Hurley, Christopher Anthony; (2003) Cationic lipids and investigations into non-viral gene delivery systems. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes investigations carried out into the role of cationic lipids in non-viral delivery of DNA, using a lipid/peptide/DNA (LPD) delivery system. Initially, the principles of gene therapy and current strategies to deliver genes to their targets are described. A literature review of the synthesis and effectiveness of cationic lipids used for gene therapy is presented. This section introduces the structure of lipid aggregates and lipid/DNA complexes important to gene delivery and the methods used to study them. The lipid/peptide/DNA vector is introduced and the advantages it possesses are discussed. The results and discussion starts in Chapter 2, which outlines the synthetic procedures employed to generate N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) lipid analogues. The results of a systematic structure-activity relationship with these compounds are presented and discussed. The influences of lipid chain length, unsaturation and formulation on transfection efficiencies are considered. In Chapter 3 a novel route established to the enantiomerically pure cationic lipids is presented. The influence of optical isomers on the LPD transfection efficiencies is outlined. The synthesis and biological activity of dicationic lipid analogues and polyethylene glycol lipid analogues are given in Chapter 4 and Chapter 5, again together with structure-activity data. The synthetic routes to lipid-amino acid conjugates using S-serine are outlined in Chapter 6, where several synthetic strategies are considered. In Chapter 7 the results of mechanism of action studies using fluorescent correlation spectroscopy, confocal microscopy, azo-dye solublisation and differential scanning calorimetry are presented and the results discussed together with the structure-activity data determined. An overall summary and possible future areas of research are discussed in Chapter 8. A formal description of the experimental methods and procedures is presented in Chapter 9.

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