Photoactivation strategies for delivery of platinum prodrugs; oxygen independent photodynamic therapy (PDT)

Lead Research Organisation: University of Warwick
Department Name: Chemistry

Abstract

People suffering from cancer are typically treated with either surgery, radiotherapy or chemotherapy. Currently the world's most widely used chemotherapeutic drugs are platinum-based; a leading example is cisplatin, a compound containing platinum with a 2+ charge. It is generally accepted that the anticancer activity of cisplatin and other closely related platinum compounds arises from their ability to damage DNA in cancer cells leading to cell death.The existing platinum drugs are highly toxic to both healthy and cancerous cells in the body. As a result, serious side-effects of treatment are a frequent and serious problem in chemotherapy. These side-effects can be so severe that treatment has to be stopped, leading to treatment failure and ultimately to the death of the patient. In some cases the cancerous cells in the bodies of patients become resistant after repeated doses of the drugs; then the cells are not killed by the drug and the cancer is not cured. This research project aims to develop new platinum anticancer drugs which work in a different way to cisplatin. If the platinum drug could be made harmless until it enters the cancer cells and then be activated only in the tumour tissue, this would greatly reduce unwanted side-effects, allow treatment of cisplatin-resistant tumours, and may also allow treatment of a wider range of cancers. Our proposed strategy is a new one. We will use compounds containing platinum with a 4+ charge. These will not be reactive towards cells and must be converted to platinum 2+ compounds before they kill cells. We will activate them specifically in cancer and not in other normal cells using a directed fine beam of light. To introduce even greater selectivity for cancer cells, we will tag the compounds with labels that are selectively recognised and taken up by cancer cells in preference to normal cells (peptides, antibodies). Our strategy will introduce new mechanisms for killing cancer cells, just what is needed to circumvent resistance to current platinum drugs. Our encouraging preliminary data suggest that we can make compounds that are more effective than cisplatin itself.Exciting is the prospect of using new optical devices to activate our compounds. These photonic crystal fibres can deliver laser light of a very precise colour over long distances. This should lead to more controllable activation and perhaps the prospect of reaching internal sites of the human body which are currently inaccessible to irradiation.This research project aims to design (with the help of computer predictions), synthesise and characterise new photoactivatable platinum complexes. The synthesis of these complexes is anticipated to be challenging since they must be made without direct exposure to light. They will be tested for features such as stability, solubility and cell uptake, and their photoactive properties determined. Extensive investigation into the spectroscopic properties of these new complexes will be carried out and much use will be made of nuclear magnetic resonance techniques to understand the mechanisms through which these complexes change chemically following activation by light. We will also use standard chemical techniques such as mass spectrometry, UV-Vis spectroscopy, and X-ray crystallography to fully characterise our new compounds. The distribution of the platinum complexes within cells and the selective platination of DNA and proteins and activity of the complexes towards different types of cancer cells will also be investigated.Since longer wavelengths of light (e.g. red light) penetrate tissue more deeply than shorter (e.g. blue light); a challenge will be to design compounds which are activated by irradiation of light with these longer wavelengths. This may be possible through using compounds which are able to absorb two photons at once, or by careful design of the ligands on the complexes.

Publications

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Barry NP (2014) Fabrication of crystals from single metal atoms. in Nature communications

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Butler JS (2012) Tryptophan switch for a photoactivated platinum anticancer complex. in Journal of the American Chemical Society

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Butler JS (2013) Targeted delivery of platinum-based anticancer complexes. in Current opinion in chemical biology

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Chen JS (2010) Photochemistry in photonic crystal fiber nanoreactors. in Chemistry (Weinheim an der Bergstrasse, Germany)

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Farrer N (2012) Proton Sponge Phosphanes: Reversibly Chargeable Ligands for ESI-MS Analysis in European Journal of Inorganic Chemistry

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Farrer NJ (2018) Platinum(iv) azido complexes undergo copper-free click reactions with alkynes. in Dalton transactions (Cambridge, England : 2003)

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Farrer NJ (2010) A potent trans-diimine platinum anticancer complex photoactivated by visible light. in Angewandte Chemie (International ed. in English)

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Farrer NJ (2011) Probing platinum azido complexes by 14N and 15N NMR spectroscopy. in Chemistry (Weinheim an der Bergstrasse, Germany)

 
Description We designed new photoactivatable platinum anticancer complexes with low toxicity in the dark and potent activity against cancer cells when irradiated with light.

Importantly we were able to synthesise them with good yields, show that they were water-soluble and could be activated by visible light in a range of cancer cells.

We developed multinuclear NMR and MS methods which allowed studies of their structures and reactivity in solution.

This research provided a stong basis for developing new collaborations in Europe include COST Action, and led to new work with complexes conjugated to cancer cell-targetting peptides which is on-going.

We arev hopeful that eventually we will advance towards clinical trials with our new platinum photochemotherapeutic agents.
Exploitation Route Biologists are interested in testing our compounds for activity in surface cancer which are currently difficult to treat in the clinic such as oesophageal and bladder cancers.

In this area access to funding for such translational work is still hard to find (since it is expensive) but we keep trying.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www2.warwick.ac.uk/fac/sci/chemistry/research/sadler/
 
Description Public lectures- Cafe scientifique, Rotary club Schools lectures in UK, Hong Kong and China BBS News broadcast
First Year Of Impact 2010
Sector Chemicals,Education,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description EPSRC
Amount £15,000 (GBP)
Funding ID 28408 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description European Research Council
Amount £1,315,811 (GBP)
Funding ID 247450 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start  
 
Description Photoactivated antibiotics 
Organisation University of Warwick
Department School of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesis of photoactive ruthenium complexes. Determination of antibacterial activity in the presence and absence of light.
Collaborator Contribution Provision of facilities for culture and assay of bacteria and their growth
Impact Chemistry Life Sciences
Start Year 2013
 
Description Ultra high resolution mass spectrometry 
Organisation University of Warwick
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesis and reactions of organometallic and photoactivated anticancer metal complexes
Collaborator Contribution Characterisation of metallodrugs and their adducts with DNA, oligonucleotides, proteins and peptides by FT ICR MS, including the use ofseparation by nanoHPLC and a variety of ion fragmentation techniques
Impact Physical chemistry, medicinal inorganic chemistry Mass spectrometry evidence for cisplatin as a protein cross-linking reagent H. Li, Huilin, Y. Zhao, H.A. Phillips, Y. Qi, T-Y. Lin, P.J. Sadler, P. O'Connor Analytical Chem. 2011, 83, 5369-5376.Use of Top-down and Bottom-up Fourier Transform Ion Cyclotron Resonance Mass Spectrometry for Mapping Calmodulin Sites modified by Platinum Anticancer Drug H. Li , T-Y, Lin , S.L. Van Orden , Y. Zhao , M.P. Barrow , A.M. Pizarro , Y. Qi , P.J. Sadler , and P.B O'Connor Anal. Chem. 2011, 83, 5369-5376. Protein Flexibility is Key to Cisplatin Crosslinking in Calmodulin H. Li, S.A. Wells, J.E. Jimenez-Roldan, R.A. Römer, Y. Zhao, P.J. Sadler, P.B. O'Connor Protein Science 2012, 21, 1269-1279. Mapping the Protein-Binding Sites for Novel Iridium(III) Anticancer Complexes Using Electron Capture Dissociation Y. Qi, Z. Liu, H. Li, P.J. Sadler, P.B. O'Connor Rapid Comm. Mass Spec. 2013, 27, 2028-2032. Insights into the Binding Sites of Organometallic Ruthenium Anticancer Compounds on Peptides Using Ultra-High Resolution Mass Spectrometry R.H. Wills, A. Habtemariam, A.F. Lopez-Clavijo, M.P. Barrow, P.J. Sadler, P.B. O'Connor J. Am. Soc. Mass Spectrom. 2014, 25, 662-672. Mass Spectrometric Strategies to Improve the Identification of Pt(II)-Modification Sites on Peptides and Proteins H. Li, Huilin, J.R. Snelling, M.P. Barrow, P.J.Sadler, P. O'Connor J. Amer. Soc. Mass Spec. 2014, 25. 1217-1227.
Start Year 2010
 
Title Modulator for a Pharmacological Agent 
Description Modulator for a Pharmacological Agent 
IP Reference GB1215498.5 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact Modulator for a Pharmacological Agent