Photoactivatable metal complexes: exciting potential in biotechnology and medicine?

• Professor Peter J Sadler FRS, University of Warwick, UK
• Audio recording (mp3)

Biography

Peter Sadler obtained his BA, MA and DPhil in Chemistry at the University of Oxford. Subsequently he was a Medical Research Council Research Fellow at the University of Cambridge and National Institute for Medical Research. From 1973-96 he was Lecturer, Reader and Professor at Birkbeck College, University of London, and from 1996-2007 Crum Brown Chair of Chemistry at the University of Edinburgh. In June 2007 he took up a Chair in Chemistry at the University of Warwick where he was Head of Department from 2007-2010. He is a Fellow of the Royal Society of Edinburgh (FRSE) and the Royal Society of London (FRS), and a European Research Council Advanced Investigator. His research interests are centred on the chemistry of metals in medicine, including the design of photoactivated transition metal anticancer complexes.

• Dr Nicola J Farrer, University of Warwick, UK

Biography

Nicola Farrer received her degree (Natural Sciences, 2003) and subsequently her PhD (2007) from the University of Cambridge. Her doctoral work involved developing readily ionisable phosphine ligands with a view to detecting catalytic intermediates by electrospray mass spectrometry, and was supervised by Prof. Brian Johnson (University of Cambridge), with the bulk of the analytical work undertaken in the lab of Dr. Scott McIndoe (University of Victoria, Canada). She returned to the UK to join the group of Professor Peter Sadler at the University of Warwick as a post-doctoral fellow in September 2007, working on one- and two-photon photoactivatable metal complexes for application as anti-cancer prodrugs. Her research interests also include multinuclear NMR spectroscopy and chemical applications of photonic crystal fibres. In 2010 she was awarded Chartered Chemist status by the Royal Society of Chemistry. She is currently taking a career break, following the birth of her son James in October 2010.

• Professor Akhil R Chakravarty, Indian Institute of Science, India

Biography

Akhil R Chakravarty received his PhD (1982) from the Calcutta University on a thesis titled “Aspects of the chemistry of ruthenium complexes” under the supervision of Professor Animesh Chakravorty at the Indian Association for the Cultivation of Science, Calcutta. He later joined Texas A&M University (USA) as a post-doctoral fellow under the supervision of Professor F A Cotton and studied bimetallic complexes having metal-metal multiple bonds. He joined Indian Institute of Science at Bangalore, India, in 1985 as an assistant professor and currently is a Professor in the department of Inorganic and Physical Chemistry.  He is a Fellow of the Indian Academy of Sciences (FASc), Indian National Science Academy (FNA) and Academy of Sciences for the Developing World (FTWAS). He has received the S S Bhatnagar Award and is a J C Bose national fellow. He has guided 20 PhD students and published 200 research papers in peer reviewed journals. His research interests are primarily focused on the development of the chemistry of metal-based photocytotoxic agents using bio-essential 3d metal ions.

• Professor Peter Ford, University of California Santa Barbara, USA
• Audio recording (mp3)

Biography

Peter Ford joined the UCSB faculty in 1967 after earning a PhD with Kenneth B Wiberg at Yale and serving as a NSF Postdoctoral Fellow with Henry Taube at Stanford. He has also been Visiting Fellow at the Australian National University (1974), Guest Professor at the University of Copenhagen (1981), an Alexander von Humboldt Senior Scientist Researcher in Germany (1992 & 1999 at Regensberg; 2010 at Muenster) and Guest Investigator at the US National Cancer Institute (1994).  He was 2004-06 President of the Inter-American Photochemical Society.  At UCSB, Professor Ford has served as Research Advisor for 60 PhD graduates and numerous BS, MS and postdoctoral students. 

Research interests:

• Photochemistry applications for delivering bioactive molecules to physiological targets.
• Reaction mechanisms of small molecule bioregulators.
• Catalytic conversion of biomass.

Professor Ford has been recognized with a Dreyfus Foundation-Teacher Scholar award, a Senior Fulbright Fellowship, an A von Humboldt-Stiftung US Senior Scientist Research Prize, the 1992 Richard C Tolman Medal of the American Chemical Society, election as a Fellow of the AAAS and the 2008 Award in Photochemistry of the InterAmerican Photochemical Society.

• Professor Dr Ulrich Schatzschneider, Julius-Maximilians-Universität, Germany
• Audio recording (mp3)

Biography

Ulrich Schatzschneider studied chemistry at the Heinrich-Heine-Universität in Düsseldorf and obtained his PhD at the Max-Planck-Institute for Bioinorganic Chemistry in Mülheim an der Ruhr, Germany in 2001 under the supervision of Professor Dr Eva Rentschler and Professor Dr Karl Wieghardt. He spent the next 2 years as a postdoc in the group of Professor Dr Jacqueline K Barton at the California Institute of Technology in Pasadena, USA, supported by a research fellowship from the Deutsche Forschungsgemeinschaft (DFG). In 2004, he returned to Germany to start his independent scientific career, first at the University of Heidelberg and from 2006 to 2010 at the Ruhr-Universität in Bochum (RUB). He obtained his habilitation in inorganic chemistry from RUB in 2010 and was appointed as Associate Professor of Bioinorganic Chemistry at the Julius-Maximilians-Universität in Würzburg in September 2010. His scientific interests are focused on multi-modal bioimaging and therapeutic applications of transition metal complexes and their bioconjugates. In particular, his research group is active in the fields of CO releasing molecules (CORMs) and organometal–peptide bioconjugates.

Abstract

In addition to nitric oxide and hydrogen sulfide, carbon monoxide is now well-established as the third endogenous gasotransmitter in higher organisms, with a delicate balance of cytoprotective vs. cytotoxic activity, depending on the local concentration in tissue. Since CO gas itself is difficult to dose and handle, potential therapeutic applications of carbon monoxide in human medicine will rely on the development of easy-to-handle delivery systems for this gasotransmitter.

A particularly attractive way is the inactivation of carbon monoxide by binding to a transition metal center. Such "caged CO" could then be released from the metal coordination sphere by a proper stimulus at the target site in the organism. Various triggers have been explored in the field of CO releasing molecules (CORMs), including ligand exchange reactions in buffer, enzyme-triggered CO release, and changes in the redox environment of the CORM. In contrast, the Schatzschneider group focuses on the photoactivated release of carbon monoxide from transition metal complexes in PhotoCORMs.

After a short introduction on endogenous CO production by heme oxygenase enzymes, we will discuss the general requirements for therapeutically useful CORMs and present our most recent results to achieve light-triggered carbon monoxide delivery from PhotoCORMs at high excitation wavelengths and incorporation of these systems into active and passive targeting vectors like peptides and nanoparticles.

• Professor Dr Alexander Schiller, Friedrich-Schiller-University Jena, Germany
• Audio recording (mp3)

Biography

Alexander Schiller studied chemistry at the University of Munich (LMU) and completed his PhD in 2006 under the supervision of Professor K Severin at the École Polytechnique Fédérale de Lausanne (Switzerland). His thesis was focused on biomimetic catalysis with immobilized transition metal complexes. For a postdoctoral stay he moved to the University of California, Santa Cruz. Together with Professor B Singaram and Dr R Wessling he worked on fluorescent saccharide sensors. At Empa (Switzerland) he held a position as project leader on stimuli-responsive materials. In June 2009 he joined the Friedrich-Schiller-University of Jena as a junior professor of the Carl-Zeiss foundation. His present research interests include immobilised transition metal complexes for NO and CO delivery and supramolecular analytical chemistry for carbohydrates. Professor Schiller is member of the editorial board of “Reviews in Inorganic Chemistry” (De Gruyter) and holds the presidency of the GDCh Ortsverband Jena.

Abstract

Nitric oxide (NO) and carbon monoxide (CO) act as important messenger molecules in the human body.[1] NO- and CO-releasing materials (NORMAs & CORMAs) are impor-tant for the development of gasotransmitter delivering devices for therapeutic purposes; toxic metabolites after gas release are kept in the matrix. NO and CO photodonors use light as a convenient non-invasive on/off trigger since it allows the accurate control of site, timing and dosage.[2] Here we report the concept of embedding water-insoluble, photoactive NO and CO metal complexes into nanofibrous polymer non-wovens.[3] NO and CO release into the surrounding medium is performed by light stimulation of the high surface area materials.

For the generation of NORMAs, novel rutheniumnitrosyl complexes {RuNO}6 have been synthesized.[4] For the CORMAs, Mn₂(CO)₁₀ and Fe(CO)₅ were used.[5] These metal complexes were non-covalently embedded into nanofibrous polylactide non-wovens by electrospinning.[6] The hybrid materials showed differences in their fiber morphologies. The NORMAs exhibited a smooth fiber matrix; the CORMA with Mn₂(CO)₁₀ gave highly porous fibers. Identity of the metal complexes was retained in the electrospinning process. Leaching of the metal complexes out of the polymeric matrices into water was negligible due to their water insolubility. Cytotoxicity tests of the NORMA with 3T3 cells (mouse fibroblasts) revealed a very low mortality rate. Irradiation at λ = 366 nm (UV-A) in water, using an adapted fluorescent NO assay, showed a significant phototriggered NO release from the non-wovens.[4] Rapid CO release from CORMAs was detected by the myoglobin assay and vibrational spectroscopy.[5]

[1] R Motterlini, L E Otterbein, Nat Rev Drug Discov 2010, 9, 728.
[2] D Crespy, K Landfester, U S Schubert, A Schiller, Chem Commun 2010, 46, 6651.
[3] A Schiller, in Molecules at Work. Selfassembly, Nanomaterials, Molecular Machinery, (Ed: B Pignataro), Wiley-VCH, Weinheim, 2012, 315-338.
[4] C Bohlender, M Wolfram, H Görls, W Imhof, R Menzel, A Baumgärtel, U S Schubert, U Müller, M Frigge, M Schnabelrauch, R Wyrwa, A Schiller, J Mater Chem 2012, 22, 8785.
[5] R Wyrwa, M Schnabelrauch, C Altmann, A Schiller, DE10 2012 004 132.2, patent pending.
[6] A Greiner, J Wendorff, Angew Chem, Int Ed 2007, 46, 5670.

• Professor Pradip Mascharak, University of California Santa Cruz, USA
• Audio recording (mp3)

Biography

Pradip Mascharak was born in Jaipur, India.  He received his PhD from the Indian Institute of Technology, Kanpur, in 1979.  In the same year, he joined the research group of Professor Richard Holm at Stanford University and later moved to Harvard University.  He also worked with Professor Stephen J Lippard at the Massachusetts Institute of Technology for two years before joining the University of California, Santa Cruz (UCSC), in late 1984.  He is currently a Professor of Chemistry and Biochemistry at UCSC.  His research focuses on (a) modeling of the active sites of metalloenzymes, (b) design of metal complexes that exhibit oxygenase activity in the presence of peroxides and dioxygen, and (c) syntheses of novel photoactive NO-donors for the treatment of malignancies and infections.  The research is funded by the National Science Foundation and the National Institutes of Health.  Professor Mascharak is an Alfred Sloan Fellow and a Fellow of the American Association for the Advancement of Science.

Abstract

During the past three decades, the roles of nitric oxide (NO) in various physiological and pathological pathways have been firmly established. This tiny diatomic molecule plays very different roles in biology depending on its concentration. At nanomolar concentrations, it acts as a signaling molecule to control blood pressure and neurotransmission. Quite in contrast, at elevated (micromolar) levels, the same molecule triggers programmed cell death or exhibits strong antimicrobial effects. We have recently designed and synthesized several molecules that can selectively deliver high doses of NO to malignant sites under the total control of light and cause cell destruction.  These unusual NO-donors are ideal candidates for Photodynamic Therapy for skin cancer.  In addition, they can be employed to combat other localized cancers such as prostate and breast cancer.  We have also been successful in eradicating drug-resistant pathogens via NO delivery.  Since bacteria and fungi seldom exhibit resistance to NO (at least for now), treatment with NO offers a new and effective line of treatment for chronic infections. Inclusion of our compounds in biocompatible materials makes the delivery platforms quite safe and target-specific. This talk will include discussions on the fundamentals and potentials of these intriguing treatment modalities.

• Professor Claudia Turro, Ohio State University, USA
• Audio recording (mp3)

Biography

Claudia Turro received her BS with Honors in 1987 from Michigan State University. She worked with Daniel G Nocera and George E Leroi at Michigan State University and received her PhD in 1992. She was awarded a Jane Coffin Childs Memorial Fund for Medical Research Postdoctoral Fellowship to continue postodoctoral work at Columbia University with Nicholas J Turro from 1992 to 1995. She has been a faculty member at The Ohio State University since 1996. She received the Early CAREER Award by the National Science Foundation in 1998, the Arnold and Mabel Beckman Foundation Young Investigator Award in 1999, was named a 2010 Fellow of the American Chemical Society, and a 2011 Fellow of the American Association for the Advancement of Science.  She was elected Vice-President (2011-12) and President (2013-14) of the Inter-American Photochemical Society and Chair of the Bioinorganic Subdivision of the Division of Inorganic Chemistry of the American Chemical Society (2012-15).

Abstract

The presentation will include comparison of quantum yields and ultrafast spectroscopy pointing at different pathways for ligand exchange from the initially generated singlet in Ru(II) complexes.  The population of both the triplet ligand-field (LF) and the triplet metal-to-ligand charge transfer (MLCT) states from the initially populated singlet MLCT is believed to result in a dramatic increase in ligand exchange in some complexes.  The bifurcation from the singlet MLCT  is also explored for potential use in PDT schemes.  Exploration of other transition metals and drug release will also be discussed.

• Professor Chi-Ming Che, University of Hong Kong, P R China
• Audio recording (mp3)

Biography

Professor Chi-Ming Che received his BSc and PhD in 1978 and 1982, respectively, from The University of Hong Kong (HKU). From 1980 to 1983, he studied at the California Institute of Technology under the guidance of Professor Harry B Gray. Thereafter, he returned to his alma mater, where he was promoted to Chair Professor of Chemistry in 1992. Since 1997 he has been the Dr Hui Wai-Haan Chair of Chemistry in HKU. His research interests include inorganic and organic synthesis; metal-ion promoted organic transformations; reactive metal-ligand multiple bonded complexes; inorganic photochemistry; luminescent materials; bioinorganic chemistry; and inorganic medicines. Over 100 PhD students have successfully completed their studies at HKU under his supervision. With more than 700 publications and an H-index of 78, Professor Che is one of the ISI Highly Cited Researchers. He is a current member of the international advisory board of Chemistry-A European Journal, Chemistry-An Asian Journal, Chemical Science, ChemCatChem, ChemPlusChem and Journal of Inorganic Biochemistry.

In 1995 Professor Che was elected as a member of the Chinese Academy of Sciences and became the first CAS member from Hong Kong and the youngest CAS member at that time. He was elected as a Fellow of World Innovation Foundation (2004), a Fellow of Federation of Asian Chemical Societies (2005), a Fellow of TWAS in Chemical Sciences (2007), and a Fellow of The Royal Society of Chemistry (2009). He received the following awards or prizes: National Natural Science Prize of China (1993), Croucher Senior Fellowship (1997), Chung-Hsing S&T Lectureship (1997), Distinguished Research Achievement Award of the University of Hong Kong (2000), IUF Invited Professorship of France (2000), Federation of Asian Chemical Societies Foundation Lectureship (2003), Visiting Scientist of National Research Council of Italy (2004), Pfizer Signature Lecture (2006), TWAS Prize in Chemistry (2006), 1st Class State Natural Science Award of China (2006), Seaborg Lectureship at the University of California at Berkeley (2007), Prize of Ho Leung Ho Lee (HLHL) Foundation for Scientific and Technological Progress (2007), Edward Clark Lee Lectureship at University of Chicago (2008), the Leader of Year 2008 Hong Kong (Research), Fellow of Royal Society of Chemistry (2008) and Molecular Sciences Forum Lecture Professorship at Institute of Chemistry, CAS (2009).

• Professor John Kelly, Trinity College Dublin, Republic of Ireland
• Audio recording (mp3)

Biography

John Kelly obtained his BSc from the University of Manchester, MSc from McMaster University (supervisor, John McCullough) and PhD from the University of London (supervisor, George Porter).  After a Leverhulme Teaching Fellowship at the University of the West Indies, Jamaica and postdoctoral work at the Max Planck Institut für Strahlenchemie, Mülheim he joined Trinity College Dublin as a lecturer in 1973.  He was elected as Fellow in 1978, promoted to Associate Professor in 1987 and to Professor of Chemistry in 2006.  He was Director of Science of Materials (1989-1973), Head of the Department of Chemistry (1994–2000) and the first Director of the Dublin Chemistry Graduate Programme (2008-2010). He is currently Fellow Emeritus.  His research interests are in photochemistry, transient spectroscopy, nucleic acids, photo-active metal complexes and nanoparticles, with applications in bio-sensing and energy conversion.

Abstract

For many years dipyrido[3,2-a:2’,3’-c]phenazine (dppz) complexes have been extensively studied as probes for DNA. 

[Ru(phen)₂(dppz)]³⁺ (phen = 1,10-phenanthroline) has attracted particular attention as it acts as a DNA-light switch, being non-luminescent in water  but emitting when bound to DNA. By contrast [Ru(TAP)₂(dppz)]²⁺ (TAP = 1,4,5,8-tetraazaphenanthrene) [2] and [Cr(phen)₂(dppz)]³⁺ [3]  are luminescent in aqueous solution but not upon binding to DNA.  This is due to reduction of the metal complex excited state by guanine as has been demonstrated by picosecond transient spectroscopy (with both visible and IR monitoring) for [Ru(TAP)₂(dppz)]²⁺ [2] and also for  [Re(CO)₃(dppzF₂)]²⁺ [4].

Although it is accepted that the dppz ligand intercalates between the DNA base-pair, the precise mode of binding deduced from spectroscopic and biophysical measurements has been a matter of debate.  Recent successful crystallisation by the Cardin group of both Ru(TAP)₂(dppz)]²⁺  [5] and  [Ru(phen)₂(dppz)]²⁺  [6] with small defined-sequence DNA has for the first time  provided a wealth of information on the interaction of these complexes with DNA and allowed a comparison with other DNA- intercalating molecules

References
[1] B M Zeglis et al, Chem Comm, 2007, 44, 4565-4579
[2] B Elias  et al, Chemistry – Eur J, 2008, 14, 369-375.
[3] M Wojdyla  et al,  Photochem. Photobiol. Sci, 2010, 9, 1196-1202.
[4] Q Cao et al, Photochem. Photobiol. Sci, 2011, 10, 1355-1364.
[5] J P Hall et al, Proc Natl Acad Sci,  2011, 108, 17610-17614
[6] H Niyazi et al, Nature Chemistry, 2012, in press.

• Dr Samantha Higgins, Virginia Tech, USA
• Audio recording (mp3)

Biography

Dr Samantha L H Higgins graduated from Randolph-Macon College, Ashland, VA in 2006 with her BSc in chemistry. Recently, Samantha received her PhD from Virginia Polytechnic Institute & State University, Blacksburg, VA. She studied mixed-metal supramolecular complexes and their applications in photodynamic therapy, under the direction of Professor Karen J Brewer.

Abstract

Ru(II) and Os(II) polypyridyl chromophores have been readily studied for applications in DNA photomodification due to their enhanced photophysical and interesting photochemical properties. Coupling a Ru(II) or Os(II) chromophore to a remote bioactive site, such as Pt(II) or Rh(III), through a polyazine bridging ligand provides a supramolecular complex characterized by redox, spectroscopic, and photophysical properties. Studies of the mixed-metal complexes in the presence of DNA show enhanced photoinduced activity using low energy visible light within the therapeutic window (600-900 nm). The supramolecular complexes, [(Ph₂phen)₂M^II(dpp)Pt^IICl₂]Cl₂ (Ph₂phen = 4,7-diphenyl-1,10-phenanthroline and M = Ru(II) or Os(II)) display unique DNA photobinding and photocleavage properties by utilizing their lowest lying ³metal-to-ligand charge transfer (³MLCT) excited state to facilitate ligand loss at the remote Pt(II) center. Modifying the molecular architecture to [(TL)₂M^II(dpp)Rh^IIICl₂(TL’)](PF₆)₃ (TL = terminal ligand on the chromophore, M = Ru(II) or Os(II) and TL’ = terminal ligand on the Rh(III) center) provides for distinctive oxygen independent photobinding and photocleavage features, a result attributed to unit population of the ³MLCT excited state, which is coupled to the lower lying ³metal-to-metal charge transfer (³MMCT) excited state. The varied mechanisms of DNA photocleavage in these supramolecular systems provide a fresh look at mixed-metal systems in photodynamic therapy.

• Dr James Thomas, University of Sheffield, UK
• Audio recording (mp3)

Biography

Jim Thomas was educated at the Universities of Reading and Birmingham. Following postdoctoral work with Jean-Marie Lehn in Strasbourg and Chris Hunter in Sheffield, he stayed in Sheffield to take up a Royal Society University Research Fellowship, becoming a permanent member of staff in 2004. He is currently a Reader in Coordination Chemistry. His research involves molecular recognition of anions, molecules and biomolecules, self-assembly, and the construction of functional molecular architectures.

Abstract

Ruthenium(II) polypyridyl complexes that interact reversibly with DNA can display high binding affinities and selectivities [1,2] as well as interesting photophysical properties [3]. Although such complexes offer potential as in cellulo probes for luminescence microscopy, poor cellular uptake by live cells restricts the use of such molecules.

In recent studies we have shown that complexes such as 1 and 2 are taken up by both live eukaryotic and prokaryotic cells where they bind to nuclear DNA as evident by both luminescence and transmission electron microscopy[4] suggesting they may find use as cellular specific imaging agents and/or therapeutics [5].

A distinctive property of 2 - revealed by in vitro and in cellulo studies - is that high affinity binding of specific DNA structures leads to distinctive emission signatures [4,6].Herein we present progress in this area, including structural studies aimed at delineating the cause of this complex’s structural binding preferences [7].

Acknowledgments: We thank EPSRC for its Life science DTC and PoC fund.

References
[1] (a) C Metcalfe, J A Thomas, Chem Soc Rev2003, 32, 214. (b) M R Gill, J A Thomas, Chem Soc Rev, in press.
[2] P Waywell, V Gonzalez, M R Gill, H A Adams, A J H M Meijer, M P Williamson, J A Thomas, Chem Eur J, 2010, 16, 2407.
[3] (a) S P Foxon, M Towrie, A W Parker, M Webb, J A Thomas, Angew Chem Int Ed,2007, 46, 3686-3689. (b) V G Gonzalez, T Wilson, I Kurihara, A Imai, J A Thomas, J Otsuki, Chem Commun 2008, 168.
[4] M R Gill, J Garcia-Lara, S J Foster, C G W Smythe, G Battaglia, J A Thomas, Nat Chem, 2009, 1, 662-667.
[5] M R Gill, H Derat, C G W Smythe, G Battaglia, J A Thomas, ChemBioChem, 2011, 12, 877.
[6] T Wilson, M P Williamson, J A Thomas, Org Biomol Chem, 2010, 8, 2717.
[7] T Wilson, P J Costa, V Felix, M P Williamson, J A Thomas, in preparation.

• Professor David Phillips CBE, Imperial College London, UK
• Audio recording (mp3)

Biography

David Phillips is a graduate of the University of Birmingham, [BSc Chemistry 1961, PhD 1964, Honorary DSc, 2011]. He carried out post-doctoral work in the University of Texas at Austin, 1964-6, [Fulbright Scholar], and the Institute of Chemical Physics, Academy of Sciences of USSR, Moscow 1966/7, before beginning  his University teaching and research career at the University of Southampton, Department of Chemistry, in 1967. He then moved to London in 1980 as Wolfson Professor of Natural Philosophy at the Royal Institution, and in 1989 became Hofmann Professor of Chemistry at Imperial College London, 1989-2006, Head of Department 1992-2002.  He served as Dean for the Faculties of Life Sciences and Physical Sciences, 2002-2005, and Senior Dean, 2005/6 at Imperial.  He is author of some 590 articles and reviews in his field of photochemistry, and received the Porter Medal of the European, Oceanic, and Inter-American Photochemistry Associations 2010 for this work. He is a committed populariser of science; and was awarded the Michael Faraday Award of the  Royal Society in 1997 was awarded an OBE in 1999 for services to science education, and CBE in the 2011/12 New Year’s honours list for services to Chemistry. He is currently President of the Royal Society of Chemistry.

Abstract

Photodynamic therapy, PDT, is a minimally invasive procedure used in treating a range of cancerous diseases, infections, and in ophthalmology to treat the wet form of age-related macular degeneration. The photodynamic action relies upon the simultaneous interaction between a sensitiser molecule [non-toxic in the absence of light], visible light, and molecular oxygen. The sensitiser, usually a porphryin –related molecule, excited initially to the singlet state, intersystem crosses to a longer-lived triplet state, which then produces reactive oxygen species , ROS, primarily singlet oxygen resulting from electronic energy transfer.

Current photodynamic therapy (PDT) of cancer is limited by inefficiencies involved in specifically targeting photosensitisers to tumours. Although antibodies are being explored as targeting vehicles, they present significant challenges, particularly in terms of pharmacokinetics and drug-coupling. We describe here a novel and effective system to attach covalently multiple photosensitiser molecules (both pre-clinical, pyropheophorbide-a and clinically approved, verteporfin photosensitisers) to single-chain Fvs.  Further, we demonstrate that not only do the resulting photoimmunoconjugates retain photophysical functionality, they are more potent than either free photosensitiser, effectively killing tumour cells in vitro and in vivo. For example, treatment of human breast cancer xenografts with a photo-immunoconjugate comprising an anti Her-2 scFv linked to 8 molecules of pyropheophorbide-a leads to complete tumour regression. These results give an insight into the important features that make scFvs good carriers for PDT drugs, and provide proof of concept of this unique approach to targeted photodynamic therapy (tPDT). This promises to significantly improve upon current photodynamic therapy for the treatment of cancer and paves the way for clinical application.

A second means of introducing selectivity in PDT is through spatial selection , using two-photon excitation of the sensitiser. This has the advantage of using red or near infra-red light, which greatly enhances tissue penetration. We describe the synthesis of porphyrin dimers with very large two-photon cross sections,carried out by Professor Harry Anderson’s group in Oxford,  and their effect in vitro on two cell types, and  in sealing blood vessels in vivo.

• Dr Nicola J Farrer, University of Warwick, UK

Biography

Nicola Farrer received her degree (Natural Sciences, 2003) and subsequently her PhD (2007) from the University of Cambridge. Her doctoral work involved developing readily ionisable phosphine ligands with a view to detecting catalytic intermediates by electrospray mass spectrometry, and was supervised by Prof. Brian Johnson (University of Cambridge), with the bulk of the analytical work undertaken in the lab of Dr. Scott McIndoe (University of Victoria, Canada). She returned to the UK to join the group of Professor Peter Sadler at the University of Warwick as a post-doctoral fellow in September 2007, working on one- and two-photon photoactivatable metal complexes for application as anti-cancer prodrugs. Her research interests also include multinuclear NMR spectroscopy and chemical applications of photonic crystal fibres. In 2010 she was awarded Chartered Chemist status by the Royal Society of Chemistry. She is currently taking a career break, following the birth of her son James in October 2010.

• Professor Roberto da Silva, University of Sao Paulo, Brazil
• Audio recording (mp3)

Biography

Dr Roberto S da Silva joined Pharmacy School of the University of Sao Paulo as Assistant Professor in 1986 where he works nowadays as Professor. He went on to receive his PhD in chemistry at the UNESP-Brazil in 1992, under the mentorship of Professor Elia Tfouni, where he worked on the synthesis and structural elucidation of macrocyclic ruthenium complexes. He undertook post-doctorate research with Professor A B P Lever in 1994, Peter C Ford in 2006 and David Wink in 2009. Dr da Silva’s current research combines the inorganic, bioinorganic, material chemistry and photobiological studies of his undergraduate, graduate and post-doc work to focus on creating nitrosyl ruthenium complexes that will improve the quality and efficiency of photodynamic therapy. His group’s long-term goal is to advance medical and biological research by synthesizing compounds that can deliver on site nitric oxide and singlet oxygen efficiently. His group’s multidisciplinary environment is yielding clinical applications of ruthenium compounds with emphasis on photobiological therapy.

Abstract

Photodynamic therapy (PDT) is employed in the clinical treatment of neoplasic tissues and involves activation with light irradiation of a photosensitizing agent in the presence of molecular oxygen. Even though PDT has received increasing acceptance as a clinical approach the technique has been found to fail due low oxygen concentration in tumor region and  challenges concerning the design of effective photosensitizing drugs still have to be faced. In our work we have found that of nitric oxide release following singlet oxygen (¹O₂) production upon light irradiation may be an important mechanism by which the nitrosyl ruthenium complex exhibits enhanced biological activity in cells. The structural aspects, pharmacological assays, and in vitro photoinduced cytotoxic properties of nitrosyl ruthenium complexes are described. Its biological effect on the B16F10 and MCF-7 cell lines were studied in the presence and absence of visible light irradiation. At comparable irradiation levels nitrosyl ruthenium complexes were much more effective than a compound that produce only ¹O₂; indeed, enhanced potency was detected when the nitrosyl ruthenium complex was encapsulated in a drug delivery system. Flow cytometry analysis revealed that the photocytotoxic activity was mainly due to apoptosis.

Acknowledgments:
CNPq, CAPES and FAPESP

• Dr Julie Woods, University of Dundee, UK
• Audio recordings (mp3)

Biography

Julie Woods is a scientist who received her PhD in Oncology from the University of Manchester in 1994. She is a lecturer at the Photobiology Unit, University of Dundee. Her area of interest is understanding the mechanisms underlying photochemical toxicity. She also has responsibility for the Scottish Cutaneous Porphyria Service. Porphyria is a group of diseases resulting from abnormalities in the biosynthesis of haem and can cause photochemical toxicity due to the excessive accumulation of porphyrin.  She has an active role in the Scottish Photodynamic Therapy Centre, which delivers light-activated drug therapy to both non-melanoma skin cancers and internal cancers. In its first decade, the Photodynamic Therapy Centre has performed 6000 diagnostic and/or therapeutic treatments in the brain, lung, bile duct, oral cavity, urinary tract, gullet and skin.

Abstract

The modality of light-activated chemotherapy is used in the treatment of non-melanoma skin cancer and some internal solid tumours; and also to treat hyperproliferative benign skin disease (eg. psoriasis). However, the range of photosensitisers available is limited, with most being based on a tetrapyrrole-like structure. There is a need for new photosensitisers, and with emerging developments in optical technology a rethink on how this modality can be applied to specific indications. Platinum (IV) prodrugs undergo photoreduction to the more reactive platinum (II) species (amongst other photoproducts) when irradiated. They rapidly kill tumour cells and their cisplatin-resistant derivatives in culture and are more effective than cisplatin tested under similar conditions. The trans- geometry is consistently more effective than the cis- configuration. Nuclear morphology studies and measurement of p53 stabilisation and caspase activity reveal important differences between the mechanism of action of these complexes and cisplatin. Finally, these prodrugs have no or limited toxicity or DNA reactivity in the dark, suggesting that toxicity to surrounding normal tissue could be limited. The complexes can be administered to mice at 10-fold higher doses than cisplatin with no obvious adverse effects. The photoactivated complexes described here are not simply acting as prodrugs of cisplatin. Harnessing the potent properties of platinum drugs selectively at the target site by light-activation could be beneficial for several indications including bladder and oesophageal cancer.

• Professor Colin Hopper, University College London, UK

Biography not available.

• Professor Dr Ulrich Schatzschneider, Julius-Maximilians-Universität, Germany

Biography

Ulrich Schatzschneider studied chemistry at the Heinrich-Heine-Universität in Düsseldorf and obtained his PhD at the Max-Planck-Institute for Bioinorganic Chemistry in Mülheim an der Ruhr, Germany in 2001 under the supervision of Professor Dr Eva Rentschler and Professor Dr Karl Wieghardt. He spent the next 2 years as a postdoc in the group of Professor Dr Jacqueline K Barton at the California Institute of Technology in Pasadena, USA, supported by a research fellowship from the Deutsche Forschungsgemeinschaft (DFG). In 2004, he returned to Germany to start his independent scientific career, first at the University of Heidelberg and from 2006 to 2010 at the Ruhr-Universität in Bochum (RUB). He obtained his habilitation in inorganic chemistry from RUB in 2010 and was appointed as Associate Professor of Bioinorganic Chemistry at the Julius-Maximilians-Universität in Würzburg in September 2010. His scientific interests are focused on multi-modal bioimaging and therapeutic applications of transition metal complexes and their bioconjugates. In particular, his research group is active in the fields of CO releasing molecules (CORMs) and organometal–peptide bioconjugates.

• Professor Kenneth Kam-Wing Lo, City University of Hong Kong, Hong Kong, China
• Audio recording (mp3)

Biography

Kenneth Lo obtained his PhD degree from The University of Hong Kong in 1997.  From 1997 to 1999, he worked as a Croucher Foundation Postdoctoral Research Fellow in the Inorganic Chemistry Laboratory, University of Oxford.  He joined the Department of Biology and Chemistry of City University of Hong Kong as Assistant Professor in 1999 and became Associate Professor (Scale B) in 2003, Associate Professor (Scale A) in 2007, and Professor in 2011.  He received The APA Prize for Young Scientist from the Asian and Oceanian Photochemistry Association in 2005 and The Distinguished Lectureship Award from the Chemical Society of Japan in 2011.  The main theme of his research work is the utilization of luminescent transition metal complexes as biomolecular and cellular probes.

Abstract

Many transition metal polypyridine complexes exhibit intense and long-lived emission that is very sensitive to the local environments of the complexes.  This interesting property allows the complexes to serve as useful probes for biomolecules.  Thus, we have attached various reactive functional groups to luminescent transition metal complexes such as cyclometalated iridium(III) and tricarbonylrhenium(I) polypyridine complexes to yield new labels for biomolecules.  Additionally, we have modified these complexes with a range of biological substrates and artificial pendants including indole, estradiol, biotin, lipids, fluorous chains, dendritic skeletons, and poly(ethylene glycol), and utilized the complexes as luminescent biological probes.  Interestingly, these pendants not only perturb the photophysical behavior of the complexes, but also significantly affect their biomolecular recognition and cellular uptake properties.  In this presentation, the molecular design, photophysical properties, and biological properties of a selection of these iridium(III) and rhenium(I) polypyridine complexes will be described.  The cytotoxicity, cellular uptake, and intracellular distribution of these complexes will also be discussed.

• Professor Jean-Claude Bünzli, EPFL, Switzerland and Korea University, Korea
• Audio recording (mp3)

Biography

Jean-Claude Bünzli earned a degree in chemical engineering in 1968 and a PhD in 1971 (Swiss Federal Institute of Technology, Lausanne, EPFL). He then spent two years at the University of British Columbia as a teaching postdoctoral fellow (photoelectron spectroscopy) and one year at the Swiss Federal Institute of Technology in Zürich (physical organic chemistry). He was appointed assistant-professor at the University of Lausanne in 1974 and started a research program on the coordination and spectroscopic properties of f-elements. He was promoted as a full professor of inorganic and analytical chemistry in 1980. In 2001 he transferred to EPFL where he founded the Laboratory of Lanthanide Supramolecular Chemistry. Since 2009 he is also acting as World Class University professor at Korea University (South Korea).

His present research interests deal with various aspects of luminescent lanthanide coordination and supramolecular compounds. He is developing luminescent bioprobes and bioconjugates for the detection of cancerous cells with time-resolved microscopy as well as materials for OLEDs, telecommunications, and solar energy conversion. He has published more than 300 papers and is acting as the senior editor of the Handbook on the Physics and Chemistry of Rare Earths.

Abstract

Ditopic hexadentate ligands with benzimidazole core self-assemble in water at physiological pH to yield robust and highly luminescent binuclear helicates [Ln₂(L^CX)₃]. These entities are thermodynamically stable, kinetically inert and non-cytotoxic (IC₅₀>500 μM). They enter into live cells by endocytosis and stain the endoplasmatic reticulum as shown by time-resolved luminescence microscopy [1]. The probes are also amenable to NIR excitation by multiphoton processes and can be inserted into nanoparticles [2].

Further derivatization affords helicates which can be bioconjugated to avidin and various monoclonal antibodies. When combined with microfluidic devices, the binuclear bioconjugates are highly efficient in multi detection of biomarkers expressed by cancerous cells and tissues [3].

[1] B Song, C D B Vandevyver, A-S Chauvin, J-C G Bünzli, Org Biomol Chem 2008, 6, 4125
[2] S V Eliseeva, B Song, C D B Vandevyver, A-S Chauvin, J B Wacker, J-C G Bünzli, New J Chem 2010, 34, 2915
[3] V Fernandez-Moreira, B Song, V Sivagnanam, A-S Chauvin, C D B Vandevyver, M A M Gijs, H-A Lehr, J-C G Bünzli, Analyst 2010, 135, 42

• Professor Dr Volker Albrecht, biolitec research GmbH, Germany

Biography

Volker Albrecht studied medical biochemistry, medicine and food chemistry at the Humboldt University in Berlin and received his diploma degree in biochemistry in 1968. After his doctoral thesis in biochemistry in 1972 he worked as research director for several research groups at the Central Institute of Nutrition at the Academy of Sciences of the German Democratic Republic (GDR). In 1984 he was appointed professor of biochemistry at the Academy of Sciences of the GDR. In 1989 he was appointed 2nd director at the German Institute of Nutrition responsible for biomedical research. He then switched to industry and from 1992 to 2000 was research director for chemistry, medicine and biology at the development center of Sarstedt AG & Co KG. After working as a research director and scientific consultant for the Strathmann AG & Co and Strathmann Biotech GmbH in 2001 he became research director of the biolitec AG focusing on medical applications of photodynamic therapy. From 2002 to 2004 he also served as managing director of the biolitec Pharma Ltd and since 2011 is managing director of the biolitec research GmbH Jena (Thuringia, Germany) in which all research activities of the biolitec group have been merged.

Abstract

Photodynamic therapy (PDT) is a minimal-invasive modality for the treatment of tumorous and other diseases. During PDT, a dye (photosensitizer) is administered that - after enrichment in the tumour - is irradiated with light of a specific wavelength. By interaction of the irradiated photosensitizer-molecule with molecular oxygen cell-toxic substances (especially highly reactive singlet oxygen) are formed which effectively damage the tumour. Numerous compounds have been investigated for their suitability for PDT. The most important among these are dyes from the chemical class of the tetrapyrroles (porphyrins, chlorins, phthalocyanines). Nearly all photosensitizers that are currently authorized for clinical applications are tetrapyrroles (Photofrin, Verteporfin, Temoporfin) or their biosynthetic precursors (ALA, i.e. d-aminolevulinic acid). It will be discussed what requirements metal complexes, in particular tetrapyrrole metal complexes, have to meet to be successfully used in PDT: eg photophysical parameters, factors influencing the uptake in tumour tissue, and pharmaceutical formulation.

Co-author:
Dr A Wiehe, biolitec research GmbH, Germany

• Dr Arno Wiehe, biolitec research GmbH, Germany
• Audio recording (mp3)

Biography

Arno Wiehe graduated in chemistry and history at the Free University of Berlin in Germany. During his doctoral thesis in organic chemistry with Professor Dr H Kurreck at the FU Berlin he worked on photosynthetic model systems and received his Dr rer nat in 1997. He then worked as a postdoctoral fellow at the Humboldt University in the department of physics in the group of photobiophysics with Professor Dr B Röder. During this time his research focused on tetrapyrrole applications for photodynamic therapy (PDT). In 2001 he joined the biolitec AG as a research scientist. He is now the head of the chemical research laboratory of biolitec developing new photosensitizers for PDT. In 2003/2004, during a part-time study at the Rheinische Friedrich-Wilhelms-University of Bonn he received an additional qualification as master of drug regulatory affairs and since then has also taken over responsibility in the marketing authorization of photosensitizer drug formulations.