Primary Supervisor: Dr Andrew Jupp, School of Chemistry
Secondary supervisor: Dr Isolda Romero Canelon
PhD project title: Photoactivated Ru Anti-Cancer Agents
University of Registration: University of Birmingham
The overarching aim of this project is to develop ruthenium photoactivatable complexes that can be optimised as second line anti-cancer therapy to overcome platinum resistance. The project will involve the synthesis and characterisation of the metal complexes in the Jupp group (School of Chemistry), and the subsequent investigations into their potential anti-cancer properties in the Romero-Canelon group (School of Pharmacy).
Despite recent advances in cancer research, there is still a major unmet clinical need for the treatment of platinum-resistant cancers. Cisplatin and its derivatives, carboplatin and oxaliplatin, are involved in more than half of all therapeutic regimes despite their deleterious side effects and high incidence of resistance. Such resistance, inherent or acquired, is usually associated to treatment failure and recurrence, leaving patients with minimum clinical alternatives. Given this troubling prospect, the field of metals in medicine is researching into novel complexes that can be developed as a viable second line therapy.
Ruthenium has been widely researched with this purpose and has already rendered two candidates that are currently being clinically evaluated with others in the pre-clinical stage. This metal centre has the advantage of being biocompatible, having two biologically stable oxidation states, multiple coordination geometries and most importantly, offering the possibility of alternative mechanisms of action that can overcome platinum-resistance.1,2 Furthermore, as the complexes act in a multi-targeted way and their mechanism of action is not usually DNA-based, they tend to retain potency in both, tumours that are non-sensitive to cisplatin and those who have developed post-exposure resistance.
Photoactivatable pro-drugs also have the added advantage of allowing for spatio-temporal control. In this case, the metal complex is designed to be non-toxic in the dark, so that deleterious side effects are minimised despite systemic administration. Once the pro-drug has reached the tumour site and accumulated in the desired tissues, a directed beam of light of a given wavelength is used to activate the metal complex. Only at this point, the pro-drug will render its active form and the anticancer mechanism of action will be initiated.
In this project, we aim to maximise the advantages of the two systems above. Ruthenium photoactivatable complexes could, in principle, be the key to overcome platinum resistance. We will have the flexibility of the chemical space that offers the ruthenium metal centre and the spatio-temporal control of activation. For this, we will use an organometallic piano-stool basic structure, which allows for the optimisation of drug-like properties and we will incorporate a new class of ligands recently developed in the Jupp group (currently unpublished results – please discuss directly with Andrew and Isolda for further details). The ligands are inherently tuneable, which will enable us to readily and rationally alter their properties within the ruthenium complexes, and change the wavelength of light required for photoactivation. Once the ligands and complexes have been synthesised and characterised, they will be evaluated as potential anticancer agents in a panel of cancer cell lines or various origins. Investigations into their cellular behaviour will in turn allow for the fine-tuning and optimisation of subsequent generations of complexes.
Andrew has extensive experience in the synthesis of bespoke phosphorus-containing compounds, which, due to their air- and moisture-sensitive nature, require specialised Schlenk-line and glovebox techniques. He has also previously made a range of transition metal-phosphine complexes, including those of ruthenium, and has studied the interaction of light with molecules for photoswitching applications. Isolda has a strong track-record on the development of metal-based anticancer agents, with particular focus on ruthenium organometallic complexes and photoactivatable platinum prodrugs. Together, this collaborative approach will enable the prospective student to be in an optimal position to tackle this challenging but exciting project.
- Coverdale J, Laroiya-McCarron T, Romero-Canelón I. Designing Ruthenium Anticancer Drugs: What Have We Learnt from the Key Drug Candidates? Inorganics 2019; 7: 31–46.
- Romero-Canelón I. Ruthenium, Osmium and Iridium in the Fight Agains Cancer. In: Metal-based Anticancer Agents. Royal Society of Chemistry, 2019, pp 31–61.
BBSRC Strategic Research Priority: Integrated Understanding of Health: Pharmaceuticals
Techniques that will be undertaken during the project:
The student will be learn the following skills and techniques during the course of their project – please note that there is no expectation of the student knowing some or all of these techniques prior to starting the position, all necessary training will be provided.
The chemical synthesis component of the project in the Jupp lab will involve:
- Synthesis and handling of air- and moisture-sensitive compounds using Schlenk-line and glovebox techniques.
- Characterisation of the compounds using NMR spectroscopy, single crystal X-ray diffraction, UV-Vis spectroscopy, mass spectrometry, IR spectroscopy.
- Assessment of photoswitching ability using LED light sources and a combination of UV-Vis and NMR spectroscopy.
The biological analysis component of the project in the Romero-Canelon lab will involve (but not be limited to):
- Evaluation of the stability of complexes in biologically relevant matrixes
- Anticancer screening in a panel of cancer cell lines of different origins, taking into account dark and irradiated conditions, particularly in views to determine the relation between dark and irradiated toxicity
- Exploration of the cellular fate of the complexes and how this related to the activation of cellular death pathways
- Investigations into the cellular basis for the mechanism of action of the complexes using qualitative and quantitative techniques such as confocal microscopy, flow cytometry, fluorescence, absorbance and luminescence measurements.
- Assessment of cellular distribution of the complexes using Inductively coupled plasma techniques
Contact: Dr Andrew Jupp, University of Birmingham