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Title: A bio-inspired gene therapy approach to treat metastatic prostate cancer
Author: McBride, John William
ISNI:       0000 0004 5370 9830
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Five DBVs were synthesized, expressed, purified, and complexed with plasmid DNA for analysis using a range of physicochemical and biological assays. Four of the vectors (RMHT, RM3GT, T-RMG, and T-RMR) formed cationic nanoparticles with plasmid DNA, and were capable of transfecting prostate cancer cells. Conversely RMGT formed highly cytotoxic anionic particles incapable of transfecting cells. RMHT was the most promising vector as it protected the cargo from serum and facilitated specific delivery into castrate resistant prostate cancer cells. RAT, a fusogenic peptide, is composed of an arginine rich cell penetrating peptide, a steric alpha-helicallinker, and a metastatic tumour targeting ligand named TMTP1. RAT formed non-toxic cationic nanoparticles with plasmid DNA that were capable of specifically transfecting castrate resistant prostate cancer cells through receptor-mediated endocytosis. Furthermore, RAT nanoparticies remained stable over a wide temperature range, and protected DNA from degradation by serum endonucleases. RAT was investigated in combination with iNOS plasmids driven by constitutive (CMV) and tumour type specific (hOC) promoters. RAT facilitated iNOS gene expression, and subsequent generation of μM concentrations of the NO free radical. This equated to a maximum of 59% cell kill and less than 74% clonogenicity in prostate cancer cells. Systemic delivery in vivo slightly delayed tumour growth, and therefore future considerations will include dosing strategies ,and circulation enhancement. These bio-inspired gene delivery platforms overcome a multitude of biological barriers and the results generated in this thesis warrant further investigation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available