| الوصف: |
The objectives of this thesis are to develop a simple method of synthesising glyconanoparticles, use these particles to explore the impact of particle size and hardness on lectin binding, and to develop a targeted antibiotic delivery system. Nanoparticles have various properties that can be modified to improve their performance such as: size, morphology and surface charge. They can also be surface functionalised with sugars such that they target a specific location through interaction with cell surface lectins. Glyconanoparticles may be synthesised in a variety of ways. One suitable method of preparation is emulsion polymerisation, a classic emulsion polymerisation being free radical with the addition of surfactant. Methods to improve the biological properties of the resulting latex include RAFT emulsion polymerisation and a classic free radical emulsion polymerisation, without the addition of a surfactant. The former potentially suffers from being prohibitively expensive and time consuming, and the latter from poor size control and lack of surface functionality. Glycosylated nanoparticles were initially synthesised via RAFT emulsion polymerisation; subsequently a simplified free radical surfactant free emulsion polymerisation was used, with the addition of a hydrophilic co-monomer, to improve size control and impart surface functionality. Glyconanoparticles between 50-350 nm in diameter were produced with both methods. The particles were subsequently used to determine the effect of particle size and core glass transition temperature (Tg) on lectin induced aggregation. Larger particles, and those with a "soft" core above their Tg were quantitatively shown to aggregate to a greater extent, with more particles per aggregate. The free radical technique was further used to produce a pH responsive, mannosylated nanoparticle, capable of: targeting macrophages, selectively releasing isoniazid intracellularly and breaking up after endocytosis. This system was shown to eradicate intracellular mycobacteria (BCG) in cellulo at physiological concentrations. Overall this thesis presents the facile synthesis of glyconanoparticles suitable for a wide range of applications and uses them to explore the influence of size and hardness on particle-lectin interactions. The same synthetic technique is used to produce a macrophage targeted, dual pH responsive nanoparticle capable of delivering isoniazid intracellularly. |
