -OH concentration, addition rate of monomer and, most importantly, temperature. A lower temperature and OH concentration tends to produce higher molecular weight, whereas, slower addition rates of monomer, either have no significant effect or produce a lower molecular weight polymer. These factors were used to increase the formation of a cyclic oligomer, by a side reaction, and suggest, that the polymerisation of NIMMO is complicated with endbiting and back biting reactions, along with other transfer/termination processes. These observations appear to fit the model of an active-chain end mechanism. Another cyclic monomer, glycidyl nitrate (GLYN), has been polymerised by the activated monomer mechanism. Various other monomers have been used to end-cap the polymer chains to produce hydroxy ends which are expected to form more stable urethane links, than the glycidyl nitrate ends, when cured with isocyanates. A novel monomer, butadiene oxide dinitrate (BODN), has been prepared and its homopolymerisation and copolymerisation with GL YN studied. In concurrent work the carbocationic polymerisations of isobutylene or substituted styrenes have been studied. Materials with narrow molecular weight distributions have been prepared using the diphenyl phosphate/BCl3 initiator. These systems and monomers are expected to be used in the synthesis of thermoplastic elastomers.

Synthesis and evaluation of novel ligands for quantum dot stabilisation and polymerisation studies

This thesis describes the design and synthesis of a variety of functionalised phosphine oxides and sulfides, based on the structure of trioctylphosphine oxide, synthesised for the purpose of surface modification of quantum dots. The ability of the ligands to modify the surface chemistry via displacement of the original hexadecylamine capping layer of quantum dots was evaluated. Finally the surface modified quantum dots were investigated for enhancement in their inherent properties and improved compatibility with the various applications for which they were initially designed. Upon the commencement of research involving quantum dots it became apparent that more information on their behaviour and interaction with the environment was required. The limits of the inherent stability of hexadecylamine capped quantum dots were investigated by exposure to a number of different environments. The effect upon the stability of the quantum dots was monitored by changes in the photoluminescence ability of their cores. Subtle differences between different batches of quantum dots were observed and the necessity to account for these in future applications noted. Lastly the displacement of the original hexadecylamine coating with the "designer" functionalised ligands was evaluated to produce a set of conditions that would result in the best possible surface modification. A general procedure was elucidated however it was discovered that each displacement still required slight adjustment by consideration of the other factors such as the difference in ligand structure and the individuality of the various batches of quantum dots. This thesis also describes a procedure for the addition of a protective layer to the surface of quantum dots by cross-linking the functionalised ligands bound to the surface via an acyclic diene metathesis polymerisation. A detailed description of the problems encountered in the analysis of these materials combined with the use of novel techniques such as diffusion ordered spectroscopy is provided as a means to overcome the limitations encountered. Finally a demonstration of the superior stability, upon exposure to a range of aggressive environments of these protected materials compared with those before cross-linking provided physical proof of the cross-linking process and the advantages of the cross-linking modification. Finally this thesis includes the presentation of initial work into the production of luminescent nanocrystal encoded resin beads for the specific use in solid phase combinatorial chemistry. Demonstration of the successful covalent incorporation of quantum dots into the polymeric matrices of non-functionalised and functionalised resin beads is described. Finally by preliminary work to address and overcome the possible limitations that may be encountered in the production and general employment of these materials in combinatorial techniques is given.

Evaluation of biodegradable polymer microspheres and an anionic dendrimer for the potential delivery of antisense oligonucleotides

Antisense oligonucleotides (AODNs) can selectively inhibit individual gene expression by binding specifically to rnRNA. The over-expression of the epidermal growth factor receptor (EGFR) has been observed in human breast and glioblastoma tumours and therefore AODNs designed to target the EGFR would be a logical approach to treat such tumours. However, poor pharmacokinetic/pharmacodynamic and cellular uptake properties of AODNs have limited their potential to become successful therapeutic agents. Biodegradable polymeric poly (lactide-co-glycolide) (P(LA-GA)) and dendrimer delivery systems may allow us to overcome these problems. The use of combination therapy of AODNs and cytotoxic agents such as 5-fluorouracil (5-FU) in biodegradable polymeric formulations may further improve therapeutic efficacy. AODN and 5-FU were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations (double emulsion method) and release profiles determined in vitro. The release rates (biphasic) of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Sustained release over 35 days was observed in both types of formulation. Naked and microsphere-loaded AODN and 5-FU (in separate formulations) were tested on an A431 vulval carcinoma cell line. Combining naked or encapsulated drugs produced a greater reduction in viable cell number as compared with either agent alone. However, controls and Western blotting indicated that non-sequence specific cytotoxic effects were responsible for the differences in viable cell number. The uptake properties of an anionic dendrimer based on a pentaerythritol structure covalently linked to AODNs (targeting the EGFR) have been characterised. The cellular uptake of AODN linked to the dendrimer was up to 3.5-fold higher in A431 cells as compared to naked AODN. Mechanistic studies suggested that receptor-mediated and adsorptive (binding protein-mediated) endocytosis were the predominant uptake mechanisms for the dendrimer-AODN. RNase H cleavage assay suggested that the dendrimer-AODN was able to bind and cleave the target site. A reduction of 20%, 28% and 45% in EGFR expression was observed with 0.05μM, 0.1μM and 0.5μM dendrimer-AODN treatments respectively with a reduction in viable cell number. These results indicated that the dendrimer delivery system may reduce viable cell number by an antisense specific mechanism.

Cationic ring opening polymerisation (CROP) of oxetane and its derivatives using oxonium derived initiators

Several cationic initiator systems were developed and used to polymerise oxetane with two oxonium ion initiator systems being investigated in depth. The first initiator system was generated by the elimination of a chloride group from a chloro methyl ethyl ether. Adding a carbonyl co-catalyst to a carbocationic centre generated the second initiator system. It was found that the anion used to stabilise the initiator was critical to the initial rate of polymerisation of oxetane with hexafluoroantimonate resulting in the fastest polymerisations. Both initiator systems could be used at varying monomer to initiator concentrations to control the molecular number average, Mn, of the resultant polymer. Both initiator systems showed living characteristics and were used to polymerise further monomers and generate higher molecular weight material and block copolymers. Oxetane and 3,3-dimethyl oxetane can both be polymerised using either oxonium ion initiator system in a variety of DCM or DCM/1,4-dioxane solvent mixtures. The level of 1,4-dioxane does have an impact on the initial rate of polymerisation with higher levels resulting in lower initial rates of polymerisation but do tend to result in higher polydispersities. The level of oligomer formation is also reduced as the level of 1,4-dioxane is increased. 3,3-bis-bromomethyl oxetane was also polymerised but a large amount of hyperbranching was seen at the bromide site resulting in a difficult to solvate polymer system. Multifunctional initiator systems were also generated using the halide elimination reactions with some success being achieved with 1,3,5-tris-bromomethyl-2,4,6-tris-methyl-benzene derived initiator system. This offered some control over the molecular number average of the resultant polymer system.

Zwitterionic and charge-balanced (polyampholyte) copolymer hydrogels

Zwitterionic compounds, or zwitterions, are electrically neutral compounds having an equal number of formal unit charges of opposite sign. In common polyzwitterions the zwitterionic groups are usually located in pendent groups rather than the backbone of the macromolecule. Polyzwitterions contain both the anion and cation in the same monomeric unit, unlike polyampholytes which can contain the anion and cation in different monomeric units. The use of cationic and anionic monomers (or monomers capable of becoming charged) in stoichiometric equivalent proportions produces charge-balanced polyampholyte copolymers. Hydrogel materials produced from zwitterionic monomers have been proposed for use and are used in many biomaterial applications but synthetic charge-balanced polyampholyte are less common. Certain properties of hydrogels which are important for their successful use as biomaterials, these include the equilibrium water content, mechanical, surface energy, oxygen permeability, swelling and the coefficient of friction. The zwitterionic monomer N,N-dimethyl-N-(2-acryloylethyl)-N-(3-sulfopropyl) ammonium betaine (SPDA) was synthesized with 2-hydroxyethly acrylate (HEMA) as the comonomer to produce a series of polyzwitterion hydrogels. To produce charged-balanced copolymer hydrogels two “cationic” monomers were selected; 2-(diethylamino) ethyl methacrylate (DMAEMA) and 3-(dimethylamino) propyl methacrylamide (DMAPMA) and an anionic monomer; 2-acrylamido 2,2 methylpropane sulphonic acid (AMPS). Two series’ of charge-balanced copolymers were synthesized from stoichiometric equivalent ratios of DMAEMA or DMAPMA and AMPS with HEMA as a terpolymer. The zwitterionic copolymer and both charge-balanced copolymers produced clear, cohesive hydrogels. The zwitterionic and charge-balanced copolymers displayed similar EWC’s along with similar mechanical and surface energy properties. The swelling of the zwitterionic copolymer displayed antipolyelectrolyte behavior whereas the charge-balanced copolymers displayed behaviour somewhere between this and a typical polyelectrolyte. This work describes some aspects of the polymerisation and properties of SPDA copolymers and charge-balanced (polyampholyte) copolymers relevant to their potential as biomedical / bioresponsive materials. The biomimetic nature of SPDA together with its compatibility with other monomers makes it a useful and complimentary addition to the building blocks of biomaterials.