Use this URL to cite or link to this record in EThOS: | https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.727507 |
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Title: | Development and characterisation of a multifunctional peptide-based vector for delivery of miR-34a gene therapy to metastatic prostate cancer | ||||
Author: | Loughran, Stephen |
ISNI:
0000 0004 6425 0295
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Awarding Body: | Queen's University Belfast | ||||
Current Institution: | Queen's University Belfast | ||||
Date of Award: | 2017 | ||||
Availability of Full Text: |
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Abstract: | |||||
The aim of this thesis was to develop a peptide-based gene delivery system capable of delivering plasmid miR-34a to metastatic prostate cancer cells. The arginine-rich, fusogenic peptide known as RALA was used as the basis of the gene delivery vector. Polyethylene glycol 5K (PEG5K) was conjugated to the C-terminus of the RALA peptide (RALA-P) in order to improve peptide pharmacokinetics in vivo and promote tumour accumulation by the EPR effect. RALA was combined with RALA-P at various w/w ratios in order to identify which ratio provided optimal results in vivo. At w/w 6:8, the RALA/RALA-P conglomerate resulted in a significant increase in tumour accumulation and significantly reduced accumulation in off-target organs. In order to further improve tumour specificity, PEG5K was bound to RALA via an MMP2/9-cleavable linker (RALA-c-P) resulting in further increase in transgene expression at w/w 8:6 in the tumour site. The capacity for miR-34a to slow cancer growth rate and reduce metastatic potential in prostate cancer cell lines was verified both in vivo and in vitro. miR-34a was subsequently delivered to prostate cancer xenografts using RALA/RALA-c-P nanoparticle system resulting in reduced growth and increased survival.
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Supervisor: | Not available | Sponsor: | Not available | ||
Qualification Name: | Thesis (Ph.D.) | Qualification Level: | Doctoral | ||
EThOS ID: | uk.bl.ethos.727507 | DOI: | Not available | ||
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