Cationic polymers have been widely investigated as non-viral gene delivery solutions. The aim of this thesis was to identify key design criteria for the development of transfection agents for pancreatic cancer. A library of linear cationic copolymers was successfully synthesised using Group Transfer Polymerisation (GTP) and their physicochemical properties, cytotoxicity and ability to condense and deliver miRNA were systematically investigated.

The 1st project of this thesis describes Polymer Series 1 and 2. In both series, polymer architecture was varied while MM and composition were kept constant. In Series 1, copolymers were synthesised with tri(ethylene gycol) ethyl ether methacrylate (TEGEMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA). In Series 2, oligo(ethylene gycol) methyl methacrylate (OEGMA300) and DMAEMA were used. The aim of this 1st project was to investigate the effect monomer position (architecture) has in cytotoxicity, particularly, and subsequently in miRNA condensation ability and transfection efficiency. The 2nd project of this thesis describes Polymer Series 3, where 4 statistical copolymers of increasing MM were investigated for their properties, cytotoxic effects, miRNA antagonist condensation ability and transfection efficiency. The 3rd project of this thesis describes the functionalisation of statistical and diblock OEGMA-DMAEMA copolymers, of constant MM and composition, with a permanent charge (quaternisation, Series 4, Part I) and with cy5-azide, an imaging group (Series 5, Part II). The aims of this project were: (i) to understand if the addition of permanent positive charges would have detrimental effects on cytotoxicity, while improving polyplex formation and transfection efficiency; (ii) through the addition of an imaging group, understand if OEGMA-DMAEMA polymers are internalised by a range of cell lines and if monomer position would have an effect.

In conclusion, it was identified that the position of the monomers in the polymer chain is a crucial feature in polymer design. The thermoresponsive properties of copolymers were affected by polymer architecture. It was also found that the random distribution of monomers along the polymer chain leads to more pronounced cell death than non-random (block) architectures. Such trend was also observed upon functionalisation of the copolymers with imaging groups or with permanent cationic charges.