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Title: Characterisation and evaluation of poly(2-methacryloyl-oxy) ethyl phosphorylcholine- poly(2-diisopropyl-amino) ethyl methacrylate (PMPC-PDPA) self-assembly for biomedical applications
Author: Pearson, Russell
ISNI:       0000 0004 5368 5947
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Drug Delivery Systems (DDS) can be used to improve the effectiveness of therapeutic small molecules by enabling specific targeting, lower doses and reduced side effects. Polymersomes are a fully synthetic, non-toxic DDS capable of entrapping, delivering and releasing a therapeutic cargo inside mammalian cells. Improvements to the production and purification processes for polymersomes may improve their efficiency as a DDS. The aim of this thesis was to investigate the formation of dispersed pH responsive PMPC-PDPA polymersomes specifically for drug delivery applications. Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), potentiometry and turbidity measurements were used to characterise polymersomes and their formation. The effects of sample temperature on the formation of polymersomes by pH increase was studied with the aim of controlling polymersome size. Four copolymers were used, each with identical PMPC block lengths and different PDPA block lengths. It was found that the smallest copolymer investigated(PMPC25-PDPA47) formed micelles, while the remaining three copolymers with varying lengths favoured the formation of polymersomes. Additionally, a shift in the copolymer acid dissociation constant was observed using potentiometry and a trend of smaller particles being formed at higher temperatures (30-50°C) and shorter PDPA block length (PDPA47-94) was also observed. Morphological analysis revealed the formation of polymersomes, micelles and complex structures known as genus particles. Across the four copolymers, micelles were generally formed at the higher temperatures (50°C), while genus structures were formed at low temperatures ( < 15°C) and polymersomes formed at intermediate temperatures (20-37°C).Genus particles were then studied further as there are only a handful of publications on experimentally observed genus particles formed from amphiphiles. It was observed via morphological analysis that both the number of genus events (holes) and the size of the particles increased with decreasing temperature. The theory that these structures were formed by the addition of 9 extra copolymer chains to the outside of already formed polymersomes was tested by mixing dissolved unimers with formed polymersomes at low temperatures. The resulting structures were not full genus particles but there were noticeable differences in the particle topologies compared to polymersome-only samples. The relationship between temperature and polymersome formation was also explored further by driving the formation via a temperature increase as opposed to a pH increase. This was conducted using a spectrophotometer with an inbuilt temperature control unit so that formation was measured in situ via an increase in sample turbidity. Formation through temperature change was achieved by maintaining sample pH and increasing the temperature, then TEM was used to confirm the formation of polymersomes. Finally, an improved calculation of encapsulation efficiency was produced by incorporating the measured size distribution data obtained from DLS into the estimation. An automated Size Exclusion Chromatography (SEC) system was also set up to compare the purification against currently used bench-top systems. Samples processed using the automated system and the improved calculation could be used to more accurately predict the encapsulation of a hydrophilic compound and as a point of reference for encapsulation experiments. This work demonstrates the high degree of flexibility associated with the formation process of PMPC-PDPA polymersomes and related structures for drug delivery applications. Future work would include further characterisation of genus particles, in vitro delivery studies and experimental validation of the encapsulation model.
Supervisor: Reilly, Gwendolen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available