Magnetic nanocarriers to enhance oncolytic virotherapy in breast cancer at University of Sheffield on FindAPhD.com

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Dr F Howard, Dr M Muthana No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Sheffield United Kingdom Bioinformatics Cancer Biology Immunology Pharmacology Radiology Virology

Department of Oncology and Metabolism, University of Sheffield

About the Project

Supervisors: Dr Faith Howard, Department of Oncology & Metabolism, University of Sheffield, Dr Munitta Muthana, Department of Oncology & Metabolism, University of Sheffield & Dr Alfred Fernandez-Castane, Lecturer in Chemical Engineering at Aston University

Oncolytic viruses (OV) are fast gaining acceptance as a cancer treatment modality that can activate anti-tumour immunity. However, following intravenous administration OVs are eliminated by the host’s defence mechanisms, limiting the use of OV to accessible tumours where direct tumour injection is necessary. MRI scanners offer new opportunities to magnetically guide OVs to inaccessible (deep) tumours that can’t be reached by direct injection such as metastatic breast cancers (BC).

This multi-disciplinary project aims to create a nanomedicine that chemically combines OVs with biologically derived magnetic nanoparticles called ‘magnetosomes’ synthesised by magnetotactic bacteria (MTB). The magnetosomes provide a metallic shield for the OV so that it is protected in the circulation whilst multiple species of MTB provide a platform of different shape and sized magnetosomes enabling optimisation of drug loading, biodistribution and cellular interaction. Additionally, the ability to steer them to the tumour site using MRI scanners, enhances the pharmacokinetic advantages of the nanomedicine for their enrichment at tumour sites.

We will address the biomanufacture of new MTB species for magnetosome production involving an exciting collaboration with Aston University. After which, chemical cross-linking of OVs with magnetosomes will be assessed for stability and oncolytic potential in a panel of human and murine BC cells. In vivo pharmacokinetics and anti-tumour efficacy will be assessed in-vivo in primary and metastatic mammary tumour models. We will establish how these nanomedicines mediate anti-tumour immunity by profiling immune cells isolated from tumours and corresponding tissues using flow cytometry, qPCR and histology.

Here, we propose that OV and magnetosomes can be integrated into a therapeutic nanomedicine for synergistic combinations that have the potential to tailor their delivery and retention time to specific tissues regardless of the surrounding immune profile, and thereby underpin the development of a new nano-based immunotherapy for the treatment of BC.

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience.

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Oncology & Metbolism' as the department. Please also state your first and second choice project by entering the project tiles in the 'Research Topic' box on your application.

Enquiries:

Interested candidates should in the first instance contact Dr Faith Howard - [Email Address Removed]

Funding Notes

This studentship will be 42 months in duration and include home fee and stipend at UKRI rate. EU/Overseas candidates are welcome to apply, however they would be required to fund the fee difference.

References

1. Howard, F. and M. Muthana, Designer nanocarriers for navigating the systemic delivery of oncolytic viruses. Nanomedicine (Lond), 2020. 15(1): p. 93-110.
2. Blakemore, R., Magnetotactic bacteria. Science, 1975. 190(4212): p. 377-9.
3. Vargas, G., et al., Applications of Magnetotactic Bacteria, Magnetosomes and Magnetosome Crystals in Biotechnology and Nanotechnology: Mini-Review. Molecules, 2018. 23(10).
4. Ernsting, M.J., et al., Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles. J Control Release, 2013. 172(3): p. 782-94.
5. Meriaux, S., et al., Magnetosomes, biogenic magnetic nanomaterials for brain molecular imaging with 17.2 T MRI scanner. Adv Healthc Mater, 2015. 4(7): p. 1076-83.
6. Sun, J., et al., Biocompatibility of bacterial magnetosomes: acute toxicity, immunotoxicity and cytotoxicity. Nanotoxicology, 2010. 4(3): p. 271-83.
7. Xiang, L., et al., Purified and sterilized magnetosomes from Magnetospirillum gryphiswaldense MSR-1 were not toxic to mouse fibroblasts in vitro. Lett Appl Microbiol, 2007. 45(1): p. 75-81.
8. Staniland, S., et al., Controlled cobalt doping of magnetosomes in vivo. Nat Nanotechnol, 2008. 3(3): p. 158-62.
9. Muthana, M., et al., Use of macrophages to target therapeutic adenovirus to human prostate tumors. Cancer Res, 2011. 71(5): p. 1805-15.
10. Hawtree, S., et al., Histone deacetylase 1 regulates tissue destruction in rheumatoid arthritis. Hum Mol Genet, 2015. 24(19): p. 5367-77.
11. Muthana, M., et al., Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting. Nat Commun, 2015. 6: p. 8009.
12. Fernandez-Castane, A., et al., Development of a simple intensified fermentation strategy for growth of Magnetospirillum gryphiswaldense MSR-1: Physiological responses to changing environmental conditions. N Biotechnol, 2018. 46: p. 22-30.

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