EUROPEAN SCIENCE Marine FOUNDATION Board

Nanomedicine

An ESF – European Medical Research Councils (EMRC) Forward Look report ESF focuses on science driven collaboration between the best European researchers in all disciplines. We promote the identification and advancement of leading edge science in Europe in close co-operation with our Member Organisations. We bring together leading scientists, scholars and funding agencies to explore new directions in research and to plan and implement European level research collaboration in a global context. Our main instruments include conferences, scientific foresights, collaboration programmes and support to outstanding young researchers. ESF also manages COST, an intergovernmental framework for European co-operation in the field of Scientific and Technical Research.

Integrative Biology is currently a hot topic in the Life Sciences. The potential applications of Integrative Biology will contribute significantly to maximizing the value of knowledge generated in the biomedical field and the outcome expected for the public health care system. In this context, the strategy developed by the European Medical Research Councils (EMRC), one of the five Standing Committees at ESF, aims to: • foster an interdisciplinary approach towards the Functional Genomics domain embracing all the –omics disci- plines (including the DNA, RNA, protein and other macromolecules world) and their integration into Systems Biology; • focus on biomedical applications emerging from these and related domains, such as Nanomedicine and Structural Medicine; Molecular Imaging, Genetic Epidemiology and Pharmacogenetics in order to advance the promising field of Personalized Medicine also qualified as Individualized pharmacotherapy; • develop translational research to overcome boundaries between basic research/science and clinical applica- tions (e.g., application of cell and gene therapies in Tissue Engineering and Regenerative Medicine, identifica- tion and validation of biomarkers and therapeutic/diagnostic tools that will allow the transfer of innovation through a collaborative public-private process of research and development, etc.). In this respect, special atten- tion will be paid to therapeutic domains identified as a burden for European citizens1: – cardiovascular and respiratory diseases – cancer – allergic, immunological and infectious diseases – neurodegenerative diseases including neurosciences and mental health – diabetes, digestive and renal diseases – rheumatic diseases, musculoskeletal disorders and skin diseases – rare diseases for instance through its sponsorship of The European Rare Diseases Therapeutic Initiative (ERDITI), and specific patient populations like children, the elderly and women. • gather expertise and advance the methodology for the evaluation of the socio-economic value of research in the above-mentioned fields. In addition, further attention has been paid on the identification of related regulatory and ethical issues and to the promotion of biomedical research to the European general public and political stakeholders. In this respect EMRC is a permanent observer of the Comité directeur pour la Bioéthique at the European Council and is being involved in further developments brought by the WHO and EMEA to its recommendation to build an open international reg- istry for clinical trials. • develop new partnering to support and leverage these activities, i.e. with European Agencies, intergovernmen- tal organizations (EMBO), charities, pharmaceutical and biotechnological industries, etc. Due to the progressive character of these scientific fields, the EMRC portfolio will provide flexibility to cover newly emerging trends in science in a timely manner.

1. WHO Report on “Priority Medicines for Europe and the World” (The Hague, NL, 18 November 2004) commissioned by the Government of the Netherlands.

Cover picture: An image of one selected gas-filled polymer-stabilized microcapsule obtained by electron microscopy. The “magic bullet” is spherical with a diameter of about 1.7µm and the substructure made of polymer nanoparticles is clearly visible. In order to indicate that the particles are in fact gas-filled, an imperfect capsule with a bump has been carefully selected. These kinds of particles are the basis for Ultrasound Theranostics: Antibody based microbubble conjugates as targeted in vivo ultrasound contrast agents and advanced drug delivery systems. A. Briel, M. Reinhardt, M. Mäurer, P. Hauff; Modern Biopharmaceuticals, 2005 Wiley-VCH, p. 1301 © Modern Biopharmaceuticals. Edited by J. Knäblein, 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN: 3-527-31184-X © Schering AG 1

ESF Forward Look on Nanomedicine 2005 2

Participants at the European Science Foundation’s Forward Look on Nanomedicine Consensus Conference, Le Bischenberg, 8-10 November 2004 3

Sponsored by the European Science Foundation and organised by its Standing Committee, the European Medical Research Councils (EMRC)

Steering and Organising Committee Chair: Ruth Duncan, Welsh School of Pharmacy, Cardiff University, UK Deputy-Chair: Wolfgang Kreyling, GSF National Research Centre for the Environment, and Health, Germany Members: Patrick Boisseau, CEA-Léti, France Salvatore Cannistraro, INFM, Università della Tuscia, Italy Jean-Louis Coatrieux, Inserm, Université de Rennes 1, France João Pedro Conde, Instituto Superior Técnico, Portugal Wim Hennink, Utrecht University, The Netherlands Hans Oberleithner, University of Münster, Germany José Rivas, Universidad de Santiago de Compostela, Spain EMRC: Clemens Sorg, University of Münster, Germany (Chair) Thomas Bruhn, University of Münster, Germany (Assistant to the Chair) ESF/EMRC Office: Carole Moquin-Pattey, Head of Unit Hui Wang, Science Officer

The Steering Committee would particularly like to thank the following persons for their valuable contributions: Alberto Gabizon, Israel Mauro Giacca, Italy Rogerio Gaspar, Portugal Thomas Kissel, Germany Bert Meijer, The Netherlands

The Steering Committee would also like to thank Philips Medical Systems and Schering AG who co-sponsored the Consensus Conference held at Le Bischenberg, November 2004.

5

Contents

Foreword 6 Executive Summary 7 1. Nanomedicine: A New Opportunity for Improved Diagnosis, Prevention and Treatment for Disease 11 1.1. Definition of Nanomedicine 11 1.2. Position of Nanomedicines within the Healthcare Portfolio 11 2. Current Status of Nanomedicine Research and Forward Look 13 2.1. Science and Technology 13 2.1.1. Workshop on Analytical Techniques and Diagnostic Tools 2.1.2. Workshop on Nanoimaging and Manipulation 2.1.3. Workshop on Nanomaterials and Nanodevices 2.1.4. Workshop on Drug Delivery and Pharmaceutical Development 2.1.5. Workshop on Clinical Use, Regulatory and Toxicology Issues 2.2. Research Strategy and Policy 21 2.2.1. Organisation and Funding 2.2.2. Commercial Exploitation 2.2.3. Interdisciplinary Education and Training 2.2.4. Communication 3. European Situation and Forward Look – SWOT Analysis 25 4. Recommendations and Suggested Actions 29 4.1. General Recommendations 29 4.1.1. Priority Areas in Nanomedicine for the next 5 years 4.1.2. Priority Areas in Nanomedicine for the next 10 years 4.1.3. Commercial Exploitation 4.1.4. Interdisciplinary Education and Training 4.2. Scientific Trends 29 4.2.1. Nanomaterials and Nanodevices 4.2.2. Nanoimaging and Analytical Tools 4.2.3. Novel Therapeutics and Drug Delivery Systems 4.2.4. Clinical Applications and Regulatory Issues 4.2.5. Toxicology 4.3. Research Strategy and Policy 30 4.3.1. Organisation and Funding 4.3.2. Commercial Exploitation 4.3.3. Interdisciplinary Education and Training 4.3.4. Communication 5. Bibliography 32 5.1. Key Reports on Nanotechnology and Nanomedicine 32 5.2. Key Literature on Nanotechnology relating to Medicine 33 5.3. Websites and General Information 35 6. Appendices 37 Appendix I. ESF Forward Look Workshop Participants 37 Appendix II. ESF Forward Look Consensus Conference Participants 39 Appendix III. Projected Market for Nanomedicines 43 Appendix IV. European Projects and Networks Undertaking Nanomedicine Research 43 Appendix V. Nanomedicines in Routine Clinical Use or Clinical Development 45 Appendix VI. European Companies Active in Nanomedicines’ Development 47 6

Foreword

Recent years have witnessed an unprecedented growth in research in the area of nanoscience. There is increasing optimism that nanotechnology applied to medicine will bring significant advances in the diagnosis and treatment of disease. However, many challenges must be overcome if the application of Nanomedicine is to realise the improved understanding of the patho-physiological basis of disease, bring more sophisticated diagnostic opportunities and yield more effective therapies. Both the optimism and the challenges have prompted governmental science and funding organisations to undertake strategic reviews of the current status of the field1, their primary objectives being to assess potential opportunities for better healthcare as well as the risk-benefit of these new technologies, and to determine priorities for future funding.

In early 2003, the European Science Foundation launched its Scientific Forward Look on Nanomedicine. I am pleased to see the successful conclusion of this foresight study, which has been the first such exercise focused on medical applications of nanoscience and nanotechnology. The Forward Look involved leading European experts and led to a definition of the current status of the field and debates on strategic policy issues. The recently published Policy Briefing summarised the recommendations made2.

Here the discussions and recommendations are presented in full. Implementation of these recommendations should ensure continuing European leading-edge research and development in the field of Nanomedicine, resulting in reduced healthcare costs and the rapid realisation of medical benefits for all European citizens. ESF will commit itself to taking the initiative and facilitating the relevant bodies, including ESF Member Organisations and the European Commission, for actions based on these recommendations.

Bertil Andersson ESF Chief Executive

1. Commission of the European Communities Communication: (2004) Towards a European Strategy for Nanotechnology, EU, DG Research, Brussels, (www.cordis.lu/nanotechnology). ftp://ftp.cordis.lu/pub/era/docs/3_nanomedicinetp_en.pdf NIH Roadmap: Nanomedicine (2004), NIH, USA (http://nihroadmap.nih.gov) (http://www.capconcorp.com/roadmap04) UK Royal Society and Royal Academy of Engineering (2004) Report on Nanoscience and nanotechnologies: Opportunities and uncertainties, (www.nanotec.org.uk) National Institutes of Health - National Cancer Institute (2004) Cancer Nanotechnology Plan: A strategic initiative to transform clinical oncology and basic research through the directed application of nanotechnology, NCI, NIH, USA (http://nano.cancer.gov/alliance_cancer_nanotechnology_plan.pdf) 2. ESF Scientific Forward Look on Nanomedicine: Policy Briefing 23 February 2005 (www.esf.org) 7

Executive summary

Background Procedure

Recent years have witnessed an unprecedented The ESF Forward Look on Nanomedicine was growth in research in the area of nanoscience. There conducted through a Steering Committee which is increasing optimism that nanotechnology applied initially organised a series of five specialised work- to medicine will bring significant advances in the shops held from 1 to 5 March 2004. These work- diagnosis treatment and prevention of disease. shops involved small groups of experts from However, many challenges must be overcome if the academia and industry representing the different sub- application of Nanomedicine is to realise the disciplines of the Nanomedicine field. Each group improved understanding of the pathophysiological was invited to review the issues listed above, and to basis of disease, bring more sophisticated diagnostic prepare draft recommendations in their area of opportunities, and yield more effective therapies and specific expertise (participants are listed in Appen- preventive measures. dix I). Both the optimism and the challenges have A final Consensus Conference was held at Le prompted governmental, science and funding organ- Bischenberg, France from 8 to 10 November 2004. isations to undertake strategic reviews of the current The meeting was attended by more than 70 repre- status of the field, their primary objectives being to sentatives coming from academia, industry, private assess potential opportunities for better healthcare foundations, and governmental agencies supporting as well as to assess the risk-benefit of these new scientific research. Collectively they were able to technologies, and determine priorities for future review and revise the outputs from the earlier disci- funding. The outcome of the European Science pline-specific workshops, paying special attention Foundation’s Forward Look on Nanomedicine is to the boundaries within this multidisciplinary presented here. scientific field. Moreover the Consensus Conference was able to review the underpinning topics of Objectives Science Funding and Policy Making, Commercial Exploitation, Education, and Communication. In 2003 the Medical Standing Committee of ESF Participants are listed in Appendix II. (EMRC) initiated the European Science Founda- tion’s Forward Look on Nanomedicine. The aims of Definitions this study were to gather European experts from academia and industry to: The field of ‘Nanomedicine’ is the science and ¥ Define the field technology of diagnosing, treating and preventing ¥ Discuss the future impact of Nanomedicine on disease and traumatic injury, of relieving pain, and healthcare practice and society of preserving and improving human health, using ¥ Review the current state-of-the-art of Nanomedi- molecular tools and molecular knowledge of the cines research human body. It was perceived as embracing five • Identify Europe’s strengths and weaknesses main sub-disciplines that in many ways are over- ¥ Deliver recommendations on: lapping and underpinned by the following common Ð future research trends and priorities for funding technical issues Ð organisational and research infrastructures needed at the national and European levels to support coor- ¥ Analytical Tools dinated scientific activities ¥ Nanoimaging Ð the mechanisms needed to facilitate effective ¥ Nanomaterials and Nanodevices dissemination of information to the general public ¥ Novel Therapeutics and Drug Delivery Systems and policy makers. ¥ Clinical, Regulatory and Toxicological Issues 8 EXECUTIVE SUMMARY

The aim of ‘Nanomedicine’ may be broadly Recommendations defined as the comprehensive monitoring, control, construction, repair, defence and improvement of The sub-fields indicated above significantly over- all human biological systems, working from the lapped in terms of the underpinning science (mate- molecular level using engineered devices and rials science, analytical techniques, and safety nanostructures, ultimately to achieve medical bene- issues), and the perception of the core European fit. In this context, nanoscale should be taken to strengths and weaknesses in each sub-field were include active components or objects in the size very similar. range from one nanometre to hundreds of nanome- tres. They may be included in a micro-device (that ¥ Nanomaterials and Nanodevices might have a macro-interface) or a biological envi- Advances should begin with the optimisation of ronment. The focus, however, is always on nanoin- existing technologies towards specific Nanomedi- teractions within a framework of a larger device or cine challenges. The development of new multi- biologically, within a sub-cellular (or cellular) functional, spatially ordered, architecturally varied system. systems for targeted drug delivery was seen as a priority. There is a pressing need to enhance expert- Forward Look on Nanomedicine ise in scale-up manufacture and material character- isation, and to ensure material reproducibility, Miniaturisation of devices, chip-based technologies effective quality control and cost-effectiveness. and, on the other hand, ever more sophisticated novel These issues should be addressed urgently to enable nanosized materials and chemical assemblies are rapid realisation of clinical benefit (within five already providing novel tools that are contributing years). to improved healthcare in the 21st century. Opportu- For realisation to application within the next nities include superior diagnostics and biosensors, decade new materials are needed for sensing multi- improved imaging techniques Ð from molecules to ple, complicated analytes in vitro, for applications man Ð and not least, innovative therapeutics and in tissue engineering, regenerative medicine and 3D technologies to enable tissue regeneration and repair. display of multiple biomolecular signals. Telemet- However, to realise Nanomedicine’s full poten- rically controlled, functional, mobile in vivo sensors tial, important challenges must be addressed. New and devices are required, including construction of regulatory authority guidelines must be developed multifunctional, spatially ordered, architecturally quickly to ensure safe and reliable transfer of new varied systems for diagnosis and combined drug advances in Nanomedicine from laboratory to delivery (theranostics). The advancement of bioan- bedside. alytical methods for single-molecule analysis was seen as a priority.

¥ Analytical Tools and Nanoimaging These aspects were viewed as complementary even though many of the technologies required are very different in being designed for ex vivo, cellular or in vivo/patient use. Once again the opportunity was identified to refine existing nanotechniques allowing analysis of normal and pathological tissues to quickly bring a better understanding of initiation and progression of disease. Identification of new biological targets for imaging, analytical tools and therapy is viewed as a research priority. There is a need to develop novel nanotechniques for monitoring in real time cellular and molecular processes in vivo, bringing improved sensitivity and resolution. Mechanisms to allow early translation of research based on molec- ular imaging using nanoscale tools from animal models to clinical applications should be estab- EXECUTIVE SUMMARY 9

lished. This would close the gap between molecu- Toxicology lar and cellular technologies understudy, and allow rapidly commercialisation of clinical diagnostic There is an urgent need to improve the understand- nanotechnologies. ing of toxicological implications of Nanomedicines In the longer term, research should develop a in relation to the specific nanoscale properties multimodal approach for nanoimaging technolo- currently being studied, in particular in relation to gies, and assist the design of non-invasive, in vivo their proposed clinical use by susceptible patients. analytical nanotools with high reproducibility, sensi- In addition, due consideration should be given to the tivity and reliability. Such tools would allow a para- potential environmental impact and there should be a digm shift in pre-symptom disease monitoring, and safety assessment of of all manufacturing processes. enable the use of preventative medicines at an early Risk-benefit assessment is needed in respect of stage. The simultaneous detection of several mole- both acute and chronic effects of nanomedicines in cules, analysis of all sub-cellular components at the potentially pre-disposed patients Ð especially in rela- molecular level, and replacement of antibodies as tion to target disease. A shift from risk-assessment to detection reagents are seen as particularly important proactive risk-management is considered essential at challenges for basic research. the earliest stage of the discovery, and then the devel- opment of new nanomedicines. Novel Therapeutics and Drug Delivery Systems Clinical Applications and Regulatory Issues Nanosized drug delivery systems have already entered routine clinical use and Europe has been As the technologies are designed based on a clear pioneering in this field. The most pressing challenge understanding of a particular disease, disease- is application of nanotechnology to design of multi- specific oriented focus is required for the develop- functional, structured materials able to target ment of novel pharmaceuticals. In addition, it will specific diseases or containing functionalities to be important to establish a case-by-case approach allow transport across biological barriers. In addi- to clinical and regulatory evaluation of each tion, nanostructured scaffolds are urgently needed nanopharmaceutical. High priority should be given for tissue engineering, stimuli-sensitive devices for to enhancing communication and exchange of infor- drug delivery and tissue engineering, and physically mation among academia, industry and regulatory targeted treatments for local administration of ther- agencies encompassing all facets of this multidisci- apeutics (e.g. via the lung, eye or skin). plinary approach. To realise the desired clinical benefits rapidly, the importance of focusing the design of technolo- Research Strategy, Policy gies on specific target diseases was stressed: cancer, Organisation, Funding and neurodegenerative and cardiovascular diseases were Communication identified as the first priority areas. Longer term priorities include the design of In terms of education, a need for more formal inter- synthetic, bioresponsive systems for intracellular disciplinary training courses in the area of Nanomed- delivery of macromolecular therapeutics (synthetic icine was foreseen. At the undergraduate level these vectors for gene therapy), and bioresponsive or self- would cover the basic scientific disciplines includ- regulated delivery systems including smart nanos- ing molecular biology, colloidal chemistry, cell phys- tructures such as biosensors that are coupled to the iology, surface chemistry, and membrane biophysics. therapeutic delivery systems. In addition, new programmes at master’s or early postgraduate level (preferably with combined medical and scientific training) are needed to support the rapidly developing field of Nanomedicine. Encouragement of more interdisciplinary MD/PhD degree programmes with some provision for nanoscience would provide core scientific training for both scientists and physicians. This will be essen- tial to ensure a trained workforce to oversee clinical development of new nanomedicines. 10 EXECUTIVE SUMMARY

Timely exploitation of newly emerging Nano- Conclusions medicine technologies was seen as a key issue. This is an area of general weakness. There is a need to This Forward Look on Nanomedicine has defined establish specific Nanomedicine-related schemes to the remit of this emerging and important field. promote academic-commercial partnerships. The Nanomedicine is clearly multidisciplinary and growth of clusters or highly selected teams, chosen builds on the existing expertise in a large number of for personal excellence or track record would ensure different scientific fields. most rapid progress. To facilitate industrial develop- European strengths have been identified, as have ment the establishment of more manufacturing sites the short- and long-term opportunities, and priori- with a Good Manufacturing Practice designation ties for the development of Nanomedicine-related able to support small and medium enterprises would technologies have been recognised. help in transferring projects more rapidly into clini- When applying nanotechnology to medical uses, cal development. it is particularly important to ensure thorough safety Establishment of good communication is a evaluation of any new technologies and also to universal challenge for research and development review the likely environmental impact. In each at the interface of scientific disciplines and at the specific case, careful risk-benefit evaluation is leading edge. There is a continuing need to promote required. more truly trans-disciplinary conferences. Encour- Most importantly, an open and continuing agement of goal-oriented research partnerships dialogue is required to ensure all interested parties, between large medical centres and university including the general public, are well informed as research groups is essential to progress the field. to the ongoing technology developments in the field It was noted that scientifically qualified politi- of Nanomedicine. As much has been written in the cians are not common, and the regional, national popular press, quality information is required to and European programmes seldom show alignment, assist policy makers and scientists to distinguish suggesting less than optimal communication. Seri- “science fact” from “science fiction’’. ous effort needs to be made by scientific opinion leaders in Nanomedicine to ensure that politicians Governmental are well briefed. Not only will better diagnostics, Agencies and Funding treatments and prevention for life-threatening and Policy Makers

debilitating disease bring healthcare benefits to an Regulatory Academic Scientists incl.: ageing population, research and development in Chemistry Agencies Physics Nanomedicine also offers the potential of employ- Biology Pharmaceutical Medicine and ment and economic benefits with a reduction of Engineering Nanomedicine Mathematics Related healthcare budgets. Information Technology Industries General Public

There is an urgent need to more clearly articulate and better communicate the potential benefits of Nanomedicine to the general public as a whole. Engagement of the scientific community in early dialogue with the general public is crucial in order to discover any public concerns regarding Nanomed- icine. Continuing regular dialogue is essential to address and alleviate any public concerns. 11

1. Nanomedicine: A New Opportunity for Improved Diagnosis, Prevention and Treatment for Disease

1.1. Definition of Nanomedicine 1.2. Position of Nanomedicines within the Healthcare Portfolio The field of Nanomedicine is the science and tech- nology of diagnosing, treating and preventing The highest causes of mortality in Europe are disease and traumatic injury, of relieving pain, and cardiovascular disease and cancer. In addition demo- of preserving and improving human health, using graphic changes are producing an ageing population. molecular tools and molecular knowledge of the This in itself is leading to new healthcare challenges. human body. It embraces five main sub-disciplines There is rising prevalence in diseases of the central which are in many ways overlapping and are under- nervous system, such as senile dementia, pinned by common technical issues. Alzheimer’s disease, Parkinson’s disease, and diseases associated with ageing, for example arthri- tis and ocular diseases. Whilst much progress was made in the 20th century in respect of the therapies for infectious diseases, emergence of resistance, HIV/AIDS and other new infectious diseases, for example SARS, present new challenges. Nevertheless, as the 21st century begins, we are witnessing a paradigm shift in medical practice. Nanomedicine is expected to contribute signifi- cantly to the overall healthcare portfolio. Genomics and proteomics research is already rapidly elucidating the molecular basis of many The aim of Nanomedicine may be broadly diseases. This has brought new opportunities to defined as the comprehensive monitoring, control, develop powerful diagnostic tools able to identify construction, repair, defence and improvement of genetic predisposition to diseases. In the future, all human biological systems, working from the point-of-care diagnostics will be routinely used to molecular level using engineered devices and identify those patients requiring preventative nanostructures, ultimately to achieve medical bene- medication, to select the most appropriate medica- fit. In this context, nanoscale should be taken to tion for individual patients, and to monitor response include active components or objects in the size to treatment. Nanotechnology has a vital role to play range from one nanometre to hundreds of nanome- in realising cost-effective diagnostic tools. tres. They may be included in a micro-device (that There are increasing challenges within the phar- might have a macro-interface) or a biological envi- maceutical industry to locate drugs more efficiently ronment. The focus, however, is always on nanoin- to their disease targets. As the search for improved teractions within a framework of a larger device or medicines for life-threatening and debilitating biologically a sub-cellular (or cellular) system. diseases continues, two distinct approaches are It was noted that Nanomedicine is built on the being taken to achieve this aim. The first is within science and technology of complex systems of drug discovery and builds on identification of new nanometre-scale size, consisting of at least two molecular targets which are being used to design components, one of which is an active principle, and ‘perfect fit’ drug molecules with more specific ther- the whole system leading to a special function apeutic activity. These efforts continue via: related to the diagnosis, treatment or prevention of screening of natural product molecules to identify disease. candidates with pharmacological activity; 12 1. NANOMEDICINE: A NEW OPPORTUNITY FOR IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT FOR DISEASE

Adult mortality: probabilities of death between 15 and 60 years of age by cause, selected epidemiological subregions, 2002

World Africa very high adult mortality Americas

low adult mortality © WHO world health report 2003 South-East Asia low adult mortality Europep HIV / AIDS highhigh aadultdult mmortalityortality Other communicable diseases Europep Noncommunicable diseases veryvery lowlow adultadult mortalitymortality Western Pacific low adult mortality

0 100 200 300 400 500 600 Probability of death between 15 and 60 years of age per 1000 population

preparation of carefully tailored synthetic low effective delivery gene therapy and other macro- molecular weight drugs via traditional medicinal or molecular therapeutics will be realised only with the combinatorial chemistry; aid of multicomponent, nanosized delivery vectors. ¥ nanofluidics for targeted synthesis; Non-invasive patient imaging using techniques ¥ nanodetection for target identification; and such as gamma camera imaging, magnetic reso- ¥ discovery of natural macromolecules, including nance imaging, X rays and ultrasound are important antibodies, proteins and genes that have inherent established tools used to assist diagnosis and moni- biological activity. tor response to treatment. Molecular level imaging The second, and a complementary approach, is using techniques such as positron emission tomog- the creation of drug delivery systems that can act as raphy (PET) can also provide information on drug a vehicle to carry and guide more precisely the targeting, drug metabolism and disease response to abovementioned agents to their desired site of therapy. Several nanoparticle-based magnetic reso- action. In 2002 and 2003, more biotechnology prod- nance imaging (MRI) agents have already been ucts (proteins and antibodies) and drug delivery approved for routine clinical use, and it is recog- systems were approved by the US Food and Drug nised that future application of nanotechnology has Administration as marketed products than new low an enormous potential in this field. Complex molecular weight drugs. supramolecular assemblies are already being Nanosized hybrid therapeutics (e.g. polymer- explored in research and development to yield protein conjugates) and drug delivery systems (lipo- agents for molecular imaging in the context of MRI, somes and nanoparticles) have already been approved ultrasound, optical imaging, and X-ray imaging. for routine use as medicines. The drug delivery Moreover, in the longer term, the combination of systems entering the market have been designed to imaging technologies and drug delivery systems has achieve disease-specific targeting, to control the the potential to yield theranostics devices. release of the drug so that a therapeutic concentration is maintained over a prolonged period of time, or to provide more convenient routes of administration

(e.g. oral, transdermal and pulmonary) and reach © Schering AG locations in the body that are traditionally difficult to access, such as the brain. Via the use of coatings, ever more sophisticated devices are emerging that allow localised controlled release of biologically active agents. Complex supramolecular assemblies, nanoparti- cles and polymeric materials in many different forms are already playing an important role in the construction of nanopharmaceuticals. It is clear that the contribution of nanotechnology will continue to grow in the future, and it is widely believed that 13

2. Current Status of Nanomedicine Research and Forward Look

Output of workshops held in Amsterdam March 2004 and the Consensus Conference Le Bischenberg November 2004

2.1. Science and Technology ular targets for therapy. It is perceived that many nanotechnology-derived tools will, in the future, be 2.1.1. Workshop on Analytical Techniques routinely used in diagnosis of many diseases long and Diagnostic Tools before they will be approved as treatments. In the case of these devices, nanoscale objects Workshop participants: Dr Patrick Boisseau (chair) were defined as molecules or devices within a size- Dr François Berger, Prof. A.W. McCaskie, range ofone to hundreds of nanometres that are the Dr Françoise Charbit, Dr Rosita Cottone, active component or object, even within the frame- Prof. H. Allen O. Hill, Prof. Lars Montelius, work of a larger micro-size device or at a macro- Dr Kristina Riehemann, Dr Ottila Saxl, interface. Dr Jürgen Schnekenburger, Prof. Yosi Shacham, Prof. Clemens Sorg, Dr Dimitrios Stamou, Scope of this discipline Prof. Csaba Szántay In the area of nanoanalytical techniques and diag- nostic tools that will find application in the sectors Introduction of diagnostics, medical devices and pharmaceutical There is considerable anticipation that miniaturisa- drug discovery, a wide range of technologies are tion via the application of nanotechnology and new being developed for both in vitro (diagnostics and nanotools will lead to novel surgical and analytical sensors) and in vivo use (in line sensors, implanta- tools and diagnostics for use ex vivo. It is envisaged bles and surgical tools) with a range of biological that such techniques will increase our ability to iden- targets including cells, DNA and proteins. Research tify predisposition to disease, monitor disease and development in this field is extremely multidis- progression and identify the most relevant patient ciplinary and there is considerable synergy with the treatments. Moreover, a new generation of surgical ‘nanoimaging and manipulation’ and the ‘nanoma- tools is predicted that will be able to assist diagno- terials and nanodevices’. sis and deliver therapy at a cellular level. In the Analytical and point-of-care diagnostic product context of larger ex vivo diagnostic devices, the design is already supported by the use of nanoparti- focus of this research lies on nanointeractions. cles and nanodevices. For example, biosensor tech- Europe has a relatively strong position in basic nology based on nanotechnology represents a huge research in this field but failure to exploit its inven- opportunity to revolutionise diagnostics in the tions is a continuing problem. DNA and protein healthcare environment. Healthcare professionals chips are already widely used as research tools and in primary care and hospital clinics are shortly are helping to provide a better understanding of the expecting to be able to use low-cost tests able to aid molecular basis of diseases and identify new molec- the diagnosis by simultaneous measurement of

Bioarrays and Biosensors Nanofabrication Nano-objects Detection DNA chips lab on chip nanotubes electrochemical detection protein-chips pill on chip nanowires optical detection glyco-chips nanofluidics nanoparticles mechanical detection cell-chips nanostructured surfaces electrical detection - by scanning probes - by mass spectrometry - by electronmicroscopy biosensors for single nanodevices and multiple analytes and nanoelectronics 14 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK

multiple parameters using a simple test strip with- Cells as complex 3D systems: the organisation out having to measure each parameter individually. and function of cells can not be described by Such test strips must be disposable and cost effec- the simple analysis of their contents tive. So far only single analyte strips have been

available but multisensor dry enzyme, hand-held © Jürgen Schnekenburger systems being developed in Europe are leading the way towards fast and accurate multiparameter analysis. Genome There is an opportunity to focus on technically more mature developments that are more likely to be successful, and also to address niche markets that have better prospects for exploitation. Moreover, techniques and tools developed for analysis and diag- nostics in the medical field have the potential for wider application, for example, in the context of envi- Proteome ronmental monitoring, control of food hygiene etc.

An ideal near-patient diagnostic system • Fast Minimise consultation time (<1 minute) Workshops held under the auspices of the Euro- • Simple Lay person (nurse’s aid) can use pean Federation of Pharmaceutical Industries and • Portable Take the test to the patient Associations (EFPIA) have identified a number of • Storage Room temperature for consumables bottlenecks delaying development of new pharma- • Painless Minimally invasive blood sampling ceuticals. To improve clinical performance and early • Single step One sample, one strip, many analytes access to innovative medicine there is a recognised • Platform One instrument, many diseases need for improved biomarkers and surrogate mark- ers to allow prediction of efficacy. Improved in While there is no lack of innovation in Europe, silico tools are needed for toxicogenomics, toxico- there was agreement that in many areas Europe is proteomics, and metabonomics that can be used to lagging behind. The DNA array market, for example, improve the predictability of toxicological profile is dominated by Affimetrix, an American company. of innovative medicines. While DNA chips are being widely used in research, their difficulties in securing quality assurance and regulatory approval, their production flexibility and 2.1.2. Workshop on Nanoimaging speed to result are well known. Although other more and Manipulation technically complex chips are available, so far they Imaging at the molecular level, are substantially more expensive. measurement of molecular forces Underlying research was seen as a further Euro- Workshop Participants: pean strength, particularly in relation to the identi- Prof. Jean-Louis Coatrieux, Dr Mauro Giacca fication of medical targets. Current genomics and (chairs) proteomics techniques give a limited insight into Dr Andreas Briel, Prof. Salvatore Cannistraro, cellular function. In the future, the combination of Prof. Martyn Davies, Dr Sjaak Deckers, these techniques with imaging methods such as Dr Nicole Déglon, Dr Franz Dettenwanger, TOF-SIMS analysis, and raster electron microscopy Prof. Paul Dietl, Rainer Erdmann, by atomic force microscopy of living cells will give Prof. Robert Henderson, Dr Arne Hengerer, more information on individual protein function and Dr Peter Hinterdorfer, Dr Corinne Mestais, cell signalling. Prof. Hans Oberleithner, Prof. T.H. Oosterkamp, Dr Andrea Ravasio, Dr Hui Wang

Introduction Imaging is becoming an ever more important tool in the diagnosis of human diseases. Both the develop- ment of imaging agents based on micro- or nanopar- ticles, organic dyes etc., and the development of 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK 15

highly sophisticated instruments supported by Techniques Examples powerful computation (2D, 3D reconstruction) have Optical imaging SNOM, STED, Raman SERS, already given rise to a significant move from inva- and Spectroscopy FRET, FRAP sive to less invasive clinical imaging. This is allow- Surface plasma TIRF, NIRF, Multiphoton LSM ing an ever more sophisticated imaging-based resonance Magnetic Resonance X-CT diagnosis, particularly in cancer, neurological and Imaging heart diseases. Nuclear Imaging micro-PET, SPECT Nanotechnology has an important role to play in Scanning probe AFM further developing this field. Earlier diagnosis with a microscopy and force non-invasive tool can allow earlier treatment and this microscopy treatment approach can be much less expensive and Ultrasound Optical tweezers often more effective. In addition, economists Multimodal fluorescence probe and SPM, consider living healthier, longer lives to be econom- nanoimaging fluorescence and laser ically beneficial. There are potential risks and side- is the future and tweezers effects from new imaging agents based on will link structure to opto-acoustic imaging nanomaterials, but risk-benefit analyses will be/are function and vice versa being conducted at an early stage. One of the great- est problems in the transfer of these approaches into Europe has a number of leading academic routine clinical use lies in the slow approval process groups and several leading companies who are of new materials for human use by regulatory agen- pioneers in the development of imaging techniques cies. and innovative contrast agent production (e.g. Imaging at cellular, and even sub-cellular and Bracco SpA, GE formerly Amersham, Philips molecular level, is still largely a domain of basic Medical Systems, Siemens Medical Solutions and research. However, it is anticipated that these tech- Schering AG). niques will find their way into routine clinical use. Basic research has already developed the first Atomic force microscopy (AFM) and AFM-related methods to monitor in vitro the assembly of multi- techniques have become sophisticated tools, not only component biological complexes, protein traffick- to image surfaces of molecules or sub-cellular ing and the interactions between single molecules. compartments, but also to measure molecular forces There is a recognised opportunity to use nanotech- between molecules. This is substantially increasing nology to improve these molecular imaging tech- our knowledge of molecular interactions. niques, and to construct real-time intracellular tomography. Objective methods for assessment of Scope of this discipline image quality are also needed in vitro and in vivo. Because of its interdisciplinary nature, the field of Tools are currently under development that allow in Nanoimaging and Manipulation is also identified as vitro evaluation of basic mechanisms, but it was felt having a considerable overlap with the other disci- that these could quickly be developed towards real plines, particularly in relation to nanomaterials ex vivo and clinical applications. (nanoparticles will play an ever more important role In the context of in vivo and clinical imaging, the as imaging agents), and clinical, regulatory and development of novel techniques for macromolec- toxicological issues. ular imaging was seen as a particular priority. The field termed here ‘Nanoimaging’ overlaps Europe has been at the forefront of the development with the field already called ‘Molecular Imaging’. of polymeric gamma camera imaging agents and In this case the target to be imaged will have a dendrimer-based MRI imaging agents. Improved spatial resolution in the order of 1-100 nanometres, image analysis is a particular goal. There is a need and preferably a time resolution for imaging in the to improve 3D reconstruction and quantitative data order of milliseconds. The opportunities for analysis. Improved visualisation techniques are improvements and breakthroughs with the assis- needed also for stereo-imaging, virtual and tance of nanotechnology were seen in terms of both augmented reality imaging, and image-guided existing and emerging technologies. The imaging manipulation. techniques discussed are listed: Opportunities exist for both invasive and non- invasive clinical imaging, e.g. endoscopy for targeted imaging, use of optical catheters and devel- opment of nanosized systems allowing manipula- 16 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK

tion, target selection, local stimulation and poten- materials and drug delivery system development. tially local modification. Historically, radiolabelled antibodies have already Development of more sophisticated imaging been transferred to market as diagnostic tools in equipment requires an integrated approach. Under- cancer, and in the form of radiolabelled antibodies pinning research must involve all aspects of the and antibody conjugates as a therapeutic agent. It can process. be argued that the radiolabelled therapeutic antibody Parallel to the development of the analytical is the first nanosized theranostic. equipment, research and clinical development is Development of molecular imaging diagnostics ongoing to provide a new generation of nanoimag- is expected to have a major impact on healthcare in ing agents. These include both synthetic nanoparti- the future and the opportunities are summarised cles (including dendrimers and polymeric below. nanoparticles) and biological nanoparticles (nanoor- ganisms). In the future it is likely that these imaging tools will become ever more complex, multicompo- 2.1.3. Workshop on Nanomaterials nent systems combining contrast agents and track- and Nanodevices ing probes (e.g. quantum dots, magnetic and Workshop participants: superparamagnetic beads, nanoshells and nanocol- Prof. Jeffrey Alan Hubbell, Prof. Ruth Duncan loids) with new targeting ligands. For targeted (chairs), Prof. Wim Hennink, systems, carriers can be used which may require Prof. Helmut Ringsdorf (co-chairs), additional surface modification, and linkers that Prof. Hans Börner, Prof. João Pedro Conde, bring additional challenges for physicochemical Dr John W Davies, Prof. Harm-Anton Klok, characterisation and safety evaluation. In some cases Prof. Helmuth Möhwald, Dr Mihail Pascu, combination of a range of signal modalities (e.g. Prof. José Rivas, Dr Christoph Steinbach, organic dyes) is also used. Imaging and contrast Prof. Manuel Vázquez, Dr Peter Venturini, agent design has a considerable overlap with nano- Dr Petra Wolff, Prof. Andrew McCaskie

Molecular Imaging Diagnostics (MDx): Impact on healthcare in the future

Genetic DNA Developing First Progressing disposition mutations molecular symptoms disease © Philips signature

Screening Diagnosis Treatment & Today Follow- & Staging Monitoring up Earlier diagnosis, optimized workflow • Unspecific • Diagnostic • Surgery • Diagnostic markers imaging • Cath-lab imaging • POC • Biopsies • Radiation • Unspecific imaging therapy markers • Mammo- graphy Future

Screening Diagnosis Treatment & Follow- & Staging Monitoring up

• Specific • Molecular • Mini-invasive • MI, MDx markers imaging: surgery • Non-invasive, (MDx) quantitative, • Local/target- Quantitative whole-body ed drug imaging • CA Diagnosis delivery & tracing • Tissue analy- sis (MDx) 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK 17

Introduction tro-mechanical systems (MEMS), nanoparticles, All aspects of Nanomedicine rely on progress in and polymer therapeutics. There are also consider- nanomaterials research, and the nanoengineering able strengths in engineering materials (surfaces and needed to create devices to realise their goals. Mate- nanosized and nanostructured polymers and rials science is being employed to generate probes colloids) to control and direct cellular function for and techniques that are helping to understand basic biomedical applications, and the materials science biological mechanisms. On the other hand, emer- relating to tissue engineering and regenerative gence of more sophisticated nanomaterials and medicine, bioactive materials and the related stem nanodevices is required to develop diagnostic and cells as sources. surgical tools, drug delivery systems and in vivo The overall Nanomedicine-related goals for the diagnostics into routine clinical practice. Moreover, research and development in nanomaterials and nanoscale assemblies for ligand display are already nanodevices were identified as the development of emerging as multicomponent 3D architectures able technologies to satisfy the following applications: to assist tissue engineering and promote tissue repair. Biological Applications: Nanopharmaceuticals (drugs and drug delivery • Definition of target and pathway and network systems) are nanoscale assemblies, which can be identification relatively simple; for example, nanoemulsions, nano- – Via multiple, co-assembled biomolecules particles or polymer conjugates (of proteins or drugs), • Definition of mechanisms of signalling and signal or complex mutlicomponent systems containing transduction drugs, proteins or genes, and an array of targeting – Via artificial assemblies in vitro ligands and signal systems to enable in vitro or in vivo detection. The nanomaterials and nanodevices Medical Applications: that are being developed have scales from molecule- • Drug targeting to assembly-to functional device in the nanometre- – Whole body, cellular, sub-cellular localisation size range. of drugs, proteins and genes This field is rapidly moving from the develop- • Drug discovery ment of individual building blocks to multifunc- – High Throughput Screening technology with tional, often biomimetic and bioresponsive systems. biomolecular or cellular read-outs The combined knowledge and expertise of synthetic – Novel bioactives, obtained through nanotechnology – Novel drug delivery systems and physical chemistry as well as biological chem- istry are required for the development of effective • Diagnostics and sensing nanomaterials and nanodevices that are efficient and – In vitro (multiple analyte detection) and in vivo safe in the biological environment. • Regenerative medicine Most importantly, it was noted that the research – Materials to regulate cell signalling and in nanomaterials and nanodevices must strive for differentiation, and also controlling morphogenesis thus helping to bring functional integration biological and medical relevance with this in mind. The potential timescale for development of practi- cal-to-use systems could be relatively short. As Enabling technologies currently being developed nanodiagnostics, e.g. a dendrimer-MRI agent, are include new systems for physical assembly, new already in clinical development, it can be predicted routes to macromolecular synthesis via chemical that those nanodiagnostics under in vitro develop- and biosynthesis. In the latter case, minimisation of ment today should be available for clinical evalua- nanoparticle or polymer polydispersity and hetero- tion within the next few years. Over the next few geneity is essential for use in the construction of decades, considerable growth in the routine clinical nanopharmaceuticals. use of in vivo nanodiagnostics as well as nanother- Further development of combinatorial chemistry apy was predicted. and biology is a certainty bringing multiple-func- tionality into library design to provide high-level Scope of this discipline functional screening technology. The planar 10-100 Europe is particularly strong in physical and multi- nm scale systems for screening and detection that functional chemical assembly of nanostructures will emerge will have multiple, integrated detection (supramolecular chemistry), and colloid and poly- systems. Hierarchical, oriented, multicomponent mer science including development of micro-elec- displays of biological molecules with passivation of 18 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK

background effects were seen as a particular chal- Liposomes Antibodies Viruses as and their viral vectors lenge. Control and feedback technologies are conjugates needed to enable biomolecular recognition to be Polymer transferred into practical-to-use detector develop- © Prof. Ruth Duncan micelles ment. For analytical systems, increased sensitivity is needed, and analysis of functional systems. Nanopharmaceuticals Development of new materials with complex functionality is already ongoing. This is particularly important in the context of tissue engineering scaf- folds and arrays for detection. Spatial control of functionalisation is needed with ordered display of Nanoparticles Polymer-protein Unimolecular polymer orthogonal functionality, and the ability to design conjugates and dendrimer conjugates into a system-triggered control of response; that is, new bioresponsive materials. Improved methods for surface functionalisation of colloids and surfaces are They include liposomal anticancer agents, antibody- needed as well as new and validated analytical tech- drug conjugates, polymer-protein conjugates, niques to ensure safety and reproducibility. Integra- nanoparticle-based imaging agents and an anti- tion of multiple-functionality (fluidics, with cancer delivery system (see Appendix VI). There are manipulation and detection) will enable translation also a large number of constructs (including the first to implantable configurations with telemetric detec- polymer-based gene delivery system) in clinical tion and control. development. These can be viewed as the first- generation Nanomedicines and future developments 2.1.4. Workshop on Drug Delivery will build on these successes. and Pharmaceutical Development Scope of this discipline Workshop participants: The nanosized drug delivery systems currently Dr María José Alonso, Prof. Ruth Duncan (chairs), Prof. Thomas Kissel (co-chair) under development are either self-assembling, or Dr Oliver Bujok, Prof. Patrick Couvreur, involve covalent conjugation of multicomponent Prof. Daan Crommelin, Dr Julie Deacon, systems, e.g. drug, protein and polymer. The mate- Dr Luc Delattre, Prof. Mike Eaton, rials used to create such drug delivery systems typi- Prof. Claus-Michael Lehr, Dr Laurant Levy, cally include synthetic or semi-synthetic polymers, Prof. Egbert Meijer, Dr Milada Sirova, and/or natural materials such as lipids, polymers and Prof. Karel Ulbrich, Prof. Arto Urtti, proteins. If classified by function, many materials Prof. Ernst Wagner, Dr Jaap Wilting used for drug delivery are bioresponsive and/or biomimetic. An increasing number of nanosystems Introduction are being proposed as drug carriers. They include Nanopharmaceuticals can be developed either as micelles, nanoemulsions, nanoparticles, nanocap- drug delivery systems or biologically active drug sules, nanogels, liposomes, nanotubes, nanofibres, products. This sub-discipline was defined as the polymer therapeutics and nanodevices. Magnetic science and technology of nanometre size scale nanoparticles are being developed for diagnostic complex systems, consisting of at least two compo- imaging and disease targeting, for example, liver nents, one of which is the active ingredient. In this and lymph node targeting following intravenous field the concept of nanoscale was seen to range administration. from 1 to 1000 nm. For the past thirty years, Europe has pioneered Over the last three decades Europe has been at the development of many of these technologies and the forefront of the research and development of research in the area of nanodrug delivery is still nanosized drug carriers including liposomes, forging ahead. Pharmaceutical science is especially nanoparticles, antibodies and their conjugates, poly- strong, but research is increasingly interdisciplinary mers conjugates, molecular medicine (including both across Europe and indeed globally. There is proteins) and aspects of nanobiotechnology includ- already a number of major programmes and strate- ing tissue engineering and repair. gic initiatives in Europe promoting interdisciplinary There are a growing number of marketed nano- research and training in drug delivery, although sized drug delivery systems and imaging agents. there has not been any clear emphasis within the 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK 19

EU Framework 6 Programme (FP6) to promote With good interaction between academia and networks of excellence and specific projects able to industry, increased European funding to strengthen enhance activities in the area of Nanomedicine. the translational research and development, and There are three principal goals of drug delivery building on past successes, these goals can be research today: more specific drug delivery and realised quickly. However, tremendous challenges targeting; greater safety and biocompatibility; and also lie ahead. There is still a lack of communica- faster development of new, safe medicines. To tion in a field where the multidisciplinarity of the achieve these goals the current nanotechnologies research continues to grow. At the research stage, being applied to drug delivery and pharmaceutical chemistry-physics-pharmaceutical science-biology- research include the following: medicine must work in concert. There is a concern that regulatory hurdles may become so high that the Nanotechnologies industry will be reluctant to accept the risk of devel- • Supramolecular chemistry-Self assembling drug oping innovative technology. In addition, because carriers and gene delivery systems of the variable quality of the scientific representa- • Nanoparticles and nanocapsules tion within public debate and concerns raised about • Antibody technologies nanotechnology as a whole, there is an apprehen- • Polymer-drug conjugates sion that the general public may be reluctant to • Polymer-protein and antibody conjugates accept new concepts and technologies. • Nano-precipitation, nanocrystals • Emulsification technologies • Liposome technology 2.1.5. Workshop on Clinical Use, Regulatory • In situ polymerisation and Toxicology Issues • Tissue engineering and repair Workshop participants: • Dendrimer technologies Dr Wolfgang Kreyling, Prof. Rogério Gaspar (chairs), • Molecular imprinting Dr Paul J. A. Borm (co-chair) Prof. Luc Balant, Dr Janna de Boer, In parallel to the technology development there Dr Thomas Bruhn, Prof. Kenneth Donaldson, is a need to develop pharmaceutical formulations Dr Benoit Dubertret, Prof. Ruth Duncan, that can be conveniently administered to patients Prof. Mike Eaton, Prof. Mauro Ferrari, and that display acceptable shelf-life stability. Prof. Alberto Gabizon, Prof. Varban Ganev, Validated analytical techniques are also needed Dr Andreas Jordan, Prof. Harm-Anton Klok, to confirm the identity, strength and stability of Prof. Jørgen Kjems, Dr Mihail Pascu, complex nanomedicines. New chemical and physi- Prof. Helmut Ringsdorf, Dr Valérie Lefèvre-Seguin, cal techniques must be developed during scaling-up. Dr Ottila Saxl, Dr Milada Sirova, Prof. Karel Ulbrich During research and development molecular imaging techniques (e.g. AFM) are increasingly Introduction being used, and in vitro (e.g. caco-2 cells, blood brain As for any other conventional medicine, the entire life barrier models, and skin models) and in vivo models cycle of nanopharmaceuticals includes production, are being developed to understand better cellular and distribution, clinical administration, consumer safety whole-body pharmacokinetics. There is also a need (human body effects and side-effects), and waste to examine carefully pharmacokinetic and pharma- disposal. While the clinical applications usually codynamic correlations to allow carefully design of concern only the selected stages of the life cycle, toxi- drug targeting and controlled release systems. cological effects may exist in all the stages. Both clin- ical applications and toxicology of nanopharmaceuti- In the near future, nanodrug delivery systems and cals must be studied and examined comprehensively. pharmaceutical research have the potential to When designing a clinical protocol for a nano- contribute significantly to the furtherance of Nano- pharmaceutical there are new challenges. Clinical medicine. The key topics of investigation are: trials and epidemiology studies may be significantly ¥ vectors that will overcome the biological barriers different from those for conventional diagnostic and for effective gene delivery therapeutic agents. Early dialogue and collaboration ¥ cancer targeting between scientists, clinicians, toxicologists and regu- ¥ brain delivery latory authorities are increasingly recognised as one ¥ combination of the potential of antibody targeting of the important issues to ensure rapid clinical uses with nanoparticle and liposome technology. of safe nanopharmaceuticals. 20 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK

Scope of this discipline uses e.g. veterinary) Nanoscale objects, typically but not exclusively with ¥ consumer and staff safety dimensions smaller than 100 nm, smaller than ¥ waste management/fate in environment. 200 nm for ultrafiltrable range and smaller than 1 000 nm for dendrimers, exhibit fundamentally Although the nanopharmaceuticals that have different physical, chemical and biological proper- already entered routine clinical use have been rigor- ties from those of the corresponding mass materials. ously tested with regard to safety, there have been These distinctive properties, together with the comparatively few toxicological studies published nanoscale size which is in the same scale of the natu- on nanopharmaceuticals. However, this issue needs rally occurring biomolecules, promise revolutionary to be explored, based on the large literature in the potential applications in clinical practice. Nanomed- toxicology field describing the effects of nanopar- icines or nanopharmaceuticals may therefore be ticles, either present in the environment as pollu- defined as nanoscale material to be used for clinical tants or made as a result of the industrial production diagnosis, treatment, and prevention of human disor- of non-medical and non-biological materials. ders. Nanomedicine application depends on the structures and mechanisms which are functional Cancer Chemotherapy and Drug Targeting only on nanoscale-mediated macro-molecular and supra-molecular assemblies. Increased Therapeutic Index

In particular, the following areas were considered:

Technology Application Toxicity Activity Nanopharmaceuticals Cancer – in current use or Antiviral agents entering routine use Arteriosclerosis in the short-term future Chronic lung diseases (within 5 years) Diabetes Nanopharmaceuticals Gene therapy – with potential clinical Tissue engineering applications in the longer Tissue/cell repair term future (10 years) Europe has considerable experience in the clini- Nanodevices Delivery of diagnostic cal development of nanopharmaceuticals (particu- and therapeutic agents larly in cancer). Pre-clinical toxicology to ‘good laboratory practice’ (GLP) has assessed antibody- There are very strict regulations and approval drug conjugates, polymer-drug conjugates and processes for any medicine (via regulatory agencies nanoparticle-based chemotherapy. During the devel- such as FDA, EMEA etc.) or any material proposed opment of novel anticancer treatments there is for human use. It must undergo rigorous toxicology always a careful evaluation of risk-benefit. studies as part of the regulatory approval process. Since Europe has particular strengths in the However, the special properties of nano-objects that research areas of toxicology of inhaled ambient or are only exhibited at the nanoscale suggest that occupational fine and ultrafine particles there is an nanopharmaceuticals may also require a new array excellent opportunity to redress the current mismatch of toxicological and safety tests. It was agreed that between studies on toxicology of nanomaterials and new strategies in toxicology for Nanomedicine must those involved in research and development of go hand-in-hand with the development of nanophar- Nanomedicine-related technologies. maceuticals in order to ensure the safe yet swift As there seems to be enormous prospects for the introduction of nanomedicines to clinical use. application of nanotechnology in medicine, the Euro- The toxicology of nanopharmaceuticals, nano- pean Nanomedicine research community should act imaging agents and nanomaterials used in device proactively to seize the opportunity to clearly define manufacture should be considered during their entire the ground rules for the related toxicological life cycle: research, and the related clinical and industrial devel- ¥ stages of production/manufacture opment of these important technologies. ¥ preclinical and clinical development (or for other As yet there are no regulatory authority guide- 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK 21

lines specific to Nanomedicine. As the number of 2.2. Research Strategy and Policy nanopharmaceuticals increases there is a need to review and define appropriate regulatory authority 2.2.1. Organisation and Funding guidelines directed towards each new class of Workshop participants: Nanomedicine. It would be timely to produce ‘Good Prof. Claus-Michael Lehr (chair), Clinical Practice’ (GCP) guidelines that may be Prof. A.W. McCaskie (co-chair) applied to the clinical development of specific fami- Dr María José Alonso, Prof. Luc Balant, lies of drug delivery systems or therapeutics. Some Dr Janna de Boer, Prof. Salvatore Cannistraro, examples of well-established categories of pharma- Dr Rosita Cottone, Dr Nicole Déglon, ceuticals involving nano-objects are polymer- Dr Franz Dettenwanger, Prof. Thomas Kissel, protein, polymer-drug conjugates and nanoparticle- Prof. Helmuth Möhwald, Dr Mihail Pascu, associated chemotherapy. There may be specific Prof. Clemens Sorg, Dr Christoph Steinbach, clinical endpoints that are unique to these nanomed- Prof. Manuel Vázquez, Dr Petra Wolff icines, and there may also be specific issues relating to good manufacturing practice (GMP) compliance. It was suggested that current funding mechanisms Second generation nanopharmaceuticals are do not adequately address the needs of Nanomedi- already being, or will be, developed based on first cine. The structure of programmes and the diversity generation systems. An integrated strategy will be of sources (e.g. European, national, regional and the key for toxicological evaluation of new nano- charities) can obscure routes to funding. This is materials that are emerging. There is a need for pre- further limited by traditional borders between scien- clinical and clinical test standardisation and an tific disciplines; e.g. chemistry, physics, biology, evaluation of the environmental impact of these medicine and engineering, which can effectively systems in the context of academic research and exclude transdiscipline and interface research. In industrial development. On a case by case basis many cases the funding opportunities are often there is a need to define toxicokinetics, toxicoge- restricted by the requirement of an industrial part- nomics, and toxicoproteomics. This field might be ner. Moreover, selection criteria can often be politi- defined as ‘Toxiconanomics’. This research effort cal, rather than based on scientific excellence. The should be conducted by virtual networks of basic fact that EU FP6 applications were channelled into and applied scientists using existing expertise as a main themes of ‘Health’ or ‘Nanotechnology’ was starting point. Industrial collaboration should be a contributory factor, leading to the ineffectiveness used to establish standard reference materials. of FP6 to successfully support the stated Nanomed- icine objectives of this scheme. The possibility of an EU Technology Platform in Nanomedicine was noted and welcomed. It was noted that there is an opportunity to improve communication/coordination between the different funding agencies across Europe. There is a specific need to reflect the multidisciplinary nature of Nanomedicine in funding opportunities presented. The funding opportunities available for basic technological research must initially be available for pure academic groups without an underlying requirement of an industry partner. All calls for proposals and applications should encourage the appointment of multiple partners from different disciplines with internationally leading expertise. The evaluation of such multidisciplinary proposals must be undertaken by a multidisciplinary expert panel using the same format used by the US National Institutes of Health (NIH) study groups. Whilst the European networking instruments (e.g. COST, Network of Excellence etc.) are considered 22 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK

helpful, in the future there must also be enough ment involving both specialised small and medium funding to undertake basic and applied Nanomedi- enterprises (SMEs) as well as larger companies. To cine research (that is, for salaries, instruments, and encourage rapid technology transfer there is a need consumables). to generate clusters or highly selected teams chosen Means to improve funding and organisation at for personal excellence, and not to fragment resources. the level of political bodies, policy makers and Nanomedicine is particularly multidisciplinary national organisations were identified. The funda- so there are many opportunities to cross-licence mental requirements to progress Nanomedicine technologies; for example diagnostics and pharma- quickly are more investment for Nanomedicine R ceuticals. Joint ventures involving confidential R&D & D, greater understanding of the complexities of relationships could be very successful, but with a this multidisciplinary area, and a higher priority for complex supply chain, the intellectual property port- specific technologies that will improve healthcare folio needs careful management. Good communi- for society in Europe. cation and project management skills are needed. To be competitive and effective in commerciali- Specific opportunities include: sation, speedy globalisation is imperative. European ¥ Those aspects of Nanomedicine that have been funding schemes often dictate the choice of part- realised and transferred into practice today have ners. To be effective in Nanomedicine development arisen from previous basic research programmes. a global perspective is needed involving growing Universities should be able to pursue a more entre- partnership with the USA and other funding agen- preneurial freedom and spirit to increase inven- cies. To encourage the establishment of more effec- tiveness that will feed the future technology tive SMEs working in the Nanomedicine field, more pipeline. focused funding and a fast response to grant appli- ¥ Nanomedicine should be discussed in terms of cations are needed. pharmacoeconomic value at an early stage with As Nanomedicine becomes fashionable, a good regulatory authorities, policy makers and health- understanding of the end user-supplier interface is care stakeholders. vital. Companies that appreciate the medical needs ¥ The potential of Nanomedicine to create not only and the practicalities of their technology will be best new products, but also new jobs (socioeconomic placed to commercialise. There is a need to promote value) needs to be appreciated. meetings and a technology directory to assist indus- ¥ Public awareness about the opportunities and real- try to network. However, Nanomedicine presents a istic risks of Nanomedicine is necessary and can complex array of end-users. The medical doctors’ be brought about by educational programmes. wish list of technologies is not yet commercially National support for Nanomedicine would be validated. Large companies have a time horizon for enhanced when action groups and patient-support market entry that is too short for many new tech- groups are more aware of the benefits that these nologies, while the activities of SMEs is often too technologies can already bring. confidential to allow wide discussion. This can make dialogue difficult. There is a real need to increase confidence in Nanomedicine technologies by losing 2.2.2. Commercial Exploitation the hype and focusing resources to pick winners.

Workshop participants: Dr Julie Deacon (chair), Dr Oliver Bujok, Dr Françoise Charbit, Dr John Davies, 2.2.3. Interdisciplinary Education Dr Sjaak Deckers, Dr Benoit Dubertret, and Training Prof. Mike Eaton, Rainer Erdmann, Workshop participants: Dr Arne Hengerer, Dr Corinne Mestais, Prof. Hans Oberleithner (chair), Dr Pierre Puget, Dr Jürgen Schnekenburger, Prof. Robert Henderson (co-chair) Prof. Csaba Szántay Dr Patrick Boisseau, Dr Paul J. A. Borm, Dr Luc Delattre, Prof. Varban Ganev, Transferring the technologies arising from Nanomed- Dr Peter Hinterdorfer, Prof. Jørgen Kjems, icine research into clinical reality and generating Dr T.H. Oosterkamp, Dr Andrea Ravasio, commercial value from research will rely on the Dr Kristina Riehemann, Prof. Arto Urtti, generation of intellectual property, licensing, tech- Dr Peter Venturini, Prof. Ernst Wagner, nology transfer, and collaborative product develop- Dr Jaap Wilting 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK 23

The standard of university education in Europe, in 2.2.4. Communication physics, chemistry, biology, pharmacy and medi- Workshop participants: cine, to master’s level, is very high. It was noted that Dr Ottila Saxl (chair), Prof. Ruth Duncan, specific Nanomedicine training should be developed Prof. Harm-Anton Klok, Dr Valérie Lefèvre-Seguin, rapidly to provide an educated workforce and Dr Mihail Pascu, Prof. Helmut Ringsdorf. researchers to support this rapidly growing field. New programmes providing education and training Communication issues were discussed in relation in Nanomedicine should encourage interdiscipli- to: (i) difficulties in communication within the narity. master’s courses, or early postgraduate multidisciplinary scientific environment; (ii) medical or scientific training should be developed communication between the scientists and the with a focus on Nanomedicine. policy makers; and importantly (iii) the perception In recent years there has been a reduction in the of the general public. basic science component of undergraduate medical In general, government departments, research degrees. Although this may be appropriate for many ministries and university faculties continue to oper- clinicians, there is a danger that there will be a ate in separate compartments. A paradigm shift in shortfall in the number of clinician-scientists. These the way of operation is needed. Otherwise there is are the very people needed to support the transfer no doubt that Europe will lose out in developing a of Nanomedicine into routine clinical practice. leading position in Nanomedicine, an area that Widespread adoption of MD/PhD degree demands a multidisciplinary approach. This will be programmes, with some provision for nanoscience exacerbated by the emphasis on converging tech- training, should be encouraged to provide core nologies in FP7 as the basis of future products. scientific training for clinicians. In addition, new A major barrier to collaboration is the lack of funding is needed to support the introduction of understanding between scientists of different disci- such courses, and also for postgraduate clinical plines. This needs to be addressed by the establish- training in nanoscience. ment of more truly transdisciplinary research groups In Europe, training in different scientific disci- and more truly transdisciplinary conferences and plines is currently highly focused, which is a great workshops. The creation of transdisciplinary goal- strength. However, this presents the danger of indi- driven ‘clusters’, virtual centres and ‘poles’ should viduals lacking knowledge outside their own field, also be actively encouraged. Partnerships should be possibly preventing productive communication encouraged between large medical centres and across disciplines. It was proposed that formal inter- university research groups, leading to goal-oriented disciplinary training programmes should be insti- research. Transdisciplinary meetings should be held tuted, focusing on basic scientific topics; for within medical centres and sponsored by a medical example molecular biology, colloidal chemistry, cell leader. This could be facilitated through available physiology, surface chemistry, and membrane instruments at the European level. Additionally, the biophysics. numbers of transdisciplinary PhDs should be Several European Centres of Excellence should increased, as well as transdisciplinary exchanges at be established (possibly relating to the sub-disci- every level Ð from secondary to tertiary. plines of Nanomedicine) to provide an interdisci- The benefits and the threats of Nanomedicine plinary environment in which participants can need to be clearly articulated to the politicians and ‘speak the same language’, thus helping to bridge policy makers. Benefits include employment poten- the gap between chemical, physical and biomedical tial and the ability to meet the needs of the ageing scientists. This would provide the infrastructure for population. Threats include losing out on important direct interactions between scientists, clinicians and economic opportunities and not meeting the aims of entrepreneurs; e.g. ‘Nanomedicine Centres’. Such the Lisbon agenda. Serious consideration needs to centres could also be used to provide structures for be also given to lobbying politicians by opinion undergraduate courses that encourage an interdisci- leaders in the Nanomedicine world. There is also a plinary frame of mind and allow establishment of lack of scientifically qualified politicians, and Erasmus-type programmes for Nanomedicine. communication problems have already resulted in Importantly, both academic scientists and clini- a lack of alignment of the regional programmes, the cians should have the opportunity and training to national programmes and the EU programmes. help them identify methods for commercial In the recent past, many top quality transdisci- exploitation of their work. plinary projects and/or papers have not been recog- 24 2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK

nised as such, as the reviewers lack the necessary knowledge. Failure to recognise the significance of our success in multidisciplinary activities has been a great loss to European scientific growth. One way forward is that the national and European funding agencies that provide funds and who audit research output take a lead in pushing for equal weighting for transdisciplinary research. Nanotechnology has to counter two preconcep- tions in the mind of the general public. Nanotech- nology was initially (and continues to be) popu- larised through science fiction, and many of the well-established nanoimages are figments of the imagination of Hollywood-inspired artists. Secondly, it suits sensation-seeking journalists to compare nanotechnology with the already discredited geneti- cally modified organisms (GMO) technology. The fact that nanotechnology is such a broad area Ð covering most if not all areas of technological devel- opment, and particularly in the context of the pres- ent argument Ð can make the term Nanomedicine almost incomprehensible to the general public. To avoid backlash, Nanomedicine-related devel- opments must be presented in a realistic way, with- out overhyping. It is important to focus on the real benefits that people understand: better diagnostics, smaller doses, fewer side-effects, disease targeted therapy, better efficacy, etc. The media must be handled intelligently and with caution. And there could be a benefit in provid- ing them with carefully constructed ‘copy’ in advance of any new development. Individuals who have to interact with the press should receive special training. It was also considered important to improve the breadth of communication; through possibly organising thematic meetings aimed at informing focus groups. Nanomedicine awareness- raising activities need public funding (at all levels) in order to ensure a continued dialogue with all stakeholders. 25

3. European Situation and Forward Look – SWOT Analysis

All the technology based workshops held in Amsterdam from 1 to 5 March 2004 were independently invited to conduct a SWOT analysis regarding the current status of European activities in the field. There was considerable consensus across these groups and the results were summarised and presented at the Consensus Conference held at Le Bischenberg. Below is a summary of the most significant points agreed.

Strengths

Funding and Academic Research Environment Commercial Technology Strategic Issues and Education for Research Exploitation and Development

• The diversity • The strong • There are already • There are a number • Molecular and of funding sources educational base in several major European of world leading clinical imaging provides a wide Europe and training clusters and Centres of European companies in techniques, and range of funding style Excellence in the Field imaging/contrast agent contrast agent research opportunities of Nanomedicine and nano- and development are pharmaceuticals areas particular strengths

• European • Potential exists • There are a number • Existing expertise programmes such as to rapidly expand of SMEs working in drug delivery the EU Marie-Curie Nanomedicine R & D in the technology research and the scheme and the ESF and pharmaceutical clinical development of training courses areas relating to nanopharmaceuticals provide good training Nanomedicine opportunities although more focus should be put on Nanotechnology in Medicine

• There are many • Visionary institutions • Ongoing • Strong basic sciences, leading academic such as the New Drug standardisation efforts particularly in groups in the sub- Development Office at the European - antibody disciplines of and Cancer Research Medicines Agency technologies Nanomedicine UK have facilitated for the Evaluation - nanoparticle early phase cancer of Medical Products technologies clinical trials and (EMEA) - polymer therapeutics supported translational - gene delivery systems activities, especially - biological models for for innovative nano- cell and tissue-based pharmaceuticals in vitro screening

• Leading research groups in ultrafine particle toxicology 26 3. EUROPEAN SITUATION AND FORWARD LOOK – SWOT ANALYSIS

Weaknesses

Funding and Academic Research Environment Commercial Technology Strategic Issues and Education for Research Exploitation and Development

• EU programmes • Insufficient integration • The size of many • Inefficient translation • Interfacing clinical lack long-term of clinical research nanotechnology of concept to product medicine and basic strategy as it changes regional clusters and because of inadequate research every 5 years. medical research venture capital, Nanomedicine centres is too small excessive bureaucracy research needs both a and lack of medical short-and a long-term input strategy.

• Low funding rates • Too much replication • Small clusters often • Interaction with the • Interfacing basic and complex of R&D efforts in lack adequate funding numerous regulatory biological sciences administrative universities and in authorities, and materials sciences procedures have been companies across (fragmentation) and problems associated Europe differences in with FP6 regulations can deter those considering product development

• FP6 has not been • Specific guidelines, • Lack of ability to • Lack of competitive effective for regulations and test interact with regulating edge in chip-based supporting research protocols for agencies at the technologies and development of Nanomedicine are still investigational new Nanomedicine awaiting to be drug (IND) stage when developed developing new technologies, compared with USA

• Too little funding • Compared to the • Inadequate industrial for application- USA and Asia: investment in long-term oriented and requirement of ethical (or basic) research and translational research approval for many relatively few aspects of Nano- companies to cooperate medicine research with or assist with are more demanding commercialisation

• Lack of a • Recent change in • Ineffective coordinated European clinical trial regulations organisation of Research Council able (new EU directive) will the health system and to allocate funding delay clinical trials for inadequate provision based only on nanopharmaceuticals, of accredited labs can excellence without a particularly in cancer limit options for clinical political agenda research and development in the field of Nanomedicine 3. EUROPEAN SITUATION AND FORWARD LOOK – SWOT ANALYSIS 27

Opportunities

Funding and Academic Research Environment Commercial Technology Strategic Issues and Education for Research Exploitation and Development

• Identification of • European courses • Better use of human • Better exploitation • Development of Nanomedicine as a integrating the resources e.g. well- of innovation at the a new generation of key area for funding biological and physical educated people European level through nanosized materials in FP7. Explicitly sciences toward coming from Eastern easier access to venture and devices that can removing the divide nanoscience, Europe capital, better dialogue be used as a tool kit between Health and nanobiology, and most with regulatory agencies Nanotechnology importantly • Increased and government • Design of innovative nanotechnology collaborations between support for R & D diagnostics and applied to medicine European companies in Nanomedicine. biosensors (e.g. imaging and Accelerate Nano- pharmaceutical) and medicine research academic institutions from lab to clinic and then the market

• Improved healthcare • Via new education • Establish enhanced • Move towards cost • Design of for European citizens programmes establish a job opportunities and a effective patient- nanopharmaceuticals technically skilled competitive individualised and implantable workforce able to international position in treatments, and point of devices for improved address the challenges Nanomedicine care diagnostics drug delivery of Nanomedicine research and development

• Establish Networks • Proactive risk • Use experience with • Design of vectors of Excellence in the management with an first generation able to sub-disciplines of immediate feed back to anticancer - assist drugs to better Nanomedicine via Nanomedicine nanopharmaceuticals to reach their target coordination of development at the rapidly develop second (transferring recognised leading earliest time point generation medicines across biological edge researchers and with increased barriers) companies specificity with less - ensure biotech drugs toxic side effects for a reach their intracellular wider range of target targets diseases

• At the European • Reduced health costs • Development and National level by earlier detection of of nanomaterials able establish well defined predisposition allowing to control biological goal oriented use of preventative signalling and provide Nanomedicine intervention, and more a biomolecular display focused projects effective monitoring of for tissue engineering building on specific chronic illness leading and to promote tissue technical expertise to improved therapy repair 28 3. EUROPEAN SITUATION AND FORWARD LOOK – SWOT ANALYSIS

Threats

Funding and Academic Research Environment Commercial Technology Strategic Issues and Education for Research Exploitation and Development

• EU and/or national • Failure to respond • Continued erosion of • Difficulties in • Lack of scientific bureaucracy limiting quickly to the need for the European managing intellectual dissemination and the best use of more multidisciplinary pharmaceutical property with many truly interdisciplinary funding for research training targeted at industry different national patent exchange in the field and innovation Nanomedicine, leading organisations. Poorly of Nanomedicine to Inadequately trained capitalised companies workforce can lose their intellectual property base

• Continued • Increasing lack • Pharmaceutical • Inability to secure • Mismatch between fragmentation of science companies sufficient funding (and studies on toxicology of efforts in the (under)graduates concentrating their time) to commercialise of nanomaterials Nanomedicine field, research outside innovative products and Nanomedicine particularly economic, • Too many young Europe researchers in certain political, and researchers leaving sub-disciplines regulatory aspects Europe, particularly to USA via brain-drain

• Discrepancies • Researchers • Overregulation • Failure to consider between promises becoming unwilling and inadequate the environmental and facts in funding to take on high risk funding for small impact of new materials projects because of the companies need to generate data • Failure to consider (success) for subsequent the safety of new project evaluation materials in respect of proposed applications

• Negative public and • Lack of a balanced political perception. understanding of A different perception the risk-benefit of by the public on risks Nanomedicine-related of the use of products in their many nanopharmaceuticals forms and applications was noted, compared to the uses of nanotechnology in hi-tech products; e.g. computers and mobile telephones 29

4. Recommendations and Suggested Actions

bility, and own journal 4.1 General Recommendations ¥ Support to clusters for internal cooperation and European coordination 4.1.1. Priority areas in Nanomedicine for the next 5 years 4.1.4. Interdisciplinary Education ¥ Engineering technology for immobilising cells or and Training molecules on surfaces ¥ Trained people for technology management and ¥ Programmes to generate reproducible and reliable transfer (PhD + MBA) platforms integrating micro- and nanotechnologies ¥ Tailored education on management for scientists ¥ Methods to deposit such platforms and such ¥ Fellowships to support academics gaining experi- components ence in industry ¥ Proactive risk management with an immediate ¥ Multidisciplinary training feedback to Nanomedicine development ¥ Fellowships for complementary education for ¥ Clinical applications scientists ¥ Development of satisfactory sensitivity of in vivo methods ¥ Developing of non-invasive in vivo diagnostic 4.2. Scientific Trends systems ¥ Implantable or injectable parenteral nanodevices 4.2.1. Nanomaterials and Nanodevices for diagnosis and therapy General directions should be: ¥ optimisation of existing technologies to specific 4.1.2. Priority areas in Nanomedicine Nanomedicine challenges for the next 10 years ¥ development of new multifunctional, spatially ¥ Understanding of the cell as a 3D complex system ordered, architecturally varied systems for targeted ¥ Bioanalytical methods for single-molecule analy- drug delivery sis ¥ enhancement of expertise in scale-up manufacture, ¥ Nanosensing of multiple, complicated analytics characterisation, reproducibility, quality control, for in vitro measurement of biochemical, genomic and cost-effectiveness and proteomic networks, their dynamics and their Specific directions should be: regulation ¥ new materials for sensing of multiple, complicated ¥ Nanosensing in vivo with telemetrically controlled, analytes for in vitro measurement functional, mobile sensors ¥ new materials for clinical applications such as ¥ Rapid fingerprinting of all components in blood tissue engineering, regenerative medicine and 3D samples display of multiple biomolecular signals ¥ telemetrically controlled, functional, mobile in 4.1.3. Commercial Exploitation vivo sensors and devices ¥ European seed funds for nanotechnology applied ¥ construction of multifunctional, spatially ordered, to medicine architecturally varied systems for diagnosis and ¥ Intellectual Property management combined drug delivery (theranostics) ¥ Improved interactions with the EU regulatory ¥ advancement of bioanalytical methods for single- system to promote rapid commercialisation of molecule analysis innovation ¥ Establishing incubators for innovative companies 4.2.2. Nanoimaging and Analytical Tools in nanomedical applications Specific developments should include: ¥ New reference organisation (such as EMBO) in short term nanobiotechnolgy/nanomedicine possibly with ¥ use and refinement of existing nanotechniques in prestigious positions, scientific excellence, visi- normal and pathological tissues for the under- 30 4. RECOMMENDATIONS AND SUGGESTED ACTIONS

standing of initiation and progression of disease ¥ case-by-case approach for clinical and regulatory ¥ development of novel nanotechniques for moni- evaluation of Nanomedicines toring in real time cellular and molecular processes ¥ highly prioritised communication and exchange of in vivo and for molecular imaging to study patho- information among academia, industry and regu- logical processes in vivo, with improved sensitiv- latory agencies with a multidisciplinary approach ity and resolution ¥ identification of new biological targets for imag- 4.2.5. Toxicology ing, analytical tools and therapy General directions should be: ¥ translation of research based on molecular imag- ¥ improved understanding of toxicological implica- ing using nanoscale tools from animal models to tions of nanomedicines in relation to material prop- clinical applications erties and proposed use by the potentially predis- ¥ closing of the gap between the molecular and posed, susceptible patient cellular technologies and the clinical diagnostic ¥ thorough consideration of the potential environ- nanotechnologies mental impact, manufacturing processes and ulti- Specific developments should include: mate clinical applications in toxicological investi- longer term gations for nanomedicines ¥ development of a multimodal approach for nano- ¥ risk-benefit assessment for both acute and long- imaging technologies term effects of nanomedicines with special consid- ¥ design of non-invasive in vivo analytical nanotools eration on the nature of the target disease with high reproducibility, sensitivity and reliability ¥ a shift from risk assessment to proactive risk for use in pre-symptom disease warning signal, management at the earliest stage of new nanomed- simultaneous detection of several molecules, icines discovery and development analysis of all sub-cellular components at the molecular level, and replacement of antibodies as detection reagents by other analytical techniques 4.3. Research Strategy and Policy

4.2.3. Novel Therapeutics and Drug Delivery 4.3.1. Organisation and Funding Systems Recommendations Specific developments should include: ¥ improved coordination and networking of research short term activities and diverse range of funding sources at ¥ application of nanotechnology to develop multi- the European, national and regional levels functional structured materials with targeting capa- ¥ creation of new Nanomedicine-targeted funding bilities or functionalities allowing transport across schemes to better facilitate both transdisciplinary biological barriers and interface research that is critical for success in ¥ nanostructured scaffolds (tissue engineering), Nanomedicine stimuli-sensitive devices and physically targeted ¥ establishment of European Centres of Excellence treatments in the field of Nanomedicine ¥ a focus on cancer, neurodegenerative and cardio- ¥ modification of funding mechanisms for basic vascular diseases and on local-regional delivery technological research to permit academic-group- (pulmonary/ocular/skin) only applications Specific developments should include: ¥ development of funding procedures with sufficient longer term scale and scope; for example with longer term ¥ a synthetic, bioresponsive systems for intracellu- funding rather than continuous short-term funding lar delivery of macromolecular therapeutics and cycles, to enable research for seriously tackling bioresponsive/self-regulated delivery systems goal-oriented problems (smart nanostructures such as biosensors coupled ¥ establishment of economic and social benefits of to delivery systems) Nanomedicine and communication of them to stakeholders and the public 4.2.4. Clinical Applications and Regulatory Suggested Action Issues ¥ coordinated funding of basic research in Nano- General directions should be: medicine through ESF EUROCORES and Euro- ¥ disease-oriented focus for Nanomedicine devel- pean Commission FP7 instruments (e.g. ERA-Net) opment in specific clinical applications 4. RECOMMENDATIONS AND SUGGESTED ACTIONS 31

4.3.2. Commercial Exploitation threats from inaction: the benefits consisting of Recommendations employment potential and meeting the medical ¥ establishment of a scheme supporting academic/ needs of the ageing population; and the threats commercial ventures, such as a European version including missed economic opportunities of the Small Business Innovative Research program ¥ engagement of the scientific community in regu- of the US National Institutes of Health lar dialogue with the general public in order to ¥ involvement of clusters or highly selected teams, discover likely public concerns early, and contin- chosen for personal excellence or track record uation of dialogue to address and alleviate public ¥ establishment of more manufacturing sites with concerns by the presentation of clear facts ‘Good Manufacturing Practice’ designation to ¥ supply of non-specialist information on potential support small and medium enterprises for trans- benefits of Nanomedicine to the general public in ferring projects more rapidly into clinical devel- a timely fashion, with the emphasis on the fact that opment Nanomedicine is based on mimicking the elegance Suggested Actions of nature ¥ liaise with regulatory authority for Good Manu- Suggested Actions facture Practice designation ¥ organise truly transdisciplinary conferences using ¥ conduct policy study on the feasibility for a the ESF Research Conference scheme or related European Small Business Innovative Research schemes at the European Commission programme ¥ set up a communication entity, possibly in the form of a small enterprise, to report scientific find- 4.3.3. Interdisciplinary Education and Training ings and innovation to the public. Recommendations ¥ establishment of formal interdisciplinary training courses, mainly at the undergraduate level, cover- ing basic scientific disciplines such as molecular biology, colloidal chemistry, cell physiology, surface chemistry, and membrane biophysics ¥ institution of new programmes, at master’s or early postgraduate level (with combined medical and scientific training), to support the rapidly devel- oping field of Nanomedicine ¥ encouragement of more interdisciplinary MD/PhD degree programmes, with some provision for nanoscience, to provide core scientific training for both scientists and clinicians in the longer term Suggested Action ¥ facilitate the establishment of interdisciplinary train- ing courses, masters and MD/PhD programmes via ESF networking instrument (a la carte Programme), COST and European Commission instruments (e.g. Network of Excellence)

4.3.4. Communication Recommendations ¥ promotion of more truly transdisciplinary confer- ences focusing on the specific themes of Nano- medicine to facilitate better communication between research disciplines ¥ encouragement of goal-oriented research partner- ships between large medical centres and univer- sity research groups ¥ clearer articulation and better communication of the benefits of embracing Nanomedicine and the 32

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¥ M. Shin, O. Ishii, T. Sueda, J.P. Vacanti (2004) ¥ W. Kreyling, M. Semmler, M. Moller (2004). Dosimetry Contractile cardiac grafts using a novel nanofibrous and toxicology of ultrafine particles. Journal of Aerosol mesh. Biomaterials, 25, 3717-3723. Medicine, 17, 140-52.

¥ L.A. Smith, P.X. Ma (2004) Nano-fibrous scaffolds for ¥ G. Oberdorster, E. Oberdorster, J. Oberdorster (2005) tissue engineering. Colloids and Surfaces. Nanotoxicology: an emerging discipline evolving from B, Biointerfaces, 10, 125-131. studies of ultrafine particles. Environmental Health Perspectives, 113, 823-839. ¥ Y. Tabata (2005) Nanomaterials of drug delivery systems for tissue regeneration. Methods in Molecular ¥ J.W. Park, C.C. Benz, F.J. Martin (2004) Future Biology, 300, 81-100. directions of liposome- and immunoliposome-based cancer therapeutics. Seminars in Oncology, 31, 96-205. ¥ C. Williams, T.M. Wick (2004) Perfusion bioreactor for small diameter tissue-engineered arteries. Tissue Engineering, 10, 930-941. ¥ E.K. Yim, R.M. Reano, S.W. Pang, A.F. Yee, C.S. Chen, 5.3. Websites and General K.W. Leong (2005) Nanopattern-induced changes in Information morphology and motility of smooth muscle cells. Biomaterials, 26, 5405-5413. It should be noted that many web sites contain ¥ S. Zhang (2003) Fabrication of novel biomaterials relevant information but they are not necessarily through molecular self-assembly. Nature Biotechnology, designated “Nano” 21, 1171-1178. ¥ The world service for nanotechnology nanotechweb.org

Clinical, Regulatory and Toxicological Aspects ¥ News.Nanoapex.com is one of the best nanotechnology ¥ P.J.A. Borm (2002) Particle toxicology: From coal news services on the web news.nanoapex.com/ mining to nanotechnology. Inhalation Toxicology, • Científica Ð the nanobusiness company 14, 311-324. http://www.cientifica.com/

¥ P.J. Borm, W. Kreyling (2004) Toxicological hazards of ¥ Nanotechnology news at Chemical & Engineering News inhaled nanoparticlesÐpotential implications for drug Chemical & Engineering News - Nanotechnology delivery. Journal of Nanoscience and Nanotechnology, 4, 521-531. ¥ European Nanotechnology Gateway http://www.nanoforum.org/ ¥ V.L. Colvin (2003) The potential environmental impact of nanomaterials. Nature Biotechnology, 10, 1166-1170. ¥ iNano website containing links to several companies and ¥ R.D. Brook, B. Franklin, W. Cascio, Y. Hong, institutions that could be helpful in the start-up phase G. Howard, M. Lipsett, R. Luepker, M. Mittleman, of new companies J. Samet, S. C. Smith, Jr., I. Tager (2004) Air pollution http://www.inano.dk/sw179.asp and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and ¥ Pronano Prevention Science of the American Heart Association. Swedish site for the promotion of nanotechnology Circulation, 109, 2655-71. in industry http://www.pronano.se/ ¥ K. Donaldson, V. Stone, C. L. Tran, W. Kreyling, P. J. Borm (2004) Nanotoxicology. Occupational and ¥ The Institute of Nanotechnology provides news and Environmental Medicine, 61, 727-728. background information on new developments in nanoscience ¥ K. Donaldson, D. Brown, A. Clouter, R. Duffin, www.nano.org.uk W. MacNee, L. Renwick, L. Tran, V. Stone (2002) The pulmonary toxicology of ultrafine particles. Journal of Aerosol Medicine, 15, 213-20. 36 5. BIBLIOGRAPHY

¥ Nanotechnology database, at Loyola College, Maryland, North American Nanoinitiatives USA ¥ National Nanotechnology Initiative, the largest itri.loyola.edu/nanobase/ American nanocooperation, USA ¥ The Foresight Institute www.nano.gov www.foresight.org/NanoRev/index.html ¥ NanoBioTechnology Center, a National Science ¥ Nanonordic Foundation Center, USA www.nanonordic.com/extra/page/ www.nbtc.cornell.edu/

¥ The Royal Society: Nanotechnology and Nanoscience ¥ The Canadian National Research Council’s National http://www.nanotec.org.uk/ Institute for Nanotechnology www.nrc.ca/nanotech/home_e.html

Journals ¥ National Institute for Nanotechnology - University Alberta; It should be also noted that many journals http://www.nint.ca/ contain relevant information but they are not ¥ Pacific Northwest National Laboratory’s effort necessarily designated “Nano”. in nanoscience www.pnl.gov/nano/index.html ¥ IEE Proceedings Nanobiotechnology www.iee.org/proceedings/nbt ¥ Center for Nanotechnology, University of Washington http://www.nano.washington.edu/ ¥ For the latest articles in nanoscience and nanotechnology, visit the AIP/APS Virtual Journal of ¥ Center for Biological and Environmental Nanoscale Science and Technology www.vjnano.org Nanotechnology, Rice University (CBEN) http://www.ruf.rice.edu/%7Ecben/ ¥ Chemical & Engineering News, October 16, 2000: Nanotechnology pubs.acs.org/cen/nanotechnology/7842/7842 nanotechnology.html

¥ Nano Letters; pubs.acs.org/journals/nalefd/index.html

¥ Nanotechnology focuses on the interdisciplinary approach to nanoscale science www.iop.org/EJ/S/3/354/journal/0957-4484

¥ Scientific American : Nanotechnology http://www.sciam.com/nanotech/www.sciam.com/ nanotech

¥ International Journal of Nanomedicine http://www.dovepress.com/IJN.htm

¥ Journal of Nanobiotechnology: http://www.jnanobiotechnology.com/home/

¥ Particle and Fibre Toxicology www.particleandfibretoxicology.com

¥ Journal of Nanoparticle Research www.springeronline.com/sgw/cda/frontpage/0,11855, 4-10100-70-35588310-0,00.html

¥ Journal of Aerosol Medicine http://www.liebertpub.com/publication.aspx?pub_id=24

¥ International Journal of Nanomedicine www.dovepress.com/IJN_ed_profile.htm

¥ Journal of Nanotoxicology http://www.tandf.co.uk/journals/titles/17435390.asp 37

6. Appendices

Appendix I Campus de Beaulieu 35042 Rennes Cedex ¥ France ESF Forward Look Workshop Participants [email protected] Amsterdam, Netherlands, 1-5 March 2004 Dr Andreas Briel Schering AG Workshop on Analytical Techniques and Drug Delivery Systems Diagnostic Tools, Amsterdam, 1 March 2004 13342 Berlin ¥ Germany [email protected] Dr Patrick Boisseau (Chair) CEA-Nano2Life Prof. Salvatore Cannistraro 17 rue des Martyrs Dipartimento di Scienze Ambientali 38054 Grenoble Cedex 9 ¥ France Istituto Nazionale per la Fisica della Materia [email protected] Università della Tuscia 01100 Viterbo ¥ Italy Dr François Berger [email protected] Centre Hospitalier Universitaire Rue des Carabins-Ancienne Prof. Martyn Davies 38043 Grenoble ¥ France Laboratory of Biophysics and Surface Analysis [email protected] School of Pharmacy, University of Nottingham University Park Prof. H. Allen O. Hill Nottingham NG7 2RD ¥ United Kingdom Inorganic chemistry laboratory [email protected] University of Oxford South Parks Road Dr Sjaak Deckers Oxford OX1 3QR ¥ United Kingdom Molecular Imaging and Diagnostics [email protected] Philips Medical Systems Nederland BV P.O. Box 10.000 Dr Jürgen Schnekenburger 5680 DA Best ¥ Netherlands Gastroenterologische Molekulare Zellbiologie, UKM [email protected] University of Münster Domagkstr. 3A Prof. Paul Dietl 48149 Münster ¥ Germany Institute of Physiology [email protected] University of Innsbruck Fritz-Pregl-Str. 3 Prof. Yosi Shacham 6020 Innsbruck ¥ Austria University Research Institute for NanoScience and [email protected] NanoTechnology Tel Aviv University Rainer Erdmann Ramat Aviv, 69978 Tel Aviv ¥ Israel PicoQuant GmbH [email protected] Rudower Chaussee 29 (IGZ) 12489 Berlin ¥ Germany Dr Dimitrios Stamou [email protected] Laboratory of physical chemistry of polymers and membranes (LCPPM) Dr Mauro Giacca EPFL International Centre for Genetic Engineering and 1051 ausanne ¥ Switzerland Biotechnology (ICGEB) [email protected] Padriciano 99 34012 Trieste ¥ Italy [email protected] Workshop on Nanoimaging and Manipulation, Dr Corinne Mestais Amsterdam, 2 March 2004 CEA Grenoble Prof. Jean-Louis Coatrieux (Chair) Département Système pour l’Information et la Santé Lab. Traitement du Signal et de l’Image 17, Rue des Martyrs Université de Rennes 1 38054 Grenoble Cedex 09 ¥ France [email protected] 38 APPENDIX I

Prof. Hans Oberleithner Prof. Ruth Duncan (Co-chair) Institute of Physiology Centre for Polymer Therapeutics University of Münster Welsh School of Pharmacy Robert-Koch-Str. 27a Cardiff University 48149 Münster ¥ Germany Redwood Building [email protected] King Edward VII Avenue Cardiff CF10 3XF ¥ United Kingdom [email protected] Workshop on Nanomaterials and Nanodevices, Prof. Daan Crommelin Amsterdam, 3 March 2004 Department of Pharmaceutics Prof. Jeffrey Alan Hubbell (Chair) Utrecht Institute for Pharmaceutical Sciences Laboratoire de médecine régénérative et PO Box 80082 de pharmacobiologie 3508 TB Utrecht ¥ Netherlands EPFL [email protected] 1015 Lausanne ¥ Switzerland Prof. Patrick Couvreur [email protected] Faculté de Pharmacie Prof. Wim Hennink (Co-chair) Universite de Paris-Sud Department of Pharmaceutics 5 rue J-B Clement Utrecht Institute for Pharmaceutical Sciences 92296 Chatenay-Malabry ¥ France Utrecht University [email protected] 3508 TB Utrecht ¥ Netherlands Prof. Mike Eaton [email protected] UCB-Celltech Prof. João Pedro Conde 216 Bath Road Department of Materials Engineering Slough, Berks SL1 4EN ¥ United Kingdom Instituto Superior Tecnico [email protected] Av. Rovisco Pais 1 Prof. Thomas Kissel 1096 Lisboa ¥ Portugal Institut für Pharmazeutische Technologie und [email protected] Biopharmazie Dr John W Davies Philipps-Universität Marburg Polymer Laboratories Ltd Ketzerbach 63 Essex Road 35032 Marburg ¥ Germany Shropshire [email protected] Church Stretton SY6 6AX ¥ United Kingdom Prof. Claus-Michael Lehr [email protected] Department of Biopharmaceutics and Pharmaceutical Prof. Helmuth Möhwald Technology Max-Planck-Institute of Colloids and Interfaces Saarland University Wissenschaftspark Golm Im Stadtwald, Bldg. 8.1 14476 Potsdam ¥ Germany 66123 Saarbrucken ¥ Germany [email protected] [email protected]

Prof. José Rivas Prof. Egbert Meijer Dpto. Física Aplicada, Campus Universitario Sur Laboratory of Macromolecular and Organic Chemistry Universidad de Santiago de Compostela Eindhoven University of Technology 15782 Santiago de Compostela ¥ Spain Den Dolech 2 , STO 4.36 [email protected] 5600 MB Eindhoven ¥ Netherlands [email protected]

Workshop on Drug Delivery and Pharmaceutical Development, Amsterdam, 4 March 2004 Workshop on Clinical Applications and Toxicology, Amsterdam, 5 March 2004 Prof. María José Alonso (Chair) Department of Pharmaceutical Technology Dr Wolfgang Kreyling (Chair) Faculty of Pharmacy GSF National Research University of Santiago de Compostela Centre for Environment and Health 15782 Santiago de Compostela ¥ Spain Institut für Inhalationsbiologie [email protected] Ingolstädter Landstrasse 1 85764 Neuherberg ¥ Germany [email protected] APPENDIX II 39

Dr Paul J. A. Borm Dr Patrick Boisseau Centre of Expertise in Life CEA Ð Nano2Life Sciences (CEL) 17 rue des Martyrs Hogeschool Zuyd 38054 Grenoble Cedex 9 ¥ France Nieuw Eyckholt 300 [email protected] 6419 DJ Heerlen ¥ Netherlands Prof. Salvatore Cannistraro [email protected] Dipartimento di Scienze Ambientali Prof. Kenneth Donaldson Instituto Nationale per la Fiscica della Materia ELEGI Colt Laboratory Università della Tuscia School of Clinical Sciences and Community Health, 01100 Viterbo ¥ Italy Medical School [email protected] University of Edinburgh Prof. Jean-Louis Coatrieux Wilkie Building, Teviot Place Lab. Traitement du Signal et de l’Image Edinburgh EH 8 9AG ¥ United Kingdom Université de Rennes 1 [email protected] Campus de Beaulieu Prof. Alberto Gabizon 35042 Rennes Cedex ¥ France Shaare Zedek Med. Ctr. [email protected] Oncology Institute Prof. Hans Oberleithner POB 3235 Institute of Physiology Jerusalem 91031 ¥ Israel University of Münster [email protected] Robert-Koch-Str. 27a Dr Rogério Gaspar 48149 Münster • Germany Laboratory of Pharmaceutical Technology [email protected] Faculty of Pharmacy University of Coimbra 3000 Coimbra ¥ Portugal ESF Member Organisations and [email protected] Representatives/Political Bodies

Dr Andreas Jordan Dr Janna de Boer MagForce Applications The Netherlands Organisation for Health Research Center of Biomedical Nanotechnology and Development (NWO) Campus Charite, CBN, Haus 30 P.O. Box 93245 Spandauer Damm 130 2509 AE The Hague ¥ Netherlands 14050 Berlin ¥ Germany [email protected] [email protected] Dr Oliver Bujok VDI Technologiezentrum GmbH Physikalische Technologien Graf-Recke-STr. 84 Appendix II 40239 Düsseldorf • Germany [email protected] ESF Consensus Conference Participants Dr Jean Chabbal Le Bischenberg, France, 8-10 November 2004 Dept. Microtech. Biol.&Health CEA-L2t Steering Committee 17, Rue des Martyrs Prof. Ruth Duncan (Chair) 38054 Grenoble Cedex 09 ¥ France Centre for Polymer Therapeutics [email protected] Welsh School of Pharmacy Dr Françoise Charbit Cardiff University CEA Grenoble Redwood Building LETI-DTBS King Edward VII Avenue 17, Rue des Martyrs Cardiff CF10 3XF ¥ United Kingdom 38054 Grenoble Cedex 09 ¥ France [email protected] [email protected]

Dr Wolgang Kreyling (Deputy-chair) Dr Rosita Cottone GSF National Research Centre for Environment Mission Affaires Européennes on sabbatical of BMBF and Health (Ministry of Research, Germany) Direction de Institut für Inhalationsbiologie la Technologie Ministère délégué à la Recherche Ingolstädter Landstrasse 1 1, rue Descartes 85764 Neuherberg ¥ Germany 75005 Paris ¥ France [email protected] [email protected] 40 APPENDIX II

Dr Julie Deacon Prof. Manuel Vázquez UK Micro and Tanotechnology Network Instituto de Ciencia de Materiales de Madrid, CSIC Farlan Cottage Campus de Cantoblanco Lower Road 28049 Madrid ¥ Spain Cookham, Berks SL6 9HJ ¥ United Kingdom [email protected] [email protected] Dr Peter Venturini Dr Nicole Déglon National Institute of Chemistry CEA/Service Hospitalier Frédéric Joliot Hajdrihova 19 4, place du Général Leclerc 1000 Ljubljana ¥ Slovenia 91401 Orsay Cedex France ¥ France [email protected] [email protected] Dr Petra Wolff Dr Luc Delattre Bundesministerium für Bildung und Forschung (BMBF) Département de Pharmacie Referat 511 Nanomaterialien Pharmacie Galénique et Magistrale Heinemannstr. 2 Université de Liège 53175 Bonn ¥ Germany Avenue de l’Hôpital, 1 – Bât. B36 [email protected] 4000 Liege 1 ¥ Belgium [email protected] Academic Experts Dr Franz Dettenwanger VolkswagenStiftung Prof. María José Alonso Kastanienallee 35 Department of Pharmaceutical Technology 30519 Hannover ¥ Germany Faculty of Pharmacy [email protected] University of Santiago de Compostela 15782 Santiago de Compostela ¥ Spain Dr Mauro Ferrari [email protected] The National Cancer Institute 110U Davis Heart and Lung Research Institute Dr Paul J.A. Borm 31 Center Drive MSC 2580 Centre of Expertise in Life Sciences (CEL) The Ohio State University Hogeschool Zuyd Room 10A52 Nieuw Eyckholt 300 473 West 12th Avenue 6419 DJ Heerlen ¥ Netherlands Columbus OH 43210-1002 ¥ USA [email protected] [email protected] Prof. Hans Börner Dr Valérie Lefèvre-Seguin Max Planck Institute of Colloids and Interfaces Direction de la Recherche, Ministère délégué Department of Coloid Chemistry à la Recherche Research Campus Golm 1, rue Descartes ¥ 75005 Paris ¥ France Am Mühlenberg 1 [email protected] 14424 Potsdam ¥ Germany [email protected] Dr Corinne Mestais CEA Grenoble Dr Benoit Dubertret Département Système pour l’Information et la Santé ESPCI, Laboratoire d’Optique Physique 17, Rue des Martyrs CNRS UPRA0005 38054 Grenoble Cedex 09 ¥ France 10, rue Vauquelin [email protected] 75231 Paris Cedex 10 ¥ France [email protected] Prof. Julio San Roman CSIC Prof. Alberto Gabizon Institute of Polymers Shaare Zedek Med. Ctr. Juan de la Cierva 3 Oncology Institute 28006 Madrid ¥ Spain POB 3235 [email protected] Jerusalem 91031 ¥ Israel [email protected] Dr Christof Steinbach Dechema e.V. Prof. Varban Ganev Theodor-Heuss-Allee 25 Medical University of Sofia 60486 Frankfurt a.M. ¥ Germany 2 Zdrave Street [email protected] 1431 Sofia ¥ Bulgaria [email protected] APPENDIX II 41

Dr Mauro Giacca Prof. A.W. McCaskie International Center for Genetic Engineering Surgical&Reproductive Sciences and Biotechnology (ICGEB) Medical School, University of Newcastle upon Tyne Padriciano 99 Newcastle upon Tyne NE2 4HH ¥ United Kingdom 34012 Trieste ¥ Italy [email protected] [email protected] Prof. Helmuth Möhwald Dr Robert M. Henderson Max-Planck-Institute of Colloids and Interfaces Department of Pharmacology, University of Cambridge Wissenschaftspark Golm Tennis Court Road 14476 Potsdam ¥ Germany Cambridge CB2 1PD ¥ United Kingdom [email protected] [email protected] Prof. Lars Montelius Dr Peter Hinterdorfer Division of Solid State Physics Institute for Biophysics Department of Physics Johannes Kepler Universität Linz Lund University Altenbergerstr. 69 Box 117 A-4040 Linz ¥ Austria SE-221 00 Lund ¥ Sweden [email protected] [email protected]

Prof. Thomas Kissel Prof. Roeland J.M. Nolte Institut für Pharmazeutische Technologie Department of Organic Chemistry und Biopharmazie University of Nijmegen Philipps-Universität Marburg Toernooiveld 1 - U 052 Ketzerbach 63 6525 ED Nijmegen ¥ Netherlands 35032 Marburg ¥ Germany [email protected] [email protected] Dr T.H. Oosterkamp Prof. J¿rgen Kjems Leiden Institute of Physics Department of Molecular Biology Leiden University University of Arhus Niels Bohrweg 2 C.F.Mollers Alle, Build. 130 2333 CA Leiden ¥ Netherlands DK-8000 Aarhus C ¥ Denmark [email protected] [email protected] Dr Pierre Puget Prof. Harm-Anton Klok Département Systèmes pour l’information et la santé Ecole polytechnique fédérale de Lausanne (EPFL) (DSIS) Institute de matériaux, Laboratoire de polymères LETI - CEA Grenoble Ecublens 17, rue des Martyrs CH-1015 Lausanne ¥ Switzerland 38054 Grenoble cedex 9 ¥ France [email protected] [email protected]

Prof. Jean-Marie Lehn Dr Andrea Ravasio Institut de Science et d’Ingénierie Supramoléculaires Department of Physiology Laboratoire de Chimie Supramoléculaire University of Innsbruck ISIS/ULP Fritz-Pregl-Str. 3 8, allée Gaspard Monge 6020 Innsbruck ¥ Austria BP 70028 ¥ F-67083 Strasbourg Cedex [email protected] [email protected] Prof. Helmut Ringsdorf Prof. Claus-Michael Lehr University of Mainz Department of Biopharmaceutics and Pharmaceutical Raum 00.125 Technology Düsenbergweg 10-14 Saarland University 55128 Mainz ¥ Germany Im Stadtwald, Bldg. 8.1 [email protected] 66123 Saarbrucken ¥ Germany Dr Jürgen Schnekenburger [email protected] Gastroenterologische Molekulare Zellbiologie, UKM Prof. C.R. Lowe University of Münster Institute of Biotechnology Domagkstr. 3A University of Cambridge 48149 Münster • Germany Tennis Court Road [email protected] Cambridge CB2 1QT ¥ United Kingdom [email protected] 42 APPENDIX II

Dr Milada Sirova Rainer Erdman Institute of Microbiology ASCR PicoQuant GmbH Videnska 1083 Rudower Chaussee 29 (IGZ) 142 20 Prague 4 ¥ Czech Republic 12489 Berlin ¥ Germany [email protected] [email protected]

Prof. K. Ulbrich Dr Rogério Gaspar Czech Republic Academy of Science Laboratory of Pharmaceutical Technology Faculty of Pharmacy Institute of Macromolecular Chemistry University of Coimbra Heyrovského námestí 2 3000 Coimbra ¥ Portugal CZ-162 06 Prague 6 ¥ Czech Republic [email protected] [email protected] Dr Arne Hengerer Prof. Arto Urtti Siemens Medical Solutions University of Kuopio MR MI Department of Pharmaceutics Karl-Schall-STr. 4 P.O.Box 1627 91054 Erlangen ¥ Germany FIN-70211 Kuopio ¥ Finland [email protected] [email protected] Dr Laurent Levy Prof. Ernst Wagner Nanobiotix Pharmaceutical Biotechnology Rue Pierre et Marie Curie - BP27/01 Department of Pharmacy 31319 Labege Cedex ¥ France Ludwig-Maximilians Universität München (LMU) [email protected] Butenandtstr. 5-13 Dr Kristina Riehemann 81377 Munich ¥ Germany Integrated Functional Genomics (IFG) [email protected] University of Münster von-Esmarch-Str. 56 Dr Jaap Wilting 48149 Münster • Germany Utrecht Institute Pharmaceutical Sciences [email protected] University of Utrecht Sorbonnelaan 16 Prof. Csaba Szántay Jr. 3585 CA Utrecht ¥ Netherlands Spectroscopic Research Division [email protected] Chemical Works of Gedeon Richter Ltd. H-1475 Budapest P.O.B. 27 ¥ Hungary [email protected] Industrial & Regulatory Experts Dr Andreas Briel Schering AG Nanotechnology Information Suppliers Drug Delivery Systems 13342 Berlin ¥ Germany Dr Ottila Saxl [email protected] The Institute of Nanotechnology 6 The Alpha Centre Dr John W Davies University of Stirling Innovation Park Polymer Laboratories Ltd Stirling, FK9 4NF ¥ United Kingdom Essex Road [email protected] Church Stretton Shropshire, SY6 6AX ¥ United Kingdom [email protected] ESF/EMRC/COST Dr Sjaak Deckers Molecular Imaging and Diagnostics Prof. Luc P. Balant Philips Medical Systems Nederland BV COST TC Medicine & Health P.O. Box 10.000 ¥ 5680 DA Best ¥ Netherlands Department of Psychiatry [email protected] University of Geneva 2, Chemin du Petit-Bel-Air Prof. Mike Eaton UCB-Celltech 1225 Chene-Bourg ¥ Switzerland 216 Bath Road [email protected] Slough Dr Thomas Bruhn Berks SL1 4EN ¥ United Kingdom Institute of Experimental Dermatology [email protected] University of Münster von-Esmarch-Str. 58 48149 Münster • Germany [email protected] APPENDIX III 43

Nathalie Geyer Ambisome¨ (liposomal amphotericin B) are > $100 European Science Foundation million (€83.77 million) sales per annum 1, quai Lezay Marnésia BP 90015 ¥ 67080 Strasbourg Cedex ¥ France * Vision paper and basis for a strategic research agenda for [email protected] NanoMedicine, European Technology Platform on NanoMedicine - Nanotechnology for Health Ð Dr John Marks EU publication September 2005 European Science Foundation 1, quai Lezay Marnésia BP 90015 ¥ 67080 Strasbourg Cedex ¥ France [email protected]

Prof. Mihail Pascu Appendix IV ESF-COST Office Medicine and Health; Biomaterials European Projects and Networks Undertaking 149, Avenue Louise Nanomedicine Research P.O. BOX 12 1050 Brussels ¥ Belgium European Networks [email protected] EU funding opportunities in the Nanotechnology Prof. Clemens Sorg Research Area Institute of Experimental Dermatology www.cordis.lu/nanotechnology/ University of Münster von-Esmarch-Str. 58 Communication on nanotechnology from the European 48149 Münster • Germany Commission, ‘Towards a European strategy on [email protected] nanotechnology’ www.cordis.lu/nanotechnology/src/communication.htm Dr Hui Wang European Science Foundation Illustrated brochure entitled ‘Nanotechnology, Innovation 1, quai Lezay Marnésia for tomorrow’s world’ ftp://ftp.cordis.lu/pub/ BP 90015 ¥ 67080 Strasbourg Cedex ¥ France nanotechnology/docs/nano_brochure_en.pdf [email protected] The PHANTOMS Nanoelectronics Network scheme www.phantomsnet.net

A general European site on European nanoscience and technology. Appendix III www.nanoforum.org/

Projected Market for Nanomedicines European National Nanocentres The Swiss ‘National Centre for Nano Scale Science’ at The market of nanomedicines is rapidly rising as new prod- Universität Basel ucts are being approved. It is expected that this market will www.nanoscience.unibas.ch/ reach a significant economic potential within 5 to 10 years. Currently, little data is available on the market of nanomed- Nanoscience @ Cambridge University icines in Europe. http://www.nanoscience.cam.ac.uk/ London Centre for Nanotechnology Market size worldwide 2003 for medical devices http://www.london-nano.ucl.ac.uk/ and pharmaceuticals* Medical devices €145 billion Nanolink at University of Twente Pharmaceuticals €390 billion Nanolink www.mesaplus.utwente.nl/nanolink/ Expected market growth: 7-9% annually Centre of Competence Nano-Scale Analysis in Hamburg Within the market of pharmaceuticals, advanced drug deliv- www.nanoscience.de/ ery systems account for approximately 11% market share http://www.nanoanalytik-hamburg.de/shtml/index. (€42.9 billion). This market is expected to expand rapidly as shtmlhttp://www.nanoanalytik-hamburg.de/shtml/ only a few products are currently in clinical application and index.shtml many more in clinical trials or in the process of being approved. As an example, the current estimates for Centre for NanoScience based at Ludwig-Maximillians- Doxil¨/Caelyx¨ (PEGylated liposomal doxorubicin) Universität, München are $300 million (€251.32 million) sales per annum www.cens.de/ 44 APPENDIX IV

Centre of Competence NanoBioTechnology, Saarland, Contact: Sergey Piletsky Germany Email: [email protected] www.nanobionet.de/ HEPROTEX Centre of Competence NANOCHEM, Saarbrücken, Objectives: To develop a joint research infrastructure for Germany development of protective textiles. With new innovations www.cc-nanochem.de in textiles, forms will become more widely used in surgical procedures than for just traditional uses such as The German Ministry of Education and Research wound care. supports six national Competence Centres Contact: Hilmar Fuchs www.nanonet.de/nanowork/indexe.php3 Email: [email protected] Nano-World, The Computer-Supported Cooperative INCOMED Learning Environment on Nanophysics, a Swiss Virtual Objectives: The aim is to reduce 90% of implant Campus complications, by way of an innovative method of www.nanoworld.unibas.ch/zope/nano/en coating objects with a thin layer of hydroxylapatite, Center for NanoMaterials at Technische Universiteit bioactive glass or mixtures of both in order to give Eindhoven, Holland biocompatible surfaces. www.cnm.tue.nl Contact: Christoph Schultheiss Email: [email protected] Center for Ultrastructure Research, Austria www.boku.ac.at/zuf/ INTELLISCAF Objectives: The aim is to produce intelligent scaffolds Institute of Nanotechnology at the Forschungszentrum using nanostructured particles and surfaces to give Karlsruhe materials which will help regenerate tissues such as bone http://hikwww1.fzk.de/int/english/welcome.html or skin on their implantation. DFG-Centrum für Funktionelle Nanostrukturen Contact: Soeren Stjernqvist http://www.cfn.uni-karlsruhe.de/index.html Email: [email protected]

Nanostructures Laboratory at MFA Research Institute for MENISCUS-REGENERATIO Technical Physics and materials science Objectives: The aim is to use tissue engineering to http://www.mfa.kfki.hu/int/nano/ produce an artificial meniscus with a structure similar to the natural tissue. Paul Scherrer Institut - Laboratory for Micro- and Contact: Claudio de Luca Nanotechnology Email: [email protected] http://lmn.web.psi.ch/index.html

Nano-Science Center at K¿benhavns Universitet http://www.nano.ku.dk/ EU 6th Framework Programme

MIC National Micro- and Nanotechnology Research Search: http://eoi.cordis.lu/search_form.cfm Center at DTU Microrobotnic surgical instruments http://www.mic.dtu.dk/ Project Acronym: (none). NanoBIC - NanoBioCentrum at University of southern Objectives: To develop microrobotic surgical instruments Denmark for new types of surgery. http://www.sdu.dk/Nat/nanobic/index.php Contact: Georges Bogaerts Email: [email protected]

MOBIAS European Projects Objectives: To develop a way to manufacture implants BIOMIN and scaffolds with several materials and to vary the Objectives: The aim of the project is to form composition throughout the structure, to give multiple nanostructure composites of biomaterials and inorganic functions. compounds for applications in, e.g. implants. Contact: Gregory Gibbons Contact: Ralph Thomann Email: [email protected] Email: [email protected] NA.BIO.MAT BIOSMART Objectives: The design and development of self- Objectives: To establish an infrastructure for coordinating assembling biocompatible polymers, for applications in, research into the design and application of biomimetic e.g., tissue engineering. materials and smart materials with biorecognition Contact: Gaio Paradossi functions, including new porous biorecognition materials Email: [email protected] for tissue engineering. APPENDIX V 45

Nanoarchitecture NMMA Objectives: Nanostructuring modification of biomaterials Objectives: To carry out interdisciplinary research (for for tissue engineering and other biomimetic applications. medical applications) into the possibilities Contact: Vasif Hasirci nanotechnology offers for shaping surface and internal Email: [email protected] structure, and using molecular biology to control interactions between materials and cells. NanoBone Contact: Krzysztof Kurzydlowski Objectives: To apply nanotechnology, in terms of Email: [email protected] structuring, to bone repair and regeneration. Contact: Fernando Monteiro NONMETALLICIMPLANTS Email: [email protected] Objectives: To create new/improved polymer materials for implants and scaffolds, with the necessary structure to Nanostres optimise their function. Objectives: To use nanotechnology techniques to create Contact: Jan Chlopek implants and implant technologies for skeletal tissues. Email: [email protected] Contact: Josep Anton Planell Email: [email protected] SAM-MED-NET Objectives: To gain a better understanding of self NB-TISS-INTER-MED assembly mechanisms for applications in biomimetic Objectives: To redress the issue of the decreasing materials (e.g. tissue engineering). European market share in medical devices. Contact: Frederic Cuisinier Contact: Ian McKay Email: [email protected] Email: [email protected]

Appendix V

Nanomedicines in Routine Clinical Use or Clinical Development

Liposomal formulations in clinical use and clinical development Product Status Payload Indication Daunoxome¨ Market daunorubicin cancer Doxil¨/Caelyx¨ Market doxorubicin cancer Myocet¨ Market doxorubicin cancer Ambisome¨ Market amphotericin B fungal infections Amphotech¨ Market amphotericin B fungal infections

Monoclonal antibody-based products in the market Antibody Target Payload Use Therapeutic antibodies Rituxan¨ CD20 inherent activity CD20+ve Non-Hodgkin’s Lymphoma Herceptin¨ HER2 inherent activity HER2 +ve breast cancer Antibody-drug conjugates Mylotarg¨ CD33 calicheamicin Acute Myeloid Leukaemia Radioimmunotherapeutics Tositumomab¨ CD20 [131I]iodide Non-Hodgkin’s Lymphoma- targeted radiotherapy Zevalin¨ CD20 90Yttrium Non-Hodgkin’s Lymphoma- targeted radiotherapy Immunotoxins Anti-B4-blocked ricin CD19 blocked ricin Non-Hodgkin’s lymphoma targeted immunotoxin Anti-Tac(Fv)-PE38 (LMB2) CD25 Pseudomonas Haematological malignancies exotoxin fusion protein PEG-antiTNF Fab CDP870 TNFα Phase III Rheumatoid arthritis and Crohn’s disease 46 APPENDIX V

Nanoparticles as imaging agents and drug carriers Product Compound Status Use Imaging Agents Endorem¨ superparamagnetic Market MRI agent iron oxide nanoparticle Gadomer¨ Dendrimer-based Phase III MRI agent-cardiovascular MRI agent Drug delivery Abraxane¨ Albumin nanoparticle Market Breast cancer containing paclitaxel

Polymer Therapeutics in the market or transferred into clinical development Compound Name Status Indication

Polymeric drugs Poly(alanine, lysine, Copaxone¨ Market Multiple sclerosis glutamic acid, tyrosine) Poly(allylamine) Renagel¨ Market End stage renal failure Dextrin-2-sulphate Emmelle¨ gel Market Phase III HIV/AIDS - a vaginal virucide formulated as a gel Dextrin-2-sulphate Phase III HIV/AIDS - polymer administered intraperitoneally Poly(I):Poly(C) Ampligen¨ Phase III Chronic fatigue immune dysfunction (myalgic encephalomyelitis; ME) Polyvalent, polylysine VivaGelª Phase I/II Viral sexually transmitted dendrimer containing SPL7013 diseases, formulated as a vaginal gel Polymer-oligonucleotide conjugates PEG-aptamer Macugenª NDA filed Age-related macular degeneration Polymer-protein conjugates PEG-adenosine deaminase Adagen¨ Market Severe combined immuno- deficiency syndrome SMANCS Zinostatin Stimalmer¨ Market Cancer - hepatocellular carcinoma PEG-L-asparaginase Oncaspar¨ Market Acute lymphoblastic leukamia PEG-a-interferon 2b PEG-intronª Market Hepatitis C, also in clinical development in cancer, multiple sclerosis, HIV/AIDS PEG-a-interferon 2a PEG-Asys¨ Market Hepatitis C PEG-human growth hormone Pegvisomant¨ Market Acromegaly PEG-GCSF Neulastaª Market Prevention of neutropenia associated with cancer chemotherapy PEG-antiTNF Fab CDP870 Phase III Rheumatoid arthritis and Crohn’s disease Polymer-drug conjugates Polyglutamate-paclitaxel CT-2103, XYOTAXª Phase II/III Cancer -particularly lung cancer, ovarian and oesophageal HPMA copolymer-doxorubicin PK1; FCE28068 Phase II Cancer -particularly lung and breast cancer HPMA copolymer-doxorubicin- PK2; FCE28069 Phase I/II Cancer -particularly galactosamine hepatocellular carcinoma HPMA copolymer-paclitaxel PNU166945 Phase I Cancer HPMA copolymer camptothecin MAG-CPT / PNU166148 Phase I Cancer HPMA copolymer platinate AP5280 Phase II Cancer HPMA copolymer platinate AP5346 Phase I/II Cancer Polyglutamate-camptothecin CT-2106 Phase I/II Cancer PEG-camptothecin PROTHECANª Phase II Cancer Polymeric micelles PEG-aspartic acid-doxorubicin NK911 Phase I Cancer micelle APPENDIX VI 47

Appendix VI ImaRx Therapeutics uses SonoLysis technology which employs tiny micro European Companies Active and nanobubbles injected into the bloodstream to enter into regions of thrombosis. When external ultrasound is in Nanomedicines’ Development applied, the microbubbles cavitate and dissolve blood clots into smaller particles. A list of some companies active in nanomedicines’ Website: www.imarx.com development. This list is not meant to be comprehensive. iMEDD is a biomedical company developing advanced drug iNano delivery systems based on MEMS technology. iMEDD’s website containing links to several companies and lead drug delivery platform, NanoGATE, is an implant institutions that could be helpful in the start-up phase of that uses membranes containing pores with nanometre new companies dimensions that control the diffusion of drugs at a Website: http://www.inano.dk/sw179.asp molecular level. Pronano Website: www.imeddinc.com Swedish site for the promotion of nanotechnology in LiPlasome Pharma industry has developed a prodrug and drug delivery platform that Website: http://www.pronano.se/ can be used for targeted transport of anticancer drugs. Advanced Photonic Systems APhS GmbH Their prodrug and drug delivery technology is based on Advanced Photonic Systems manufactures lasers, laser smart lipid based nanocarriers (LiPlasomes) that can be systems and components, with a focus on fast and ultra applied for targeted transport of anticancer drugs. fast-pulsed lasers. Website: liplasome.com Website: http://www.advanced-photonic-systems.com/ MagForce Applications Bio-Gate Bioinnovative Materials GmbH is a group of companies that have developed the magnetic Bio-Gate develops and tests anti-infective materials using fluid hyperthermia method (MFH). This is a minimally invasive cancer therapy that attacks cancer at the cellular nanosilver, for medicine and other industries. level whilst leaving healthy tissue largely unharmed. The Website: http://www.bio-gate.de method consists of two components; nanosized iron oxide DILAS, Diodenlaser GmbH particles (MagForce) and an external magnetic field DILAS designs and engineers various products (standard applicator (MFH). or custom designed) in the field of High Power Diode Website: www.magforce.de Lasers MagnaMedics Website: http://www.dilas.de uses its SensithermA therapy to help combat AIDS. The JenLab GmbH principle of the therapy is the selective overheating of the JenLab uses femtosecond laser technology to develop virus and the infected cells by means of magnetic instruments for biotechnology and biomedical nanoparticles. SensiTherm therapy is also used in the applications. treatment of liver tumours. Website: http://www.jenlab.de Website: www.nanovip.com

Kleindiek Nanotechnik Micromet AG Kleindiek Nanotechnik produces micro and nano is using antibodies to create novel drugs that precisely positioning systems, with high precision and resolution, and effectively combat human diseases such as cancer or combined with a large working range. rheumatoid arthritis. Website: http://www.nanotechnik.com Website: www.micromet.de

NEWCO Surgical Nanobiotix NEWCO Surgical is a supplier of innovative surgical has developed their NanoBiodrugsª which are nano- instruments and accessories throughout the UK. particles with a diameter smaller than 100nm. The core of Website: www.newco.co.uk the nanoparticle is a NanoProdrug in an inactive form that can then be activated by external physical activation. This Capsulution Nanoscience AG generates a local therapeutic effect destroying the uses LBL-Technology¨ for making unique pathological cells. Activation is achieved by a magnetic capsules, allowing the manufacture of extremely precise field similar to that of an MRI machine, or by laser. nano- and micron-sized capsules. Website: www.nanobiotix.com Website: www.capsulution.com Nanogate Technologies Flamel Technologies concentrates on inorganic-organic nanocomposites as has developed Medusa which is nanoencapsulation well as self-organising nanostructures based on chemical technology to deliver native protein drugs. nanotechnology Website: www.flamel.com Website: www.nanogate.de 48 APPENDIX VI

Nanomix Inc Companies Active in Tissue Engineering Website: nano.com Alchimer SA NanoPharm AG Alchimer develops and produces coatings for biomedical has developed nanoparticles as a drug delivery implants and microelectronics. formulation using NANODEL technology. Drugs are Website: http://www.alchimer.com/ bound to nanoparticles and then transported to their BioTissue Technologies AG specific target. It is even possible to transport drugs BioTissue produces autologous skin grafts, bone and across the blood-brain barrier. cartilage implants. Website: nanopharm.de Website: www.biotissue-tec.com NOSE GfE Medizintechnik GmbH Nanomechanical olfactory sensors. GfE develops and produces titanium-coated (‘titanized’) Website: http://monet.unibas.ch/nose/ implants. Novosom AG Website: http://www.gfe-online.de/opencms/opencms/ specialises in the development and production of gfe/en/mt/index.html liposomes, liposomal nanocapsules and liposomal IIP-Technologies GmbH vectors. IIP has developed an artificial retina that can help restore Website: www.novosom.de some sense of vision. Pharmasol GmbH Website: http://www.iip-tec.com/english/index.php4 has developed lipid nanoparticles as an alternative Micromuscle AB delivery system to polymeric nanoparticles. Micromuscle develops and produces electroactive Website: www.pharmasol-berlin.de components for medical devices. Psividia Ltd Website: http://www.micromuscle.com is a biomedical technology company which has produced pSiMedica a material designed to enable drug molecules to be held pSiMedica has developed a form of silicon that is in nanoscale pockets which release tiny pulses of a drug biocompatible and biodegradable. BioSilicon can be used as the material dissolves. The rate of dissolution can be in various medical applications. controlled so that delivery can be achieved over days or Website: http://www.psimedica.co.uk months. Website: www.psividia.com TransTissue Technologies GmbH TransTissue creates replacement tissues such as bone and SkyePharma cartilage using tissue engineering. is a leading developer, manufacturer and provider of drug Website: http://www.transtissue.com delivery technologies. One of its technologies uses nanoparticles which allow targeted drug delivery in the NAMOS GmbH lung. NAMOS produces ‘intelligent’ surface coatings for Website: www.skyepharma.com materials using nanotechnology. Website: http://www.namos.de/ c3

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