The use of a novel technology platform to create a DNA vaccine for prostate cancer

• Main Author: Cole, Grace
• Published: Queen's University Belfast 2017
• Subjects: 616.99
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.725741

The subject of this thesis is the development of a Prostate Cancer DNA Vaccine. Firstly, the thesis focuses on the design and optimisation of a dissolvable microneedle array which operates to penetrate through the outer layer of the skin, the stratum corneum, and dissolve in contact with the interstitial fluid, releasing the vaccine cargo in proximity of high number of antigen-presenting cells within the skin. This vaccine cargo is composed of DNA encoding antigenic peptides of interest, bound into nanoparticles with the cell penetrating peptide, RALA, which serves to enhance DNA uptake by antigen presenting cells. As part of the development process this work examines the suitability of different polymers for the fabrication of DNA-laden microneedles, determining the effect of each polymer on the physical characteristics of the microneedles, as well as the effect on the integrity of the RALA/DNA cargo. Following the selection of the "best" polymer for microneedle fabrication, the second chapter centers on improving the device by increasing the cargo loading and stability. To achieve this, a suitable lyophilisation process for RALA/DNA nanoparticles is identified, and a new method of fabricating the microneedles is developed. The result of this work is the development of strong, sharp microneedle prototype, capable of eliciting gene expression in vitro and in vivo. Following the design and validation of this novel DNA delivery device, the third chapter examines its' use as a platform for prostate cancer DNA vaccination. The ability of the device to elicit antigen-specific cytotoxic T lymphocyte responses against three prostate cancer tumour associated antigens (TAAs), STEAP, PSCA and PAP, is examined, and finally the ability of the platform to both prevent the development of and retard the growth of prostate tumours in a murine model is determined.