Cook, Alexander B. (2018) Highly branched and hyperbranched polymers : synthesis, characterisation, and application in nucleic acid delivery. PhD thesis, University of Warwick.

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Abstract

Polymer chemistry enables the design and development of synthetic cationic gene delivery systems with varying polymer architectures. Branched polymers have been shown to have advantages for drug delivery purposes including nucleic acid delivery. The objective of this work is to utilise advanced polymer synthesis methods to synthesise a range of cationic polymers with well controlled branched architectures and investigate their cytotoxicity, nucleic acid complexation, resulting polyplex morphology, and gene transfection efficiency.

Firstly, the synthesis of hyperbranched polymers using thiol-yne chemistry is explored with a semi-batch process to form hyperbranched polymers with well-defined molecular weights and dispersities. Following this, cationic moieties are introduced onto thiol-yne hyperbranched polymers using the ring opening polymerisation of 2-ethyloxazoline and an additional hydrolysis step to form PEI-POx copolymers with hyperbranched architectures. An investigation of plasmid DNA complexation, and in vitro toxicity and GFP plasmid gene transfection is then conducted.

RAFT polymerisation is then utilised to form highly branched polymer architectures by copolymerisation of a divinyl branching comonomer. This strategy has the advantage of being able to introduce tuneable degradation and nucleic acid release. Finally, the possibility of using RAFT to synthesise branched polymers with phosphonium cationic moieties is also investigated, and their DNA complexation, toxicity, and gene transfection efficiency compared to the equivalent cationic polyammoniums.

Overall, this thesis describes a number of advanced polymer synthesis methods to create hyperbranched and highly branched cationic polymers suitable for nucleic acid complexation, and also investigates their structure-function characteristics relating to aspects of nucleic acid delivery.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Addition polymerization, Branched polymers, Polymers in medicine, Drug delivery systems, Nucleic acids -- Therapeutic use, Transfection, Genetic transformation
Official Date:	February 2018
Dates:	Date Event February 2018 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Perrier, Sébastien
Format of File:	pdf
Extent:	xix, 220 leaves : illustrations, charts
Language:	eng

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