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Title: Developing cationic nanoparticles for gene delivery
Author: Krishnamoorthy, Mahentha
ISNI:       0000 0004 7652 1021
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2016
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Gene delivery can potentially treat acquired and genetic diseases such as cystic fibrosis, haemophilia and cancer. Non-viral gene delivery vectors are attractive candidates over viral vectors such as recombinant viruses, due to their lower cytotoxicity and immunogenicity, despite significantly lower transfection efficiencies. To improve efficiency of non-viral vectors, the investigation of the various parameters influencing DNA transfection is essential. The present study developed a versatile gene delivery system with tailored physicochemical and biological properties. The system used polymer brushes synthesised via atomic transfer radical polymerisation (ATRP), grafted from silica nanoparticles, whose charge density, grafting density, chemistry, length of brush, the size and shape can be altered. The primary focus of the study was poly(2-dimethylaminoethyl methacrylate) (PDMAEMA), known for its positive charge and DNA condensation. The ability of PDMAEMA to interact with DNA was characterised using dynamic light scattering, electrophoretic light scattering methods, surface plasmon resonance and in situ ellipsometry whilst its interaction with cells was studied via cell viability assays. The brush behaviour in response to pH and ionic strength was also studied. The charge density was altered by copolymerising with poly[oligo(ethylene glycol) methyl ether methacrylate](POEGMA) and the effect of such modification on DNA interaction was studied. PDMAEMA-grafted nanoparticles gave the highest transfection efficiency compared to other synthesised polymer brushes, but still displaying almost 2-fold lower transfection efficiency than the commercially available reagent jetPEI®. Different brush chemistries were also investigated. Poly(glycidyl methacrylate) (PGMA) decorated with oligoamines: allylamine, diethylenetriamine and pentaethylene hexamine, and PDMAEMA quaternized with alkyl halides: methyl iodide, allyl iodide and ethyl iodoacetate did not show any significant transfection, despite their performance reported in the literature. The robust system developed is a promising platform for further investigation of parameters influencing cellular uptake and gene expression, and important milestone to develop non-viral gene delivery systems.
Supervisor: Not available Sponsor: Royal Society ; Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Engineering and Materials Science ; Gene delivery ; atomic transfer radical polymerisation