title: Hyerbranched polydendrons: a new macromolecular architecture
Creators: name: Hatton, Fiona
Publisher: name: University of Liverpool Repository
Year: 2015

description: A novel architecture ‘hyperbranched polydendrons’ (hyp-polydendrons) was produced via the synthesis of low generation dendron initiators for ATRP and subsequent copolymerisation of vinyl and divinyl monomers, to give large polymeric macromolecules containing dendron moieties at the end of each primary chain. Subsequent studies of such materials were performed to assess their ability to form nanoparticles via a nanoprecipitation approach, utilising organic solvent and aqueous nanoparticle formation. It was found that the branched polymers were superior to the linear polymer analogues when assessing their nanoprecipitation behaviour. Mixed initiator hyp-polydendrons were also synthesised by the statistical incorporation of different functionality initiators into the reaction mixture. Here a G2 dendron and different PEG macroinitiators were mixed statistically to produce a series of materials where the primary chain length of the monomer HPMA was also varied. This led to a series of nanoparticles which showed a variation of internal environments when studied using different fluorescent dyes (Nile red and pyrene). Initial pharmacological experiments were promising, however, the initial set of materials did not show prolonged stability in physiologically relevant conditions when using a short PEG macroinitiator (750PEG). Extending the length of the PEG chain (2000PEG initiator) in the mixed polymerisations produced a range of materials with varying solubilities and, therefore, nanoprecipitation behaviour. Nanoparticles were formed which were stable under physiologically relevant conditions and were studied for their cytotoxicity and transcellular permeability in Caco- 2 cells. These materials showed limited toxicity at the concentrations studied and enhanced permeation though the Caco-2 cell monolayer, which is a model of the intestinal epithelial cells. Further studies of the nanoprecipitation behaviour of different molecular weight fractions of the hyp-polydendrons were conducted. This involved separation of molecular weight fractions by dialysis of the hyp-polydendrons against two different good solvents, leading to two HMW fractions and two LMW fractions. Analysis of the nanoprecipitation behaviour of these fractions showed that the HMW fractions produced particles with more narrow PdIs, and the mixing of a low amount of a HMW fraction (1 wt%) with a linear polymer improved the nanoprecipitation behaviour hugely. Encapsulation of two different guest molecules via nanoprecipitation was assessed using FRET, which can report on the proximity of two fluorophores. Dual loading of the particles with DiO and DiI in a 1:1 ratio gave particles which exhibited a FRET signal, therefore indicating that the two fluorophores were located in the same nanoparticle. Somewhat unexpectedly it was found that upon mixing of the two singly loaded particles the observed FRET ratio increased over time until it reached a similar value obtained within the dual loaded nanoparticles. This was possibly due to nanoparticle-nanoparticle collisions. Therefore hyp-polydendrons were produced and utilised to form nanoparticles via a nanoprecipitation approach. Loading of the nanoparticles was achieved and pharmacological benefits were observed for some of the nanoparticle samples, suggesting future benefits for these polymer architectures in nanomedicine applications.