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MRC DiMeN Doctoral Training Partnership: Developing a novel mode of anti-cancer therapy using tissue engineered cancer and mass spectrometry imaging


   MRC DiMeN Doctoral Training Partnership

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  Dr C Murdoch, Prof M R Clench, Dr R Bearon  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

There is increasing interest in the development of needle-free drug delivery systems for a number of diseases. A multidisciplinary team at The University of Sheffield, in collaboration with AFYX Therapeutics (afyx.com, Denmark), have developed a polymer-based patch that can adhere tightly to the oral epithelium that lines the inside of the mouth and deliver drugs (corticosteroids, anaesthetic, peptides) directly to oral lesions (Colley 2018, Clitherow 2020, Said 2021, Edmands 2022). The oral patch has successfully completed phase 2 clinical trials. This project aims to incorporate anti-cancer agents into these novel patches for the treatment of oral cancer, the incidence of which has risen by 60% in the UK in the last decade.

To progress this technology further, the oral patch requires fine-tuning in terms of controlled drug release and understanding drug absorption, its distribution in oral tissues, as well as drug metabolism and excretion. In this project you will produce oral patches by electrospinning polymer fibres to contain anti-cancer drugs at therapeutically relevant concentrations and characterise them using techniques such as scanning electron microscopy, differential thermal and X-ray diffraction analysis. You will determine the drug release profiles from these patches over-time using a number of analytical techniques (Franz Chamber/HPLC). We have previously developed tissue-engineered in-vitro models of human oral cancer (Colley 2011) that accurately mimics oral cancer in humans. You will adhere patches to oral cancer models and visualise drug permeation through the 3D tissue using Mass Spectrometry (MS) Imaging, a powerful label-free analytical technique that allows visualisation and spatial location of any specific molecule within tissues (Russo 2018, Handler 2021). You will measure oral cancer cell death after administration of the patch using a number of assays and in tissue by immunohistochemistry. In addition, rates of drug metabolism as the anti-cancer drug is de-activated by enzymes within cancer cells will be measured. The use of MS imaging combined with tissue-engineered oral cancer to develop oral patch-delivered drugs has not been performed previously. The data produced in this project will be used by mathematicians at the University of Liverpool to develop an in silico predictive model of drug delivery as part of an NC3R-sponsored project.

This multidisciplinary project will deliver extensive training in cell culture, tissue-engineering and 3D biology, a rapidly expanding area that aligns with NC3R principles. This will be combined with training in advanced tissue imaging and analytical techniques. Complementing these core techniques, the student will also obtain training in biomaterial fabrication using polymers (University of Sheffield) and network with mathematical modelers that make-up the wider multidisciplinary team, allowing first-hand insight into other disciplines and how these interact at the cutting edge of science. 

https://www.sheffield.ac.uk/dentalschool/our-people/academic-staff/craig-murdoch

https://www.shu.ac.uk/about-us/our-people/staff-profiles/malcolm-clench

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

Edmans JG, Ollington B, Colley HE, Santocildes-Romero ME, Siim Madsen L, Hatton PV, Spain SG, Murdoch C. (2022) Electrospun patch delivery of anti-TNFα F(ab) for the treatment of inflammatory oral mucosal disease. J Controlled Release. 350:146–157. doi.org/10.1016/j.jconrel.2022.08.016
Clitherow KH, Murdoch C, Spain SG, A. M. Handler AM, Colley HE, Stie MB, Nielsen HM, Janfelt C, Hatton PV, Jacobsen J (2019). Mucoadhesive electrospun patch delivery of lidocaine to the oral mucosa and spatial distribution in tissue using MALDI mass spectrometry imaging. Molecular Pharmaceutics. 16(9):3948-3956 doi.org/10.1021/acs.molpharmaceut.9b00535
Colley HE, Said Z, Santocildes-Romero ME, Baker SR, D’Apice K, Hansen J, Siim Madsen L, Thornhill MH, Hatton PV, Murdoch C. (2018) Pre-clinical evaluation of novel mucoadhesive bilayer patches for local delivery of clobetasol-17-propionate to the oral mucosa. Biomaterials 178:134-146. doi:10.1016/j.biomaterials.2018.06.009
Colley HE, Hearnden V, Jones AV, Weinreb PH, Violette SM, MacNeil S, Thornhill MH, Murdoch C. (2011) Development of tissue engineered models of oral dysplasia and early invasive oral squamous carcinoma. Brit J Cancer. 105(10):1582-92. doi 10.1038/bjc.2011.403
Lewis EEL, Barrett MRT, Freeman-Parry L, Bojar RA, Clench MR. Examination of the skin barrier repair/wound healing process using a living skin equivalent model and matrix-assisted laser desorption-ionization-mass spectrometry imaging. Int J Cosmet Sci. 2018 Apr;40(2):148-156. doi: 10.1111/ics.12446.
Russo C, Brickelbank N, Duckett C, Mellor S, Rumbelow S, Clench MR. Quantitative Investigation of Terbinafine Hydrochloride Absorption into a Living Skin Equivalent Model by MALDI-MSI. Anal Chem. 2018 Aug 21;90(16):10031-10038. doi: 10.1021/acs.analchem.8b02648.
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