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Title: Novel multifunctional delivery systems for the treatment of prostate cancer
Author: Massey, A.
ISNI:       0000 0004 5371 4816
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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The purpose of this thesis was to evaluate novel protein and peptide based delivery systems for their role in gene therapy and optimisation of anionic drug bioavailability. The recombinant protein D-SMH was found to form small nano-sized particles with plasmid DNA which were capable of specifically targeting prostate cancer cells and achieving transfection efficiencies higher than previous Designer Biomimetic Vectors. Not only was this higher transfection efficiency achieved but neither was it improved in the presence of the endosomolytic agent chloroquine indicating the functionality of the endosomal disruption motif in the sequence. D-SMH presents itself as a candidate for the logical progression past the numerous hurdles in gene delivery including DNA condensation, cell-targeting, cell penetration, endosomal disruption and nuclear localisation. RALA, a 30-mer, arginine-rich peptide was next assessed for its ability to condense siRNA and form nanoparticles capable of transfecting prostate cancer cells. Having confirmed the formation. of small «100nm), positively charged nanoparticles which achieved a transfection efficiency of 95% immediately after a 4 h transfection, the nanoparticles were found to be capable of inducing significant knockdown of the target protein Runx2 in prostate cancer cells with subsequent reduction in cancer cell proliferation. This was translated to the in vivo setting with the pilot study suggesting 80% increase in survival time. Finally, it was hypothesised that since RALA was capable of forming small nanoparticles with anionic nucleic acids, it might also be capable of behaving in the same way with anionic drugs such as the bisphosphonates. The hypothesis was proven as RALA did form small nano-sized particles with the anionic BPs as per a mass ratio. The particles were observed to be stable and induce cell death which was confirmed in vivo with an increase in survival time of 58% compared to control.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available