The development of methods for the facile synthesis of therapeutic polymer nanocarriers.
Creators: name: Bromley, Adam
Publisher: name: University of Surrey
Year: 2020

description: The work in this thesis considers the development and optimisation of methods with regards to the synthesis and formation of polymeric nanomaterials. A particular focus is placed on synthesising polymers based on N-2-hydroxypropyl methacrylamide (HPMA) and ε-caprolactone (PCL) with regards to drug delivery applications. Polyethylene glycol (PEG) and PEG-based materials were intentionally avoided due to the growing body of research surrounding the accelerated blood clearance phenomenon. Reversible addition-fragmentation chain transfer (RAFT) polymerisation was employed in the synthesis of linear, block and branched forms of poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA). Linear PHPMA was synthesised according to established synthetic methods and found to yield well defined materials (12 – 17 kg mol-1; Ð 1.02 – 1.08). Homotelechelic PCL with terminal RAFT functionalities was employed as a macro-CTA in the synthesis of PHPMA-b-PCL-b-PHPMA triblock copolymers. After optimisation of the reaction conditions a reasonably well-defined amphiphilic polymer was obtained (Mn 29 kg mol-1; Ð 1.41) which was observed to undergo spontaneous self-assembly in water (average particle diameter 44 nm). Alternative synthetic routes utilising click methodologies (thiol-ene, hetero-Diels-Alder and copper azide-alkyne cycloaddition) were investigated but ultimately did not yield any improvements when compared to the macro-CTA grafting-from approach. Hyperbranched PHPMA was synthesised by a free-radical crosslinking copolymerisation method which utilised ethylene glycol dimethacrylate (EGDMA) as a divinyl crosslinking agent. Extensive characterisation of branching parameters was performed using a combination of triple detection size-exclusion chromatography (SEC) and 1H NMR. After optimising the reaction conditions, three hyperbranched copolymers of HPMA and acetylated-HPMA (APMA) were synthesised; surface RAFT moieties underwent additional polymerisation with HPMA to ultimately yield novel PHPMA-star-(hb-PHPMA-co¬-PAPMA) core-crosslinked amphiphilic star copolymers (Mn 139 – 243 kg mol-1, Ð 1.07 – 1.27). Additionally, charge controlled nanoprecipitation of homotelechelic carboxyl terminated PCLs in a range of alkaline pH buffered solutions was performed according to a literature procedure. The lowest diameter particles were observed to form when precipitation was performed in a pH 9 aqueous phase (14 ± 1 nm), as determined by dynamic light scattering (DLS). Overall, synthesis of PHPMA-b-PCL-b-PHPMA block copolymer at higher molecular weight and lower dispersity than previously reported materials from a homotelechelic dithiobenzoate macro-CTA was achieved. Furthermore, three novel PHPMA-star-(hb-(PHPMA-co-PAPMA)) copolymers were synthesised and the branching parameters of the hydrophobic core characterised by 1H NMR spectroscopy. Preliminary work into developing a scalable synthetic procedure for producing PCL nanoparticles was undertaken. Under optimal conditions PCL-oTHPA nanoparticles were produced with a number-average particle diameter of 14 ± 1 nm (error is ± 1 S.D.).