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Title: Complexation of cationic polymers with nucleic acids for gene delivery
Author: Freund, Amy
ISNI:       0000 0004 5356 0933
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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The prospect of gene delivery for therapeutic purposes has created much hope for the treatment and prevention of diverse illnesses, both inherited and environmental. One major challenge for the realisation of this potential is the availability of a suitable vector for trafficking foreign DNA into a cell. Many viruses are effective but carry unacceptable risks of dangerous host immune response or infection. Cationic polymers have been identified as promising candidates to neutralise the DNA’s negative charge and gain entry to the cell. In this work a structural study was conducted on a range of established and novel cationic polymer vectors in complexation with nucleic acid molecules for gene delivery. The high neutron flux of the recently available SANS2D instrument on the second target station at the ISIS pulsed neutron source was used in conjunction with a stopped-flow apparatus to study the static and kinetic structure of aggregates of complexes formed between different architectures and molecular weights of polyethylenimine, a commonly used, highly cationic polyelectrolyte, and nucleic acids. Findings indicated the stability of high molecular weight branched polyethylenimine was superior to any other architecture studied. Subsequently, the zeta potential of these polymers complexed with biologically relevant siRNA molecules was studied, which suggested was established that aggregation still proceeds, even with the most apparently stable of the complexes. Finally, structural studies of the complexation between a family of synthetic, biocompatible cationic block copolymer vectors which incorporate a stabilising, hydrophilic conjugate block, designed to mitigate aggregation of the extent encountered by PEI complexes upon binding are described. The variation of neutron scattering with charge ratio of polymer to DNA was elucidated for this family of systems.
Supervisor: Lu, Jian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available