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Title: Exploring hyperbranched-polydendron chemistry and architecture for nanomedicine applications
Author: Rogers, H. E.
ISNI:       0000 0004 6059 0241
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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The introduction of amphiphilicity into hyp-polydendrons has been achieved for the first time through the use of tertiary amine functional dendritic chain-ends and branched hydrophobic polymer chains. Explorations into the chemistry and architectural components within the hyp-polydendron structure has been carried out, offering the opportunity to control both structural and chemical behaviour. These have included: variation of the chemical composition of the primary polymer chain; utilisation of different monomers within the polymerisation; variation of dendron surface and linker chemistry; variation of primary chain architecture to produce statistical and block copolymers; variation of the degree of polymerisation; and initiation by multiple initiators (dendron and non-dendron) to result in mixed surface groups on the hyp-polydendron. The synthesis and aqueous nanoprecipitation of these branched materials is compared with their linear–dendritic polymer analogues, showing that the chemical and structural variables are all capable of influencing the ability to generate nanoparticles, the resulting nanoparticle diameter and dispersity, and subsequent response to changes in pH. The incorporation of the monomer, 2-(diethylamino)ethyl methacrylate, and a new acid-cleavable brancher has resulted in the preparation of pH-responsive nanoparticles that undergo solubilisation upon the addition of acid. Additionally, the hydrolysis of aggregated nanoprecipitates into linear-dendritic polymer chains has been confirmed by gel permeation chromatography, and encouraging encapsulation and release studies demonstrate a promising platform for pH-responsive drug delivery vehicles. The co-nanoprecipitation of linear-dendritic hybrids with branched copolymers has produced stable nanoparticle dispersions. Comparative nanoparticle behavioural studies, and consequent response to changes in pH have been conducted between co-nanoprecipitated nanoprecipitates in aqueous media to similarly composed hyp-polydendron nanoprecipitates containing covalently-bound dendron chain-ends. The dye molecule fluoresceinamine has been selected as a model guest molecule for encapsulation (9 wt%) within certain nanoparticles which were stable under physiologically-relevant conditions. Cytotoxicity and transcellular permeability studies were carried out using Caco-2 cells, showing low cytotoxicity at the concentrations studied, enhanced permeation though the Caco-2 cell monolayer, and high accumulation in Caco-2 and ATHP-1 cells. Finally, the ring opening co-polymerisation of ε-caprolactone and 4,4’-bioxepanyl-7,7’-dione using dendron initiators was explored. This resulted in stable ε-caprolactone nanoprecipitates formed in aqueous media, from biodegradable polyester hyp-polydendrons. To the best of our knowledge, this is the first example of stabilised p(CL) nanoparticles in aqueous solution, without the need for additional stabilisers.
Supervisor: Rannard, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral