Shining new light on drug design: photoactivated chemotherapy

Lead Research Organisation: University of Warwick
Department Name: Chemistry

Abstract

About 11M cases of cancer are diagnosed each year and there is a pressing need for new anticancer drugs. The world’s leading anticancer drugs are platinum-based compounds such as cisplatin. These types of platinum compounds are not targeted to cancer cells and also kill healthy cells. This can result in severe side-effects and the development of resistance, so that some patients stop responding to treatment. Methods for increasing the selective activation of platinum drugs at the site of the tumour are envisaged which address these problems. We have developed new platinum-based drugs which are non-toxic in the dark, but become highly toxic when activated by light. By shining light only on the area of cancerous tissue, we can target the activation of the drug to just the selected area.
It is vital that we carry out more studies into how these drugs kill cancer cells, which will involve laboratory work and experiments to investigate if they can shrink/treat cancers. We hope that the wavelengths of light for activating these compounds make them suitable for treating surface cancers and that slight changes to the drugs will allow treatment of a wider range of cancers.

Technical Summary

With around 25 million people living with a diagnosis of cancer, new anti-cancer therapies are urgently needed. If cancer is to become a manageable disease, then these new therapies need to ensure as few side-effects as possible, and bypass the resistance mechanisms commonly seen with current treatments. In addition, treatments that could be repeated as often as required (unlike current chemotherapy or radiotherapy) would be very useful. Platinum (Pt) drugs are amongst the most successful and commonly prescribed class of anti-cancer agents (44% of 2004 market). Cisplatin and its related prodrug carboplatin have a broad spectra of anti-tumour activity. However, their use is curtailed by the serious dose-limiting side effects that are often responsible for treatment failure. These include extreme nausea and vomiting, ototoxicity and nephrotoxicity. Additionally many tumours have intrinsic or develop acquired resistance to these drugs. The side-effects of Pt drugs could be avoided if a selective activation of a Pt-prodrug could be made to take place only in the tumour tissue. Thus we have developed a series of photolabile Pt(IV) complexes that show equal or greater cytotoxicity than cisplatin tested under identical conditions in cultured tumour cells, but only when they are irradiated with UVA or blue visible light. They are relatively non-toxic in the dark. These photolabile complexes appear to kill the cells by a distinct mechanism and are not simply acting as prodrugs of cisplatin or transplatin. Moreover, they may not require oxygen (O2) for their mechanism of action, thus removing one of the limitations of current, conventional light-activated therapies. Our challenge is to develop Pt-complexes that are selectively taken up by tumour cells, and for which the wavelength of activation can be controlled, making them useful for the treatment of thin walled organs as well as thicker tumours. We also wish to demonstrate antitumour activity without an O2-dependent mechanism. Finally, we want to develop novel methods of light delivery that will optimise the therapeutic benefit of these light-activated Pt prodrugs. Thus the light-activated Pt prodrugs should combine the potent cytotoxic properties of Pt-based drugs, but with the targeting of photodynamic therapy. Success with this project will ultimately lead to more effective and less toxic therapeutics for cancer chemotherapy.

Publications

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Bruijnincx PC (2008) New trends for metal complexes with anticancer activity. in Current opinion in chemical biology

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Bruijnincx PC (2009) Controlling Platinum, Ruthenium and Osmium Reactivity for Anticancer Drug Design. in Advances in inorganic chemistry

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

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

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Farrer N (2008) Photochemotherapy: Targeted Activation of Metal Anticancer Complexes in Australian Journal of Chemistry

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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)

 
Description EPSRC DTA (MOAC)
Amount £50,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description EPSRC Project Grant EP/G006792/1 Photoactivation strategies for delivery of platinum prodrugs; oxygen independent photodynamic therapy (PDT)
Amount £418,100 (GBP)
Funding ID EP/G006792/1 
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 Czech Academy of Sciences 
Organisation Academy of Sciences of the Czech Republic
Department Institute of Biophysics
Country Czech Republic 
Sector Public 
PI Contribution Synthesis of new platinum complexes, characterisation, solution chemistry and biochemistry, investigations of photoactivation and photochemical decomposition pathways.
Collaborator Contribution Access to a wide range of advanced biophysical techniques and methods, especially aimed at characterisation of DNA adducts
Impact Warwick iCast: http://www2.warwick.ac.uk/newsandevents/icast/archive/s2week15/platinum/
 
Description Greifswald University 
Organisation University of Greifswald
Department Institute of Pharmacy Greifswald
Country Germany 
Sector Academic/University 
PI Contribution Synthesis of new platinum complexes, characterisation, solution chemistry and biochemistry, investigations of photoactivation and photochemical decomposition pathways.
Collaborator Contribution Provides access to a variety of cancer cell lines for phototoxicity testing; investigation of photinduced DNA binding, effects of glutathione, mechanism of cell cytotoxicity
Impact A manuscript is in preparation
 
Description Peptide targetting 
Organisation Sun Yat-Sen University
Department Sun Yat-Sen University Cancer Center
Country China 
Sector Academic/University 
PI Contribution Solution chemistry of Pt-paptide complexes Photocytotoxicity screening
Collaborator Contribution Synthesis and characterisation of peptides Screening of cell receptors
Impact Multidisciplinary Jouit training of research students Papers submitted
Start Year 2015
 
Description Peptide targetting 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution Solution chemistry of Pt-paptide complexes Photocytotoxicity screening
Collaborator Contribution Synthesis and characterisation of peptides Screening of cell receptors
Impact Multidisciplinary Jouit training of research students Papers submitted
Start Year 2015
 
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 Photobiology studies of new Pt(IV) anticancer drugs 
Organisation University of Dundee
Department Centre for Dermatology and Genetic Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesis of new platinum complexes, characterisation, solution chemistry and biochemistry, investigations of photoactivation and photochemical decomposition pathways.
Collaborator Contribution Specialist photobiological facilities
Impact Warwick iCast: http://www2.warwick.ac.uk/newsandevents/icast/archive/s2week15/platinum/ Publications: 18093923, 19290364, 19994893
 
Description Time-resolved spectroscopy 
Organisation Monash University
Country Australia 
Sector Academic/University 
PI Contribution Synthesis of photoactive platinum anticancer complexes Studies if their photochemistry anf photobiochemistry
Collaborator Contribution Provision of equipment for and measurement of time-resolved photochemical reactions
Impact Papers in high profile journals Media publicity
Start Year 2014
 
Description Time-resolved spectroscopy 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesis of photoactive platinum anticancer complexes Studies if their photochemistry anf photobiochemistry
Collaborator Contribution Provision of equipment for and measurement of time-resolved photochemical reactions
Impact Papers in high profile journals Media publicity
Start Year 2014
 
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
 
Description PJS Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We maintain a lab website which gives details of our publications and new developments relating to this project http://www2.warwick.ac.uk/fac/sci/chemistry/research/chemicalbiology/sadler/sadlergroup/

Contact from many interested people.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
URL http://www2.warwick.ac.uk/fac/sci/chemistry/research/chemicalbiology/sadler/sadlergroup/
 
Description School visit - Cirencester 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at Deer Park School, Cirencester, Glos.

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - Coventry 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at Bablake School, Coventry

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - Coventry 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at The Grange Extended Learning Centre, Coventry

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - Coventry 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at The Westwood School, Coventry

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - Fairford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at Farmors School, Fairford, Gloucestershire - talk given twice. The age of the audiences ranges from 16 - 18 (occasionally to 12 years old)

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - High Wycombe 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at Wycombe Abbey School, High Wycombe

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - Kenilworth 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at Kenilworth School

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - Redditch 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at Kingsley College, Redditch. The age of the audiences ranges from 16 - 18 (occasionally to 12 years old)

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009
 
Description School visit - Rugby 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Teaching Fellow in Chemistry at Warwick, presented our work on light activated platinum anti-cancer complexes at Rugby School

Stimulates the interest of school pupils in science and its medicial applications.
Year(s) Of Engagement Activity 2009