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MRC DiMeN Doctoral Training Partnership: Using red light to specifically kill cancer cells and tumours with small transition metal complexes


   MRC DiMeN Doctoral Training Partnership

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  Prof J Weinstein, Dr H Bryant, Prof S Botchway  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Summary: The project aims to develop better, more specific, less harmful anticancer compounds, that kill cancer cells only when illuminated by red light. You will work on a highly interdisciplinary, translational project at the interface of cell biology, laser spectroscopy, advanced emission imaging, synthetic chemistry, and complex in-vitro disease models.

You will join a vibrant interdisciplinary, international team, across Departments of Chemistry and Oncology&Metabolism (Medical School). The primary supervisor’s experience is photochemistry, lasers, and emission imaging (PNAS-2008-16071, ChemSci-2014-879). The second supervisor’s expertise is molecular oncology and developing novel cancer therapies. You can also have a placement at STFC Octopus facility.

Detailed description.

Conventional chemotherapy uses chemically active drugs, which attack tumour and healthy tissues, causing severe side-effects. A powerful alternative is Photodynamic Therapy (PDT). PDT uses “agents” – molecules, also called photosensitisers, PS - that are non-toxic without light. PS only become toxic when exposed to light, moving into higher-energy excited state PS*. PS* reacts with oxygen generating reactive oxygen species (ROS), which kill cells. Thus, local irradiation specifically kills the tumour leaving non-irradiated healthy cells unharmed, reducing side-effects. Transition-metal complexes are emerging as ideal PS, much better than traditionally used organic molecules. The key advantage is a much longer-lived excited state lifetime of transition metal complexes PS*, microseconds vs. nanoseconds for organic excited states. The longer lifetime gives much higher yield of singlet oxygen and other ROS, and therefore higher potential to kill cancer cells. Unlike organic molecules which rapidly decompose under light, transition metal complexes are remarkably photostable and thus are suitable for long-time imaging, and prolonged therapy. Finally, metal complexes can be comparatively easily modified, to conjugate to other structures, such as nanoparticles or peptides.

A key limitation to the clinical use of PDT-active metal-complexes is that they absorb visible light, whilst the optimal tissue penetration is in the near-IR, 700–900 nm. Our solution to harvest near-IR-light is “light-upconverting nanoparticles, UN”: these contain lanthanide ions which absorb near-IR light, and then emit blue light. Conjugating blue-light activated PS to such nanoparticles will enable PS-activation by near-IR-light. We have already optimised the synthesis of red-to-blue upconverting nanoparticles. We also have a range of Ir(III)-complexes which efficiently kill diverse cancer cells under blue-light. Now is the time to combine these technologies to achieve red-light activated-PDT agents and test them in 2D and 3D-models of cancer, discover the best combinations nanoparticle-photosensitiser, and move one step closer to the clinic.

The project involves some of the following:

Synthesise novel transition-metal complexes designed to conjugate to nanoparticles. Use laser spectroscopy to establish their photophysical properties, and the efficiency of ROS-production under red light. Determine subcellular localization using advanced imaging techniques. Establish the mechanism of cell-killing using biochemical methods including DNA damage assay. Investigate selected UN-Ir(III) in 2D- and 3D-models of oral cancer using clinically approved red-light source.

Depending on your interests, the project can be taken in a more biological, or a more chemistry&imaging direction. The University of Sheffield has world-leading research facilities in all of the above areas. 

Facilities: Sheffield-Institute-for-Nucleic-Acids, Wolfson_Imaging_Facility, Lord_Porter_LaserLaboratory Kroto_Research_Institute

Supervisors:

Professor Julia A. Weinstein | Chemistry | The University of Sheffield;

https://www.sheffield.ac.uk/oncology-metabolism/staff/bryant

CLF Stan Botchway (stfc.ac.uk)

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

Chemical Science 2014, 879. Long-lived metal complexes open up microsecond lifetime imaging microscopy under multiphoton excitation: from FLIM to PLIM and beyond - Chemical Science (RSC Publishing)
Chemistry a European Journal 2017, 234. Metal Complexes for Two-Photon Photodynamic Therapy: A Cyclometallated Iridium Complex Induces Two-Photon Photosensitization of Cancer Cells under Near-IR Light. https://doi.org/10.1002/chem.201604792
Scientific Reports, 2017, volume 7, Article number: 10743. Oxygen Mapping of Melanoma Spheroids using Small Molecule Platinum Probe and Phosphorescence Lifetime Imaging Microscopy | Scientific Reports (nature.com)
Nature Communications, 2020, 11, 5863. PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts | Nature Communications
Oncotarget, 2020, 11, 2141. MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma | Oncotarget
McKenzie, L.K., Bryant, H.E. and Weinstein, J.A. (2019) Transition metal complexes as photosensitisers in one- and two-photon photodynamic therapy. Coordination Chemistry Reviews, 379. pp. 2-29. ISSN 0010-8545 DOI:10.1016/j.ccr.2018.03.020
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