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Targeted delivery of anti-cancer drugs by MS2 virus-like particles

Yan, Ruiyang (2015) Targeted delivery of anti-cancer drugs by MS2 virus-like particles. PhD thesis, University of Leeds.

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Abstract

Problems associated with poor pharmacokinetics and biodistribution, as well as toxic off-target effects, limit the curative potential of most anti-cancer drugs. This has prompted the development of nanoparticulate drug delivery systems to impart both more favourable pharmacological properties and precise tumour targeting. The vast number of formulations, ranging from fully synthetic delivery systems to ones derived from natural sources, currently undergoing clinical trials or preclinical testing underlines the significance of this field. This project is a proof-of-concept investigation into the feasibility and effectiveness of a novel drug delivery system, based on virus-like particles (VLPs) of the MS2 bacteriophage. Doxorubicin (Dox) and an anti-BCL2 siRNA were used as model drug cargos. They were packaged inside MS2 VLPs either by chemical infusion, or via covalent attachment to an MS2 packaging signal, TR, respectively. An average loading of ~10 molecules of siRNA or ~110 molecules of Dox per VLP was achieved. Packaged cargos remained stably encapsidated; the siRNA was protected from nuclease degradation. VLPs were surface decorated with polyethylene glycol (PEG), and tumour-targeting ligands, human transferrin (Tf) or A9L, an RNA aptamer that targets prostate-specific membrane antigen (PSMA). Extensive PEGylation was achieved (~97% of coat proteins), and each VLP displayed on average ~7 molecules of Tf or ~16 molecules of A9L. PEGylation significantly reduced the non-specific cellular uptake of VLPs, and antibody binding. Further addition of tumour-targeting ligands facilitated the specific delivery of drug cargos to targeted cancer cells in culture, likely via receptor-mediated endocytosis, and induced significant cytotoxicity with an LC50 of ~10 nM for siRNA and ~800 nM for Dox. Importantly, negligible toxic effects were observed in the presence of excess free targeting ligands, or with non-targeted control cell lines. Furthermore, the cellular uptake of VLPs did not appear to induce any off-target effects. MS2 VLPs continue to show promise as a robust, flexible and effective drug delivery system. This project highlights the versatility of VLPs for displaying a range of useful ligands on their surface, as well as packaging various therapeutic cargos, and demonstrated their ability to specifically deliver drugs to targeted cancer cells. Though further studies are required, the work presented here is an important step towards fully realising the potential of this drug delivery system.

Item Type: Thesis (PhD)
Keywords: virus-like particles, cancer, drug delivery system, drug delivery, MS2, bacteriophage
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds)
The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute for Molecular and Cellular Biology (Leeds)
Identification Number/EthosID: uk.bl.ethos.656994
Depositing User: Dr Ruiyang Yan
Date Deposited: 20 Jul 2015 11:28
Last Modified: 25 Jul 2018 09:50
URI: http://etheses.whiterose.ac.uk/id/eprint/8989

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