nano medicine

An ESF – European Medical Research Councils (EMRC) Forward Look report

Nanomedicine

Marine Board

EUROPEAN SCIENCE FOUNDATION


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-operationwith 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 collaborationin a global context. Our main instruments include conferences, scientific foresights, collaborationprogrammes and support to outstanding young researchers. ESF also manages COST, anintergovernmental 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 willcontribute significantly to maximizing the value of knowledge generated in the biomedical field and the outcomeexpected for the public health care system. In this context, the strategy developed by the European MedicalResearch 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 SystemsBiology;

• focus on biomedical applications emerging from these and related domains, such as Nanomedicine andStructural Medicine; Molecular Imaging, Genetic Epidemiology and Pharmacogenetics in order to advance thepromising 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 innovationthrough 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 inthe above-mentioned fields.In addition, further attention has been paid on the identification of related regulatory and ethical issues and to thepromotion of biomedical research to the European general public and political stakeholders. In this respect EMRCis a permanent observer of the Comité directeur pour la Bioéthique at the European Council and is being involvedin 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 covernewly 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 substructuremade 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

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ESF Forward Look on Nanomedicine2005

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

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Sponsored by theEuropean Science Foundationand organised by its Standing Committee, theEuropean 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, FranceSalvatore Cannistraro, INFM, Università della Tuscia, ItalyJean-Louis Coatrieux, Inserm, Université de Rennes 1, FranceJoão Pedro Conde, Instituto Superior Técnico, PortugalWim Hennink, Utrecht University, The NetherlandsHans Oberleithner, University of Münster, GermanyJosé 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 UnitHui Wang, Science Officer

The Steering Committee would particularly like to thank the following persons for their valuable contributions:Alberto Gabizon, IsraelMauro Giacca, ItalyRogerio Gaspar, PortugalThomas Kissel, GermanyBert Meijer, The Netherlands

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

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Contents

Foreword 6Executive Summary 71. Nanomedicine: A New Opportunity for Improved Diagnosis, Prevention and Treatment for Disease 11

1.1. Definition of Nanomedicine 111.2. Position of Nanomedicines within the Healthcare Portfolio 11

2. Current Status of Nanomedicine Research and Forward Look 132.1. Science and Technology 13

2.1.1. Workshop on Analytical Techniques and Diagnostic Tools2.1.2. Workshop on Nanoimaging and Manipulation2.1.3. Workshop on Nanomaterials and Nanodevices2.1.4. Workshop on Drug Delivery and Pharmaceutical Development 2.1.5. Workshop on Clinical Use, Regulatory and Toxicology Issues

2.2. Research Strategy and Policy 212.2.1. Organisation and Funding2.2.2. Commercial Exploitation2.2.3. Interdisciplinary Education and Training2.2.4. Communication

3. European Situation and Forward Look – SWOT Analysis 254. Recommendations and Suggested Actions 29

4.1. General Recommendations 294.1.1. Priority Areas in Nanomedicine for the next 5 years4.1.2. Priority Areas in Nanomedicine for the next 10 years4.1.3. Commercial Exploitation4.1.4. Interdisciplinary Education and Training

4.2. Scientific Trends 294.2.1. Nanomaterials and Nanodevices4.2.2. Nanoimaging and Analytical Tools4.2.3. Novel Therapeutics and Drug Delivery Systems4.2.4. Clinical Applications and Regulatory Issues4.2.5. Toxicology

4.3. Research Strategy and Policy 304.3.1. Organisation and Funding4.3.2. Commercial Exploitation 4.3.3. Interdisciplinary Education and Training4.3.4. Communication

5. Bibliography 325.1. Key Reports on Nanotechnology and Nanomedicine 325.2. Key Literature on Nanotechnology relating to Medicine 335.3. Websites and General Information 35

6. Appendices 37Appendix I. ESF Forward Look Workshop Participants 37Appendix II. ESF Forward Look Consensus Conference Participants 39Appendix III. Projected Market for Nanomedicines 43Appendix IV. European Projects and Networks Undertaking Nanomedicine Research 43Appendix V. Nanomedicines in Routine Clinical Use or Clinical Development 45Appendix VI. European Companies Active in Nanomedicines’ Development 47

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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 ofNanomedicine is to realise the improved understanding of the patho-physiologicalbasis of disease, bring more sophisticated diagnostic opportunities and yieldmore effective therapies. Both the optimism and the challenges have promptedgovernmental science and funding organisations to undertake strategic reviews of the current status of the field1, their primary objectives being to assess potentialopportunities for better healthcare as well as the risk-benefit of these newtechnologies, and to determine priorities for future funding.

In early 2003, the European Science Foundation launched its Scientific ForwardLook on Nanomedicine. I am pleased to see the successful conclusion of thisforesight study, which has been the first such exercise focused on medicalapplications of nanoscience and nanotechnology. The Forward Look involvedleading European experts and led to a definition of the current status of the fieldand debates on strategic policy issues. The recently published Policy Briefingsummarised the recommendations made2.

Here the discussions and recommendations are presented in full. Implementationof these recommendations should ensure continuing European leading-edgeresearch and development in the field of Nanomedicine, resulting in reducedhealthcare costs and the rapid realisation of medical benefits for all Europeancitizens. ESF will commit itself to taking the initiative and facilitating the relevantbodies, including ESF Member Organisations and the European Commission, for actions based on these recommendations.

Bertil AnderssonESF Chief Executive

Foreword

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 strategicinitiative 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)

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Executive summary

Procedure

The ESF Forward Look on Nanomedicine wasconducted through a Steering Committee whichinitially organised a series of five specialised work-shops held from 1 to 5 March 2004. These work-shops involved small groups of experts fromacademia and industry representing the different sub-disciplines of the Nanomedicine field. Each groupwas invited to review the issues listed above, and toprepare draft recommendations in their area ofspecific expertise (participants are listed in Appen-dix I).

A final Consensus Conference was held at LeBischenberg, France from 8 to 10 November 2004.The meeting was attended by more than 70 repre-sentatives coming from academia, industry, privatefoundations, and governmental agencies supportingscientific research. Collectively they were able toreview and revise the outputs from the earlier disci-pline-specific workshops, paying special attentionto the boundaries within this multidisciplinaryscientific field. Moreover the Consensus Conferencewas able to review the underpinning topics ofScience Funding and Policy Making, CommercialExploitation, Education, and Communication.Participants are listed in Appendix II.

Definitions

The field of ‘Nanomedicine’ is the science andtechnology of diagnosing, treating and preventingdisease and traumatic injury, of relieving pain, andof preserving and improving human health, usingmolecular tools and molecular knowledge of thehuman body. It was perceived as embracing fivemain sub-disciplines that in many ways are over-lapping and underpinned by the following commontechnical issues

• Analytical Tools • Nanoimaging • Nanomaterials and Nanodevices • Novel Therapeutics and Drug Delivery Systems • Clinical, Regulatory and Toxicological Issues

Background

Recent years have witnessed an unprecedentedgrowth in research in the area of nanoscience. Thereis increasing optimism that nanotechnology appliedto medicine will bring significant advances in thediagnosis treatment and prevention of disease.However, many challenges must be overcome if theapplication of Nanomedicine is to realise theimproved understanding of the pathophysiologicalbasis of disease, bring more sophisticated diagnosticopportunities, and yield more effective therapies andpreventive measures.

Both the optimism and the challenges haveprompted governmental, science and funding organ-isations to undertake strategic reviews of the currentstatus of the field, their primary objectives being toassess potential opportunities for better healthcareas well as to assess the risk-benefit of these newtechnologies, and determine priorities for futurefunding. The outcome of the European ScienceFoundation’s Forward Look on Nanomedicine ispresented here.

Objectives

In 2003 the Medical Standing Committee of ESF(EMRC) initiated the European Science Founda-tion’s Forward Look on Nanomedicine. The aims ofthis study were to gather European experts fromacademia and industry to:• Define the field • Discuss the future impact of Nanomedicine on

healthcare practice and society• Review the current state-of-the-art of Nanomedi-

cines research• Identify Europe’s strengths and weaknesses• Deliver recommendations on:– future research trends and priorities for funding– organisational and research infrastructures neededat the national and European levels to support coor-dinated scientific activities– the mechanisms needed to facilitate effectivedissemination of information to the general publicand policy makers.

EXECUTIVE SUMMARY8

The aim of ‘Nanomedicine’ may be broadlydefined as the comprehensive monitoring, control,construction, repair, defence and improvement ofall human biological systems, working from themolecular level using engineered devices andnanostructures, ultimately to achieve medical bene-fit. In this context, nanoscale should be taken toinclude active components or objects in the sizerange from one nanometre to hundreds of nanome-tres. They may be included in a micro-device (thatmight have a macro-interface) or a biological envi-ronment. The focus, however, is always on nanoin-teractions within a framework of a larger device orbiologically, within a sub-cellular (or cellular)system.

Forward Look on Nanomedicine

Miniaturisation of devices, chip-based technologiesand, on the other hand, ever more sophisticated novelnanosized materials and chemical assemblies arealready providing novel tools that are contributingto improved healthcare in the 21st century. Opportu-nities include superior diagnostics and biosensors,improved imaging techniques – from molecules toman – and not least, innovative therapeutics andtechnologies to enable tissue regeneration and repair.

However, to realise Nanomedicine’s full poten-tial, important challenges must be addressed. Newregulatory authority guidelines must be developedquickly to ensure safe and reliable transfer of newadvances in Nanomedicine from laboratory tobedside.

Recommendations

The sub-fields indicated above significantly over-lapped in terms of the underpinning science (mate-rials science, analytical techniques, and safetyissues), and the perception of the core Europeanstrengths and weaknesses in each sub-field werevery similar.

• Nanomaterials and Nanodevices Advances should begin with the optimisation ofexisting technologies towards specific Nanomedi-cine challenges. The development of new multi-functional, spatially ordered, architecturally variedsystems for targeted drug delivery was seen as apriority. There is a pressing need to enhance expert-ise in scale-up manufacture and material character-isation, and to ensure material reproducibility,effective quality control and cost-effectiveness.These issues should be addressed urgently to enablerapid realisation of clinical benefit (within fiveyears).

For realisation to application within the nextdecade new materials are needed for sensing multi-ple, complicated analytes in vitro, for applicationsin tissue engineering, regenerative medicine and 3Ddisplay of multiple biomolecular signals. Telemet-rically controlled, functional, mobile in vivo sensorsand devices are required, including construction ofmultifunctional, spatially ordered, architecturallyvaried systems for diagnosis and combined drugdelivery (theranostics). The advancement of bioan-alytical methods for single-molecule analysis wasseen as a priority.

• Analytical Tools and Nanoimaging These aspects were viewed as complementary eventhough many of the technologies required are verydifferent in being designed for ex vivo, cellular orin vivo/patient use.

Once again the opportunity was identified torefine existing nanotechniques allowing analysis ofnormal and pathological tissues to quickly bring abetter understanding of initiation and progressionof disease. Identification of new biological targetsfor imaging, analytical tools and therapy is viewedas a research priority. There is a need to developnovel nanotechniques for monitoring in real timecellular and molecular processes in vivo, bringingimproved sensitivity and resolution. Mechanisms toallow early translation of research based on molec-ular imaging using nanoscale tools from animalmodels to clinical applications should be estab-

EXECUTIVE SUMMARY 9

lished. This would close the gap between molecu-lar and cellular technologies understudy, and allowrapidly commercialisation of clinical diagnosticnanotechnologies.

In the longer term, research should develop amultimodal approach for nanoimaging technolo-gies, and assist the design of non-invasive, in vivoanalytical nanotools with high reproducibility, sensi-tivity and reliability. Such tools would allow a para-digm shift in pre-symptom disease monitoring, andenable the use of preventative medicines at an earlystage. The simultaneous detection of several mole-cules, analysis of all sub-cellular components at themolecular level, and replacement of antibodies asdetection reagents are seen as particularly importantchallenges for basic research.

Novel Therapeutics and DrugDelivery Systems

Nanosized drug delivery systems have alreadyentered routine clinical use and Europe has beenpioneering in this field. The most pressing challengeis application of nanotechnology to design of multi-functional, structured materials able to targetspecific diseases or containing functionalities toallow transport across biological barriers. In addi-tion, nanostructured scaffolds are urgently neededfor tissue engineering, stimuli-sensitive devices fordrug delivery and tissue engineering, and physicallytargeted treatments for local administration of ther-apeutics (e.g. via the lung, eye or skin).

To realise the desired clinical benefits rapidly,the importance of focusing the design of technolo-gies on specific target diseases was stressed: cancer,neurodegenerative and cardiovascular diseases wereidentified as the first priority areas.

Longer term priorities include the design ofsynthetic, bioresponsive systems for intracellulardelivery of macromolecular therapeutics (syntheticvectors for gene therapy), and bioresponsive or self-regulated delivery systems including smart nanos-tructures such as biosensors that are coupled to thetherapeutic delivery systems.

Toxicology

There is an urgent need to improve the understand-ing of toxicological implications of Nanomedicinesin relation to the specific nanoscale propertiescurrently being studied, in particular in relation totheir proposed clinical use by susceptible patients.In addition, due consideration should be given to thepotential environmental impact and there should be asafety assessment of of all manufacturing processes.

Risk-benefit assessment is needed in respect ofboth acute and chronic effects of nanomedicines inpotentially pre-disposed patients – especially in rela-tion to target disease. A shift from risk-assessment toproactive risk-management is considered essential atthe earliest stage of the discovery, and then the devel-opment of new nanomedicines.

Clinical Applications and RegulatoryIssues

As the technologies are designed based on a clearunderstanding of a particular disease, disease-specific oriented focus is required for the develop-ment of novel pharmaceuticals. In addition, it willbe important to establish a case-by-case approachto clinical and regulatory evaluation of eachnanopharmaceutical. High priority should be givento enhancing communication and exchange of infor-mation among academia, industry and regulatoryagencies encompassing all facets of this multidisci-plinary approach.

Research Strategy, PolicyOrganisation, Funding andCommunication

In terms of education, a need for more formal inter-disciplinary training courses in the area of Nanomed-icine was foreseen. At the undergraduate level thesewould cover the basic scientific disciplines includ-ing molecular biology, colloidal chemistry, cell phys-iology, surface chemistry, and membrane biophysics.In addition, new programmes at master’s or earlypostgraduate level (preferably with combinedmedical and scientific training) are needed to supportthe rapidly developing field of Nanomedicine.Encouragement of more interdisciplinary MD/PhDdegree programmes with some provision fornanoscience would provide core scientific trainingfor both scientists and physicians. This will be essen-tial to ensure a trained workforce to oversee clinicaldevelopment of new nanomedicines.

EXECUTIVE SUMMARY10

Timely exploitation of newly emerging Nano-medicine technologies was seen as a key issue. Thisis an area of general weakness. There is a need toestablish specific Nanomedicine-related schemes topromote academic-commercial partnerships. Thegrowth of clusters or highly selected teams, chosenfor personal excellence or track record would ensuremost rapid progress. To facilitate industrial develop-ment the establishment of more manufacturing siteswith a Good Manufacturing Practice designationable to support small and medium enterprises wouldhelp in transferring projects more rapidly into clini-cal development.

Establishment of good communication is auniversal challenge for research and developmentat the interface of scientific disciplines and at theleading edge. There is a continuing need to promotemore truly trans-disciplinary conferences. Encour-agement of goal-oriented research partnershipsbetween large medical centres and universityresearch groups is essential to progress the field.

It was noted that scientifically qualified politi-cians are not common, and the regional, nationaland European programmes seldom show alignment,suggesting less than optimal communication. Seri-ous effort needs to be made by scientific opinionleaders in Nanomedicine to ensure that politiciansare well briefed. Not only will better diagnostics,treatments and prevention for life-threatening anddebilitating disease bring healthcare benefits to anageing population, research and development inNanomedicine also offers the potential of employ-ment and economic benefits with a reduction ofhealthcare budgets.

There is an urgent need to more clearly articulateand better communicate the potential benefits ofNanomedicine to the general public as a whole.

Engagement of the scientific community in earlydialogue with the general public is crucial in orderto discover any public concerns regarding Nanomed-icine. Continuing regular dialogue is essential toaddress and alleviate any public concerns.

Conclusions

This Forward Look on Nanomedicine has definedthe remit of this emerging and important field.Nanomedicine is clearly multidisciplinary andbuilds on the existing expertise in a large number ofdifferent scientific fields.

European strengths have been identified, as havethe short- and long-term opportunities, and priori-ties for the development of Nanomedicine-relatedtechnologies have been recognised.

When applying nanotechnology to medical uses,it is particularly important to ensure thorough safetyevaluation of any new technologies and also toreview the likely environmental impact. In eachspecific case, careful risk-benefit evaluation isrequired.

Most importantly, an open and continuingdialogue is required to ensure all interested parties,including the general public, are well informed asto the ongoing technology developments in the fieldof Nanomedicine. As much has been written in thepopular press, quality information is required toassist policy makers and scientists to distinguish“science fact” from “science fiction’’.

Governmental Agencies

and FundingPolicy Makers

RegulatoryAgencies

Pharmaceuticaland

NanomedicineRelated

Industries

General Public

Academic Scientists incl.:Chemistry

PhysicsBiology

MedicineEngineering

MathematicsInformation Technology

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1.1. Definition of Nanomedicine

The field of Nanomedicine is the science and tech-nology of diagnosing, treating and preventingdisease and traumatic injury, of relieving pain, andof preserving and improving human health, usingmolecular tools and molecular knowledge of thehuman body. It embraces five main sub-disciplineswhich are in many ways overlapping and are under-pinned by common technical issues.

The aim of Nanomedicine may be broadlydefined as the comprehensive monitoring, control,construction, repair, defence and improvement ofall human biological systems, working from themolecular level using engineered devices andnanostructures, ultimately to achieve medical bene-fit. In this context, nanoscale should be taken toinclude active components or objects in the sizerange from one nanometre to hundreds of nanome-tres. They may be included in a micro-device (thatmight have a macro-interface) or a biological envi-ronment. The focus, however, is always on nanoin-teractions within a framework of a larger device orbiologically a sub-cellular (or cellular) system.

It was noted that Nanomedicine is built on thescience and technology of complex systems ofnanometre-scale size, consisting of at least twocomponents, one of which is an active principle, andthe whole system leading to a special functionrelated to the diagnosis, treatment or prevention ofdisease.

1.2. Position of Nanomedicineswithin the Healthcare Portfolio

The highest causes of mortality in Europe arecardiovascular disease and cancer. In addition demo-graphic changes are producing an ageing population.This in itself is leading to new healthcare challenges.There is rising prevalence in diseases of the centralnervous system, such as senile dementia,Alzheimer’s disease, Parkinson’s disease, anddiseases associated with ageing, for example arthri-tis and ocular diseases. Whilst much progress wasmade in the 20th century in respect of the therapiesfor infectious diseases, emergence of resistance,HIV/AIDS and other new infectious diseases, forexample SARS, present new challenges.

Nevertheless, as the 21st century begins, we arewitnessing a paradigm shift in medical practice.Nanomedicine is expected to contribute signifi-cantly to the overall healthcare portfolio.

Genomics and proteomics research is alreadyrapidly elucidating the molecular basis of manydiseases. This has brought new opportunities todevelop powerful diagnostic tools able to identifygenetic predisposition to diseases. In the future,point-of-care diagnostics will be routinely used toidentify those patients requiring preventativemedication, to select the most appropriate medica-tion for individual patients, and to monitor responseto treatment. Nanotechnology has a vital role to playin realising cost-effective diagnostic tools.

There are increasing challenges within the phar-maceutical industry to locate drugs more efficientlyto their disease targets. As the search for improvedmedicines for life-threatening and debilitatingdiseases continues, two distinct approaches arebeing taken to achieve this aim. The first is withindrug discovery and builds on identification of newmolecular targets which are being used to design‘perfect fit’ drug molecules with more specific ther-apeutic activity. These efforts continue via:screening of natural product molecules to identifycandidates with pharmacological activity;

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

1. NANOMEDICINE: A NEW OPPORTUNITY FOR IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT FOR DISEASE12

preparation of carefully tailored synthetic lowmolecular weight drugs via traditional medicinal orcombinatorial chemistry; • nanofluidics for targeted synthesis; • nanodetection for target identification; and• discovery of natural macromolecules, including

antibodies, proteins and genes that have inherentbiological activity.

The second, and a complementary approach, isthe creation of drug delivery systems that can act asa vehicle to carry and guide more precisely theabovementioned agents to their desired site ofaction. In 2002 and 2003, more biotechnology prod-ucts (proteins and antibodies) and drug deliverysystems were approved by the US Food and DrugAdministration as marketed products than new lowmolecular weight drugs.

Nanosized hybrid therapeutics (e.g. polymer-protein conjugates) and drug delivery systems (lipo-somes and nanoparticles) have already been approvedfor routine use as medicines. The drug deliverysystems entering the market have been designed toachieve disease-specific targeting, to control therelease of the drug so that a therapeutic concentrationis maintained over a prolonged period of time, or toprovide more convenient routes of administration(e.g. oral, transdermal and pulmonary) and reachlocations in the body that are traditionally difficult toaccess, such as the brain. Via the use of coatings,ever more sophisticated devices are emerging thatallow localised controlled release of biologicallyactive agents.

Complex supramolecular assemblies, nanoparti-cles and polymeric materials in many differentforms are already playing an important role in theconstruction of nanopharmaceuticals. It is clear thatthe contribution of nanotechnology will continue togrow in the future, and it is widely believed that

effective delivery gene therapy and other macro-molecular therapeutics will be realised only with theaid of multicomponent, nanosized delivery vectors.

Non-invasive patient imaging using techniquessuch as gamma camera imaging, magnetic reso-nance imaging, X rays and ultrasound are importantestablished tools used to assist diagnosis and moni-tor response to treatment. Molecular level imagingusing techniques such as positron emission tomog-raphy (PET) can also provide information on drugtargeting, drug metabolism and disease response totherapy. Several nanoparticle-based magnetic reso-nance imaging (MRI) agents have already beenapproved for routine clinical use, and it is recog-nised that future application of nanotechnology hasan enormous potential in this field. Complexsupramolecular assemblies are already beingexplored in research and development to yieldagents for molecular imaging in the context of MRI,ultrasound, optical imaging, and X-ray imaging.

Moreover, in the longer term, the combination ofimaging technologies and drug delivery systems hasthe potential to yield theranostics devices.

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2.1. Science and Technology

2.1.1. Workshop on Analytical Techniques and Diagnostic Tools

Workshop participants:Dr Patrick Boisseau (chair)Dr François Berger, Prof. A.W. McCaskie, Dr Françoise Charbit, Dr Rosita Cottone, Prof. H. Allen O. Hill, Prof. Lars Montelius, Dr Kristina Riehemann, Dr Ottila Saxl, Dr Jürgen Schnekenburger, Prof. Yosi Shacham,Prof. Clemens Sorg, Dr Dimitrios Stamou, Prof. Csaba Szántay

Introduction

There is considerable anticipation that miniaturisa-tion via the application of nanotechnology and newnanotools will lead to novel surgical and analyticaltools and diagnostics for use ex vivo. It is envisagedthat such techniques will increase our ability to iden-tify predisposition to disease, monitor diseaseprogression and identify the most relevant patienttreatments. Moreover, a new generation of surgicaltools is predicted that will be able to assist diagno-sis and deliver therapy at a cellular level. In thecontext of larger ex vivo diagnostic devices, thefocus of this research lies on nanointeractions.Europe has a relatively strong position in basicresearch in this field but failure to exploit its inven-tions is a continuing problem. DNA and proteinchips are already widely used as research tools andare helping to provide a better understanding of themolecular basis of diseases and identify new molec-

ular targets for therapy. It is perceived that manynanotechnology-derived tools will, in the future, beroutinely used in diagnosis of many diseases longbefore they will be approved as treatments.

In the case of these devices, nanoscale objectswere defined as molecules or devices within a size-range ofone to hundreds of nanometres that are theactive component or object, even within the frame-work of a larger micro-size device or at a macro-interface.

Scope of this discipline

In the area of nanoanalytical techniques and diag-nostic tools that will find application in the sectorsof diagnostics, medical devices and pharmaceuticaldrug discovery, a wide range of technologies arebeing developed for both in vitro (diagnostics andsensors) and in vivo use (in line sensors, implanta-bles and surgical tools) with a range of biologicaltargets including cells, DNA and proteins. Researchand development in this field is extremely multidis-ciplinary and there is considerable synergy with the‘nanoimaging and manipulation’ and the ‘nanoma-terials and nanodevices’.

Analytical and point-of-care diagnostic productdesign is already supported by the use of nanoparti-cles and nanodevices. For example, biosensor tech-nology based on nanotechnology represents a hugeopportunity to revolutionise diagnostics in thehealthcare environment. Healthcare professionalsin primary care and hospital clinics are shortlyexpecting to be able to use low-cost tests able to aidthe diagnosis by simultaneous measurement of

2. Current Status of Nanomedicine Researchand Forward LookOutput of workshops held in Amsterdam March 2004 and the Consensus Conference Le Bischenberg November 2004

Bioarrays and Biosensors Nanofabrication Nano-objects Detection

DNA chips lab on chip nanotubes electrochemical detectionprotein-chips pill on chip nanowires optical detectionglyco-chips nanofluidics nanoparticles mechanical detectioncell-chips nanostructured surfaces electrical detection

- by scanning probes- by mass spectrometry- by electronmicroscopy

biosensors for single nanodevices and multiple analytes and nanoelectronics

2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK14

multiple parameters using a simple test strip with-out having to measure each parameter individually.Such test strips must be disposable and cost effec-tive. So far only single analyte strips have beenavailable but multisensor dry enzyme, hand-heldsystems being developed in Europe are leading theway towards fast and accurate multiparameteranalysis.

There is an opportunity to focus on technicallymore mature developments that are more likely to besuccessful, and also to address niche markets thathave better prospects for exploitation. Moreover,techniques and tools developed for analysis and diag-nostics in the medical field have the potential forwider application, for example, in the context of envi-ronmental monitoring, control of food hygiene etc.

An ideal near-patient diagnostic system

• Fast Minimise consultation time (<1 minute)• Simple Lay person (nurse’s aid) can use• Portable Take the test to the patient• Storage Room temperature for consumables• Painless Minimally invasive blood sampling• Single step One sample, one strip, many analytes• Platform One instrument, many diseases

While there is no lack of innovation in Europe,there was agreement that in many areas Europe islagging behind. The DNA array market, for example,is dominated by Affimetrix, an American company.While DNA chips are being widely used in research,their difficulties in securing quality assurance andregulatory approval, their production flexibility andspeed to result are well known. Although other moretechnically complex chips are available, so far theyare substantially more expensive.

Underlying research was seen as a further Euro-pean strength, particularly in relation to the identi-fication of medical targets. Current genomics andproteomics techniques give a limited insight intocellular function. In the future, the combination ofthese techniques with imaging methods such asTOF-SIMS analysis, and raster electron microscopyby atomic force microscopy of living cells will givemore information on individual protein function andcell signalling.

Workshops held under the auspices of the Euro-pean Federation of Pharmaceutical Industries andAssociations (EFPIA) have identified a number ofbottlenecks delaying development of new pharma-ceuticals. To improve clinical performance and earlyaccess to innovative medicine there is a recognisedneed for improved biomarkers and surrogate mark-ers to allow prediction of efficacy. Improved insilico tools are needed for toxicogenomics, toxico-proteomics, and metabonomics that can be used toimprove the predictability of toxicological profileof innovative medicines.

2.1.2. Workshop on Nanoimaging and ManipulationImaging at the molecular level, measurement of molecular forces

Workshop Participants:Prof. Jean-Louis Coatrieux, Dr Mauro Giacca(chairs)Dr Andreas Briel, Prof. Salvatore Cannistraro, Prof. Martyn Davies, Dr Sjaak Deckers, Dr Nicole Déglon, Dr Franz Dettenwanger, Prof. Paul Dietl, Rainer Erdmann, Prof. Robert Henderson, Dr Arne Hengerer, Dr Peter Hinterdorfer, Dr Corinne Mestais, Prof. Hans Oberleithner, Prof. T.H. Oosterkamp, Dr Andrea Ravasio, Dr Hui Wang

Introduction

Imaging is becoming an ever more important tool inthe diagnosis of human diseases. Both the develop-ment of imaging agents based on micro- or nanopar-ticles, organic dyes etc., and the development of

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2. CURRENT STATUS OF NANOMEDICINE RESEARCH AND FORWARD LOOK 15

highly sophisticated instruments supported bypowerful computation (2D, 3D reconstruction) havealready given rise to a significant move from inva-sive to less invasive clinical imaging. This is allow-ing an ever more sophisticated imaging-baseddiagnosis, particularly in cancer, neurological andheart diseases.

Nanotechnology has an important role to play infurther developing this field. Earlier diagnosis with anon-invasive tool can allow earlier treatment and thistreatment approach can be much less expensive andoften more effective. In addition, economistsconsider living healthier, longer lives to be econom-ically beneficial. There are potential risks and side-effects from new imaging agents based onnanomaterials, but risk-benefit analyses will be/arebeing conducted at an early stage. One of the great-est problems in the transfer of these approaches intoroutine clinical use lies in the slow approval processof new materials for human use by regulatory agen-cies.

Imaging at cellular, and even sub-cellular andmolecular level, is still largely a domain of basicresearch. However, it is anticipated that these tech-niques will find their way into routine clinical use.Atomic force microscopy (AFM) and AFM-relatedtechniques have become sophisticated tools, not onlyto image surfaces of molecules or sub-cellularcompartments, but also to measure molecular forcesbetween molecules. This is substantially increasingour knowledge of molecular interactions.


Because of its interdisciplinary nature, the field ofNanoimaging and Manipulation is also identified ashaving a considerable overlap with the other disci-plines, particularly in relation to nanomaterials(nanoparticles will play an ever more important roleas imaging agents), and clinical, regulatory andtoxicological issues.

The field termed here ‘Nanoimaging’ overlapswith the field already called ‘Molecular Imaging’.In this case the target to be imaged will have aspatial resolution in the order of 1-100 nanometres,and preferably a time resolution for imaging in theorder of milliseconds. The opportunities forimprovements and breakthroughs with the assis-tance of nanotechnology were seen in terms of bothexisting and emerging technologies. The imagingtechniques discussed are listed:

Techniques Examples

Optical imaging SNOM, STED, Raman SERS,and Spectroscopy FRET, FRAP Surface plasma TIRF, NIRF, Multiphoton LSMresonance Magnetic Resonance X-CT Imaging Nuclear Imaging micro-PET, SPECT Scanning probe AFM microscopy and force microscopy Ultrasound Optical tweezers Multimodal fluorescence probe and SPM,nanoimaging fluorescence and laser is the future and tweezerswill link structure to opto-acoustic imagingfunction and vice versa

Europe has a number of leading academicgroups and several leading companies who arepioneers in the development of imaging techniquesand innovative contrast agent production (e.g.Bracco SpA, GE formerly Amersham, PhilipsMedical Systems, Siemens Medical Solutions andSchering AG).

Basic research has already developed the firstmethods to monitor in vitro the assembly of multi-component biological complexes, protein traffick-ing and the interactions between single molecules.There is a recognised opportunity to use nanotech-nology to improve these molecular imaging tech-niques, and to construct real-time intracellulartomography. Objective methods for assessment ofimage quality are also needed in vitro and in vivo.Tools are currently under development that allow invitro evaluation of basic mechanisms, but it was feltthat these could quickly be developed towards realex vivo and clinical applications.

In the context of in vivo and clinical imaging, thedevelopment of novel techniques for macromolec-ular imaging was seen as a particular priority.Europe has been at the forefront of the developmentof polymeric gamma camera imaging agents anddendrimer-based MRI imaging agents. Improvedimage analysis is a particular goal. There is a needto improve 3D reconstruction and quantitative dataanalysis. Improved visualisation techniques areneeded also for stereo-imaging, virtual andaugmented reality imaging, and image-guidedmanipulation.

Opportunities exist for both invasive and non-invasive clinical imaging, e.g. endoscopy fortargeted imaging, use of optical catheters and devel-opment of nanosized systems allowing manipula-


tion, target selection, local stimulation and poten-tially local modification.

Development of more sophisticated imagingequipment requires an integrated approach. Under-pinning research must involve all aspects of theprocess.

Parallel to the development of the analyticalequipment, research and clinical development isongoing to provide a new generation of nanoimag-ing agents. These include both synthetic nanoparti-cles (including dendrimers and polymericnanoparticles) and biological nanoparticles (nanoor-ganisms). In the future it is likely that these imagingtools will become ever more complex, multicompo-nent systems combining contrast agents and track-ing probes (e.g. quantum dots, magnetic andsuperparamagnetic beads, nanoshells and nanocol-loids) with new targeting ligands. For targetedsystems, carriers can be used which may requireadditional surface modification, and linkers thatbring additional challenges for physicochemicalcharacterisation and safety evaluation. In some casescombination of a range of signal modalities (e.g.organic dyes) is also used. Imaging and contrastagent design has a considerable overlap with nano-

materials and drug delivery system development.Historically, radiolabelled antibodies have alreadybeen transferred to market as diagnostic tools incancer, and in the form of radiolabelled antibodiesand antibody conjugates as a therapeutic agent. It canbe argued that the radiolabelled therapeutic antibodyis the first nanosized theranostic.

Development of molecular imaging diagnosticsis expected to have a major impact on healthcare inthe future and the opportunities are summarisedbelow.

2.1.3. Workshop on Nanomaterials and Nanodevices

Workshop participants:Prof. Jeffrey Alan Hubbell, Prof. Ruth Duncan(chairs), Prof. Wim Hennink, Prof. Helmut Ringsdorf (co-chairs), Prof. Hans Börner, Prof. João Pedro Conde, Dr John W Davies, Prof. Harm-Anton Klok, Prof. Helmuth Möhwald, Dr Mihail Pascu, Prof. José Rivas, Dr Christoph Steinbach, Prof. Manuel Vázquez, Dr Peter Venturini, Dr Petra Wolff, Prof. Andrew McCaskie

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

Earlier diagnosis, optimized workflow

Genetic disposition

DNA mutations

Developingmolecular signature

First symptoms

Progressing disease

Screening Diagnosis & Staging

Treatment & Monitoring Follow-

up

• Specificmarkers(MDx)

• Molecularimaging:quantitative,whole-body

• CA Diagnosis

• Mini-invasivesurgery

• Local/target-ed drugdelivery &tracing

• Tissue analy-sis (MDx)

• MI, MDx • Non-invasive,

Quantitativeimaging

Screening Today

Future

Diagnosis & Staging

Treatment & Monitoring Follow-

up

• Unspecificmarkers

• POC imaging

• Mammo-graphy

• Diagnosticimaging

• Biopsies

• Surgery• Cath-lab • Radiation

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• Diagnosticimaging

• Unspecificmarkers

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Introduction

All aspects of Nanomedicine rely on progress innanomaterials research, and the nanoengineeringneeded to create devices to realise their goals. Mate-rials science is being employed to generate probesand techniques that are helping to understand basicbiological mechanisms. On the other hand, emer-gence of more sophisticated nanomaterials andnanodevices is required to develop diagnostic andsurgical tools, drug delivery systems and in vivodiagnostics into routine clinical practice. Moreover,nanoscale assemblies for ligand display are alreadyemerging as multicomponent 3D architectures ableto assist tissue engineering and promote tissuerepair.

Nanopharmaceuticals (drugs and drug deliverysystems) are nanoscale assemblies, which can berelatively simple; for example, nanoemulsions, nano-particles or polymer conjugates (of proteins or drugs),or complex mutlicomponent systems containingdrugs, proteins or genes, and an array of targetingligands and signal systems to enable in vitro or invivo detection. The nanomaterials and nanodevicesthat are being developed have scales from molecule-to assembly-to functional device in the nanometre-size range.

This field is rapidly moving from the develop-ment of individual building blocks to multifunc-tional, often biomimetic and bioresponsive systems.The combined knowledge and expertise of syntheticand physical chemistry as well as biological chem-istry are required for the development of effectivenanomaterials and nanodevices that are efficient andsafe in the biological environment.

Most importantly, it was noted that the researchin nanomaterials and nanodevices must strive forbiological and medical relevance with this in mind.The potential timescale for development of practi-cal-to-use systems could be relatively short. Asnanodiagnostics, e.g. a dendrimer-MRI agent, arealready in clinical development, it can be predictedthat those nanodiagnostics under in vitro develop-ment today should be available for clinical evalua-tion within the next few years. Over the next fewdecades, considerable growth in the routine clinicaluse of in vivo nanodiagnostics as well as nanother-apy was predicted.


Europe is particularly strong in physical and multi-functional chemical assembly of nanostructures(supramolecular chemistry), and colloid and poly-mer science including development of micro-elec-

tro-mechanical systems (MEMS), nanoparticles,and polymer therapeutics. There are also consider-able strengths in engineering materials (surfaces andnanosized and nanostructured polymers andcolloids) to control and direct cellular function forbiomedical applications, and the materials sciencerelating to tissue engineering and regenerativemedicine, bioactive materials and the related stemcells as sources.

The overall Nanomedicine-related goals for theresearch and development in nanomaterials andnanodevices were identified as the development oftechnologies to satisfy the following applications:

Biological Applications:

• Definition of target and pathway and networkidentification – Via multiple, co-assembled biomolecules

• Definition of mechanisms of signalling and signaltransduction– Via artificial assemblies in vitro

Medical Applications:

• Drug targeting– Whole body, cellular, sub-cellular localisation

of drugs, proteins and genes

• Drug discovery – High Throughput Screening technology with

biomolecular or cellular read-outs– Novel bioactives, obtained through nanotechnology– Novel drug delivery systems

• Diagnostics and sensing – In vitro (multiple analyte detection) and in vivo

• Regenerative medicine – Materials to regulate cell signalling and

differentiation, and also controlling morphogenesisthus helping to bring functional integration

Enabling technologies currently being developedinclude new systems for physical assembly, newroutes to macromolecular synthesis via chemicaland biosynthesis. In the latter case, minimisation ofnanoparticle or polymer polydispersity and hetero-geneity is essential for use in the construction ofnanopharmaceuticals.

Further development of combinatorial chemistryand biology is a certainty bringing multiple-func-tionality into library design to provide high-levelfunctional screening technology. The planar 10-100nm scale systems for screening and detection thatwill emerge will have multiple, integrated detectionsystems. Hierarchical, oriented, multicomponentdisplays of biological molecules with passivation of


background effects were seen as a particular chal-lenge. Control and feedback technologies areneeded to enable biomolecular recognition to betransferred into practical-to-use detector develop-ment. For analytical systems, increased sensitivityis needed, and analysis of functional systems.

Development of new materials with complexfunctionality is already ongoing. This is particularlyimportant in the context of tissue engineering scaf-folds and arrays for detection. Spatial control offunctionalisation is needed with ordered display oforthogonal functionality, and the ability to designinto a system-triggered control of response; that is,new bioresponsive materials. Improved methods forsurface functionalisation of colloids and surfaces areneeded as well as new and validated analytical tech-niques to ensure safety and reproducibility. Integra-tion of multiple-functionality (fluidics, withmanipulation and detection) will enable translationto implantable configurations with telemetric detec-tion and control.

2.1.4. Workshop on Drug Delivery and Pharmaceutical Development

Workshop participants:Dr María José Alonso, Prof. Ruth Duncan (chairs),Prof. Thomas Kissel (co-chair)Dr Oliver Bujok, Prof. Patrick Couvreur, Prof. Daan Crommelin, Dr Julie Deacon, Dr Luc Delattre, Prof. Mike Eaton, Prof. Claus-Michael Lehr, Dr Laurant Levy, Prof. Egbert Meijer, Dr Milada Sirova, Prof. Karel Ulbrich, Prof. Arto Urtti, Prof. Ernst Wagner, Dr Jaap Wilting

Introduction

Nanopharmaceuticals can be developed either asdrug delivery systems or biologically active drugproducts. This sub-discipline was defined as thescience and technology of nanometre size scalecomplex systems, consisting of at least two compo-nents, one of which is the active ingredient. In thisfield the concept of nanoscale was seen to rangefrom 1 to 1000 nm.

Over the last three decades Europe has been atthe forefront of the research and development ofnanosized drug carriers including liposomes,nanoparticles, antibodies and their conjugates, poly-mers conjugates, molecular medicine (includingproteins) and aspects of nanobiotechnology includ-ing tissue engineering and repair.

There are a growing number of marketed nano-sized drug delivery systems and imaging agents.

They include liposomal anticancer agents, antibody-drug conjugates, polymer-protein conjugates,nanoparticle-based imaging agents and an anti-cancer delivery system (see Appendix VI). There arealso a large number of constructs (including the firstpolymer-based gene delivery system) in clinicaldevelopment. These can be viewed as the first-generation Nanomedicines and future developmentswill build on these successes.


The nanosized drug delivery systems currentlyunder development are either self-assembling, orinvolve covalent conjugation of multicomponentsystems, e.g. drug, protein and polymer. The mate-rials used to create such drug delivery systems typi-cally include synthetic or semi-synthetic polymers,and/or natural materials such as lipids, polymers andproteins. If classified by function, many materialsused for drug delivery are bioresponsive and/orbiomimetic. An increasing number of nanosystemsare being proposed as drug carriers. They includemicelles, nanoemulsions, nanoparticles, nanocap-sules, nanogels, liposomes, nanotubes, nanofibres,polymer therapeutics and nanodevices. Magneticnanoparticles are being developed for diagnosticimaging and disease targeting, for example, liverand lymph node targeting following intravenousadministration.

For the past thirty years, Europe has pioneeredthe development of many of these technologies andresearch in the area of nanodrug delivery is stillforging ahead. Pharmaceutical science is especiallystrong, but research is increasingly interdisciplinaryboth across Europe and indeed globally. There isalready a number of major programmes and strate-gic initiatives in Europe promoting interdisciplinaryresearch and training in drug delivery, althoughthere has not been any clear emphasis within the

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Antibodies and their

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Polymermicelles

Polymer-protein conjugates

Unimolecular polymer and dendrimer conjugates

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With good interaction between academia andindustry, increased European funding to strengthenthe translational research and development, andbuilding on past successes, these goals can berealised quickly. However, tremendous challengesalso lie ahead. There is still a lack of communica-tion in a field where the multidisciplinarity of theresearch continues to grow. At the research stage,chemistry-physics-pharmaceutical science-biology-medicine must work in concert. There is a concernthat regulatory hurdles may become so high that theindustry will be reluctant to accept the risk of devel-oping innovative technology. In addition, becauseof the variable quality of the scientific representa-tion within public debate and concerns raised aboutnanotechnology as a whole, there is an apprehen-sion that the general public may be reluctant toaccept new concepts and technologies.

2.1.5. Workshop on Clinical Use, Regulatoryand Toxicology Issues

Workshop participants:Dr Wolfgang Kreyling, Prof. Rogério Gaspar (chairs),Dr Paul J. A. Borm (co-chair)Prof. Luc Balant, Dr Janna de Boer, Dr Thomas Bruhn, Prof. Kenneth Donaldson, Dr Benoit Dubertret, Prof. Ruth Duncan, Prof. Mike Eaton, Prof. Mauro Ferrari, Prof. Alberto Gabizon, Prof. Varban Ganev, Dr Andreas Jordan, Prof. Harm-Anton Klok, Prof. Jørgen Kjems, Dr Mihail Pascu, Prof. Helmut Ringsdorf, Dr Valérie Lefèvre-Seguin,Dr Ottila Saxl, Dr Milada Sirova, Prof. Karel Ulbrich

Introduction

As for any other conventional medicine, the entire lifecycle of nanopharmaceuticals includes production,distribution, clinical administration, consumer safety(human body effects and side-effects), and wastedisposal. While the clinical applications usuallyconcern only the selected stages of the life cycle, toxi-cological effects may exist in all the stages. Both clin-ical applications and toxicology of nanopharmaceuti-cals must be studied and examined comprehensively.

When designing a clinical protocol for a nano-pharmaceutical there are new challenges. Clinicaltrials and epidemiology studies may be significantlydifferent from those for conventional diagnostic andtherapeutic agents. Early dialogue and collaborationbetween scientists, clinicians, toxicologists and regu-latory authorities are increasingly recognised as oneof the important issues to ensure rapid clinical usesof safe nanopharmaceuticals.

EU Framework 6 Programme (FP6) to promotenetworks of excellence and specific projects able toenhance activities in the area of Nanomedicine.

There are three principal goals of drug deliveryresearch today: more specific drug delivery andtargeting; greater safety and biocompatibility; andfaster development of new, safe medicines. Toachieve these goals the current nanotechnologiesbeing applied to drug delivery and pharmaceuticalresearch include the following:

Nanotechnologies

• Supramolecular chemistry-Self assembling drug carriers and gene delivery systems

• Nanoparticles and nanocapsules • Antibody technologies • Polymer-drug conjugates • Polymer-protein and antibody conjugates • Nano-precipitation, nanocrystals • Emulsification technologies • Liposome technology • In situ polymerisation • Tissue engineering and repair • Dendrimer technologies • Molecular imprinting

In parallel to the technology development thereis a need to develop pharmaceutical formulationsthat can be conveniently administered to patientsand that display acceptable shelf-life stability.

Validated analytical techniques are also neededto confirm the identity, strength and stability ofcomplex nanomedicines. New chemical and physi-cal techniques must be developed during scaling-up.

During research and development molecularimaging techniques (e.g. AFM) are increasinglybeing used, and in vitro (e.g. caco-2 cells, blood brainbarrier models, and skin models) and in vivo modelsare being developed to understand better cellular andwhole-body pharmacokinetics. There is also a needto examine carefully pharmacokinetic and pharma-codynamic correlations to allow carefully design ofdrug targeting and controlled release systems.

In the near future, nanodrug delivery systems andpharmaceutical research have the potential tocontribute significantly to the furtherance of Nano-medicine. The key topics of investigation are:• vectors that will overcome the biological barriers

for effective gene delivery• cancer targeting• brain delivery• combination of the potential of antibody targeting

with nanoparticle and liposome technology.



Nanoscale objects, typically but not exclusively withdimensions smaller than 100 nm, smaller than200 nm for ultrafiltrable range and smaller than1 000 nm for dendrimers, exhibit fundamentallydifferent physical, chemical and biological proper-ties from those of the corresponding mass materials.These distinctive properties, together with thenanoscale size which is in the same scale of the natu-rally occurring biomolecules, promise revolutionarypotential applications in clinical practice. Nanomed-icines or nanopharmaceuticals may therefore bedefined as nanoscale material to be used for clinicaldiagnosis, treatment, and prevention of human disor-ders. Nanomedicine application depends on thestructures and mechanisms which are functionalonly on nanoscale-mediated macro-molecular andsupra-molecular assemblies.

In particular, the following areas were considered:

Technology Application

Nanopharmaceuticals Cancer– in current use or Antiviral agentsentering routine use Arteriosclerosisin the short-term future Chronic lung diseases(within 5 years) Diabetes

Nanopharmaceuticals Gene therapy– with potential clinical Tissue engineeringapplications in the longer Tissue/cell repairterm future (10 years)

Nanodevices Delivery of diagnostic and therapeutic agents

There are very strict regulations and approvalprocesses for any medicine (via regulatory agenciessuch as FDA, EMEA etc.) or any material proposedfor human use. It must undergo rigorous toxicologystudies as part of the regulatory approval process.However, the special properties of nano-objects thatare only exhibited at the nanoscale suggest thatnanopharmaceuticals may also require a new arrayof toxicological and safety tests. It was agreed thatnew strategies in toxicology for Nanomedicine mustgo hand-in-hand with the development of nanophar-maceuticals in order to ensure the safe yet swiftintroduction of nanomedicines to clinical use.

The toxicology of nanopharmaceuticals, nano-imaging agents and nanomaterials used in devicemanufacture should be considered during their entirelife cycle:• stages of production/manufacture• preclinical and clinical development (or for other

uses e.g. veterinary)• consumer and staff safety • waste management/fate in environment.

Although the nanopharmaceuticals that havealready entered routine clinical use have been rigor-ously tested with regard to safety, there have beencomparatively few toxicological studies publishedon nanopharmaceuticals. However, this issue needsto be explored, based on the large literature in thetoxicology field describing the effects of nanopar-ticles, either present in the environment as pollu-tants or made as a result of the industrial productionof non-medical and non-biological materials.

Europe has considerable experience in the clini-cal development of nanopharmaceuticals (particu-larly in cancer). Pre-clinical toxicology to ‘goodlaboratory practice’ (GLP) has assessed antibody-drug conjugates, polymer-drug conjugates andnanoparticle-based chemotherapy. During the devel-opment of novel anticancer treatments there isalways a careful evaluation of risk-benefit.

Since Europe has particular strengths in theresearch areas of toxicology of inhaled ambient oroccupational fine and ultrafine particles there is anexcellent opportunity to redress the current mismatchbetween studies on toxicology of nanomaterials andthose involved in research and development ofNanomedicine-related technologies.

As there seems to be enormous prospects for theapplication of nanotechnology in medicine, the Euro-pean Nanomedicine research community should actproactively to seize the opportunity to clearly definethe ground rules for the related toxicologicalresearch, and the related clinical and industrial devel-opment of these important technologies.

As yet there are no regulatory authority guide-

Toxicity Activity

Cancer Chemotherapy and Drug Targeting

Increased Therapeutic Index


lines specific to Nanomedicine. As the number ofnanopharmaceuticals increases there is a need toreview and define appropriate regulatory authorityguidelines directed towards each new class ofNanomedicine. It would be timely to produce ‘GoodClinical Practice’ (GCP) guidelines that may beapplied to the clinical development of specific fami-lies of drug delivery systems or therapeutics. Someexamples of well-established categories of pharma-ceuticals involving nano-objects are polymer-protein, polymer-drug conjugates and nanoparticle-associated chemotherapy. There may be specificclinical endpoints that are unique to these nanomed-icines, and there may also be specific issues relatingto good manufacturing practice (GMP) compliance.

Second generation nanopharmaceuticals arealready being, or will be, developed based on firstgeneration systems. An integrated strategy will bethe key for toxicological evaluation of new nano-materials that are emerging. There is a need for pre-clinical and clinical test standardisation and anevaluation of the environmental impact of thesesystems in the context of academic research andindustrial development. On a case by case basisthere is a need to define toxicokinetics, toxicoge-nomics, and toxicoproteomics. This field might bedefined as ‘Toxiconanomics’. This research effortshould be conducted by virtual networks of basicand applied scientists using existing expertise as astarting point. Industrial collaboration should beused to establish standard reference materials.

2.2. Research Strategy and Policy

2.2.1. Organisation and Funding

Workshop participants:Prof. Claus-Michael Lehr (chair), Prof. A.W. McCaskie (co-chair)Dr María José Alonso, Prof. Luc Balant, Dr Janna de Boer, Prof. Salvatore Cannistraro, Dr Rosita Cottone, Dr Nicole Déglon, Dr Franz Dettenwanger, Prof. Thomas Kissel, Prof. Helmuth Möhwald, Dr Mihail Pascu, Prof. Clemens Sorg, Dr Christoph Steinbach, Prof. Manuel Vázquez, Dr Petra Wolff

It was suggested that current funding mechanismsdo not adequately address the needs of Nanomedi-cine. The structure of programmes and the diversityof sources (e.g. European, national, regional andcharities) can obscure routes to funding. This isfurther limited by traditional borders between scien-tific disciplines; e.g. chemistry, physics, biology,medicine and engineering, which can effectivelyexclude transdiscipline and interface research. Inmany cases the funding opportunities are oftenrestricted by the requirement of an industrial part-ner. Moreover, selection criteria can often be politi-cal, rather than based on scientific excellence. Thefact that EU FP6 applications were channelled intomain themes of ‘Health’ or ‘Nanotechnology’ wasa contributory factor, leading to the ineffectivenessof FP6 to successfully support the stated Nanomed-icine objectives of this scheme. The possibility ofan EU Technology Platform in Nanomedicine wasnoted and welcomed.

It was noted that there is an opportunity toimprove communication/coordination between thedifferent funding agencies across Europe. There isa specific need to reflect the multidisciplinarynature of Nanomedicine in funding opportunitiespresented.

The funding opportunities available for basictechnological research must initially be available forpure academic groups without an underlyingrequirement of an industry partner. All calls forproposals and applications should encourage theappointment of multiple partners from differentdisciplines with internationally leading expertise.The evaluation of such multidisciplinary proposalsmust be undertaken by a multidisciplinary expertpanel using the same format used by the USNational Institutes of Health (NIH) study groups.Whilst the European networking instruments (e.g.COST, Network of Excellence etc.) are considered


helpful, in the future there must also be enoughfunding to undertake basic and applied Nanomedi-cine research (that is, for salaries, instruments, andconsumables).

Means to improve funding and organisation atthe level of political bodies, policy makers andnational organisations were identified. The funda-mental requirements to progress Nanomedicinequickly are more investment for Nanomedicine R& D, greater understanding of the complexities ofthis multidisciplinary area, and a higher priority forspecific technologies that will improve healthcarefor society in Europe.

Specific opportunities include:• Those aspects of Nanomedicine that have been

realised and transferred into practice today havearisen from previous basic research programmes.Universities should be able to pursue a more entre-preneurial freedom and spirit to increase inven-tiveness that will feed the future technologypipeline.

• Nanomedicine should be discussed in terms ofpharmacoeconomic value at an early stage withregulatory authorities, policy makers and health-care stakeholders.

• The potential of Nanomedicine to create not onlynew products, but also new jobs (socioeconomicvalue) needs to be appreciated.

• Public awareness about the opportunities and real-istic risks of Nanomedicine is necessary and canbe brought about by educational programmes.National support for Nanomedicine would beenhanced when action groups and patient-supportgroups are more aware of the benefits that thesetechnologies can already bring.

2.2.2. Commercial Exploitation

Workshop participants:Dr Julie Deacon (chair), Dr Oliver Bujok, Dr Françoise Charbit, Dr John Davies, Dr Sjaak Deckers, Dr Benoit Dubertret, Prof. Mike Eaton, Rainer Erdmann, Dr Arne Hengerer, Dr Corinne Mestais, Dr Pierre Puget, Dr Jürgen Schnekenburger, Prof. Csaba Szántay

Transferring the technologies arising from Nanomed-icine research into clinical reality and generatingcommercial value from research will rely on thegeneration of intellectual property, licensing, tech-nology transfer, and collaborative product develop-

ment involving both specialised small and mediumenterprises (SMEs) as well as larger companies. Toencourage rapid technology transfer there is a needto generate clusters or highly selected teams chosenfor personal excellence, and not to fragment resources.

Nanomedicine is particularly multidisciplinaryso there are many opportunities to cross-licencetechnologies; for example diagnostics and pharma-ceuticals. Joint ventures involving confidential R&Drelationships could be very successful, but with acomplex supply chain, the intellectual property port-folio needs careful management. Good communi-cation and project management skills are needed.

To be competitive and effective in commerciali-sation, speedy globalisation is imperative. Europeanfunding schemes often dictate the choice of part-ners. To be effective in Nanomedicine developmenta global perspective is needed involving growingpartnership with the USA and other funding agen-cies. To encourage the establishment of more effec-tive SMEs working in the Nanomedicine field, morefocused funding and a fast response to grant appli-cations are needed.

As Nanomedicine becomes fashionable, a goodunderstanding of the end user-supplier interface isvital. Companies that appreciate the medical needsand the practicalities of their technology will be bestplaced to commercialise. There is a need to promotemeetings and a technology directory to assist indus-try to network. However, Nanomedicine presents acomplex array of end-users. The medical doctors’wish list of technologies is not yet commerciallyvalidated. Large companies have a time horizon formarket entry that is too short for many new tech-nologies, while the activities of SMEs is often tooconfidential to allow wide discussion. This can makedialogue difficult. There is a real need to increaseconfidence in Nanomedicine technologies by losingthe hype and focusing resources to pick winners.

2.2.3. Interdisciplinary Education and Training

Workshop participants:Prof. Hans Oberleithner (chair), Prof. Robert Henderson (co-chair)Dr Patrick Boisseau, Dr Paul J. A. Borm, Dr Luc Delattre, Prof. Varban Ganev, Dr Peter Hinterdorfer, Prof. Jørgen Kjems, Dr T.H. Oosterkamp, Dr Andrea Ravasio, Dr Kristina Riehemann, Prof. Arto Urtti, Dr Peter Venturini, Prof. Ernst Wagner, Dr Jaap Wilting


The standard of university education in Europe, inphysics, chemistry, biology, pharmacy and medi-cine, to master’s level, is very high. It was noted thatspecific Nanomedicine training should be developedrapidly to provide an educated workforce andresearchers to support this rapidly growing field.New programmes providing education and trainingin Nanomedicine should encourage interdiscipli-narity. master’s courses, or early postgraduatemedical or scientific training should be developedwith a focus on Nanomedicine.

In recent years there has been a reduction in thebasic science component of undergraduate medicaldegrees. Although this may be appropriate for manyclinicians, there is a danger that there will be ashortfall in the number of clinician-scientists. Theseare the very people needed to support the transferof Nanomedicine into routine clinical practice.Widespread adoption of MD/PhD degreeprogrammes, with some provision for nanosciencetraining, should be encouraged to provide corescientific training for clinicians. In addition, newfunding is needed to support the introduction ofsuch courses, and also for postgraduate clinicaltraining in nanoscience.

In Europe, training in different scientific disci-plines is currently highly focused, which is a greatstrength. However, this presents the danger of indi-viduals lacking knowledge outside their own field,possibly preventing productive communicationacross disciplines. It was proposed that formal inter-disciplinary training programmes should be insti-tuted, focusing on basic scientific topics; forexample molecular biology, colloidal chemistry, cellphysiology, surface chemistry, and membranebiophysics.

Several European Centres of Excellence shouldbe established (possibly relating to the sub-disci-plines of Nanomedicine) to provide an interdisci-plinary environment in which participants can‘speak the same language’, thus helping to bridgethe gap between chemical, physical and biomedicalscientists. This would provide the infrastructure fordirect interactions between scientists, clinicians andentrepreneurs; e.g. ‘Nanomedicine Centres’. Suchcentres could also be used to provide structures forundergraduate courses that encourage an interdisci-plinary frame of mind and allow establishment ofErasmus-type programmes for Nanomedicine.

Importantly, both academic scientists and clini-cians should have the opportunity and training tohelp them identify methods for commercialexploitation of their work.

2.2.4. Communication

Workshop participants:Dr Ottila Saxl (chair), Prof. Ruth Duncan, Prof. Harm-Anton Klok, Dr Valérie Lefèvre-Seguin,Dr Mihail Pascu, Prof. Helmut Ringsdorf.

Communication issues were discussed in relationto: (i) difficulties in communication within themultidisciplinary scientific environment; (ii)communication between the scientists and thepolicy makers; and importantly (iii) the perceptionof the general public.

In general, government departments, researchministries and university faculties continue to oper-ate in separate compartments. A paradigm shift inthe way of operation is needed. Otherwise there isno doubt that Europe will lose out in developing aleading position in Nanomedicine, an area thatdemands a multidisciplinary approach. This will beexacerbated by the emphasis on converging tech-nologies in FP7 as the basis of future products.

A major barrier to collaboration is the lack ofunderstanding between scientists of different disci-plines. This needs to be addressed by the establish-ment of more truly transdisciplinary research groupsand more truly transdisciplinary conferences andworkshops. The creation of transdisciplinary goal-driven ‘clusters’, virtual centres and ‘poles’ shouldalso be actively encouraged. Partnerships should beencouraged between large medical centres anduniversity research groups, leading to goal-orientedresearch. Transdisciplinary meetings should be heldwithin medical centres and sponsored by a medicalleader. This could be facilitated through availableinstruments at the European level. Additionally, thenumbers of transdisciplinary PhDs should beincreased, as well as transdisciplinary exchanges atevery level – from secondary to tertiary.

The benefits and the threats of Nanomedicineneed to be clearly articulated to the politicians andpolicy makers. Benefits include employment poten-tial and the ability to meet the needs of the ageingpopulation. Threats include losing out on importanteconomic opportunities and not meeting the aims ofthe Lisbon agenda. Serious consideration needs tobe also given to lobbying politicians by opinionleaders in the Nanomedicine world. There is also alack of scientifically qualified politicians, andcommunication problems have already resulted ina lack of alignment of the regional programmes, thenational programmes and the EU programmes.

In the recent past, many top quality transdisci-plinary projects and/or papers have not been recog-


nised as such, as the reviewers lack the necessaryknowledge. Failure to recognise the significance ofour success in multidisciplinary activities has been agreat loss to European scientific growth. One wayforward is that the national and European fundingagencies that provide funds and who audit researchoutput take a lead in pushing for equal weightingfor 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 thewell-established nanoimages are figments of theimagination of Hollywood-inspired artists. Secondly,it suits sensation-seeking journalists to comparenanotechnology with the already discredited geneti-cally modified organisms (GMO) technology. Thefact that nanotechnology is such a broad area –covering most if not all areas of technological devel-opment, and particularly in the context of the pres-ent argument – can make the term Nanomedicinealmost 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 realbenefits that people understand: better diagnostics,smaller doses, fewer side-effects, disease targetedtherapy, better efficacy, etc.

The media must be handled intelligently andwith caution. And there could be a benefit in provid-ing them with carefully constructed ‘copy’ inadvance of any new development. Individuals whohave to interact with the press should receive specialtraining. It was also considered important toimprove the breadth of communication; throughpossibly organising thematic meetings aimed atinforming focus groups. Nanomedicine awareness-raising activities need public funding (at all levels)in order to ensure a continued dialogue with allstakeholders.

25

3. European Situation and Forward Look – SWOT Analysis

• The diversity of funding sourcesprovides a wide range of fundingopportunities

• The strongeducational base inEurope and trainingstyle

• Europeanprogrammes such asthe EU Marie-Curiescheme and the ESFtraining coursesprovide good trainingopportunities althoughmore focus should beput on Nanotechnologyin Medicine

• There are manyleading academicgroups in the sub-disciplines ofNanomedicine

• There are alreadyseveral major Europeanclusters and Centres ofExcellence in the Fieldof Nanomedicine

• Potential exists to rapidly expandNanomedicine R & D

• Visionary institutionssuch as the New DrugDevelopment Officeand Cancer ResearchUK have facilitatedearly phase cancerclinical trials andsupported translationalactivities, especially for innovative nano-pharmaceuticals

• There are a numberof world leadingEuropean companies inimaging/contrast agentand nano-pharmaceuticals areas

• There are a numberof SMEs working in the technology and pharmaceutical areas relating to Nanomedicine

• Ongoingstandardisation effortsat the EuropeanMedicines Agency for the Evaluation of Medical Products(EMEA)

• Molecular and clinical imaging techniques, andcontrast agent researchand development areparticular strengths

• Existing expertise in drug deliveryresearch and theclinical development ofnanopharmaceuticals

• Strong basic sciences,particularly in - antibody

technologies- nanoparticle

technologies- polymer therapeutics- gene delivery systems- biological models for

cell and tissue-basedin vitro screening

• Leading researchgroups in ultrafineparticle toxicology

Strengths

Funding andStrategic Issues

Academic Researchand Education

Environment for Research and Development

CommercialExploitation

Technology

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

3. EUROPEAN SITUATION AND FORWARD LOOK – SWOT ANALYSIS26

• EU programmeslack long-termstrategy as it changesevery 5 years.Nanomedicineresearch needs both ashort-and a long-termstrategy.

• Low funding ratesand complexadministrativeprocedures have beenproblems associatedwith FP6

• FP6 has not beeneffective forsupporting researchand development ofNanomedicine

• Too little funding for application-oriented andtranslational research

• Lack of acoordinated EuropeanResearch Council ableto allocate fundingbased only onexcellence without apolitical agenda

• Insufficient integrationof clinical research

• Too much replicationof R&D efforts inuniversities and incompanies acrossEurope

• The size of manynanotechnologyregional clusters andmedical researchcentres is too small

• Small clusters oftenlack adequate funding

• Specific guidelines,regulations and testprotocols forNanomedicine are stillawaiting to bedeveloped

• Compared to theUSA and Asia:requirement of ethicalapproval for manyaspects of Nano-medicine research are more demanding

• Recent change inclinical trial regulations(new EU directive) willdelay clinical trials fornanopharmaceuticals,particularly in cancer

• Inefficient translationof concept to productbecause of inadequateventure capital,excessive bureaucracyand lack of medicalinput

• Interaction with thenumerous regulatoryauthorities,(fragmentation) anddifferences inregulations can deterthose consideringproduct development

• Lack of ability tointeract with regulatingagencies at theinvestigational newdrug (IND) stage whendeveloping newtechnologies, comparedwith USA

• Inadequate industrialinvestment in long-term(or basic) research andrelatively fewcompanies to cooperatewith or assist withcommercialisation

• Ineffectiveorganisation of the health system andinadequate provision of accredited labs canlimit options for clinicalresearch anddevelopment in the fieldof Nanomedicine

• Interfacing clinicalmedicine and basicresearch

• Interfacing basicbiological sciences and materials sciences

• Lack of competitiveedge in chip-basedtechnologies

Weaknesses





Technology

3. EUROPEAN SITUATION AND FORWARD LOOK – SWOT ANALYSIS 27

• Identification ofNanomedicine as akey area for fundingin FP7. Explicitlyremoving the dividebetween Health andNanotechnology

• Improved healthcarefor European citizens

• Establish Networksof Excellence in thesub-disciplines ofNanomedicine viacoordination ofrecognised leadingedge researchers andcompanies

• At the Europeanand National levelestablish well definedgoal orientedNanomedicinefocused projectsbuilding on specifictechnical expertise

• European coursesintegrating thebiological and physicalsciences towardnanoscience,nanobiology, and mostimportantlynanotechnologyapplied to medicine

• Via new educationprogrammes establish atechnically skilledworkforce able toaddress the challengesof Nanomedicineresearch anddevelopment

• Better use of humanresources e.g. well-educated peoplecoming from EasternEurope

• Increasedcollaborations betweenEuropean companies(e.g. imaging andpharmaceutical) andacademic institutions

• Establish enhancedjob opportunities and acompetitiveinternational position inNanomedicine

• Proactive riskmanagement with animmediate feed back toNanomedicinedevelopment at theearliest time point

• Better exploitation of innovation at theEuropean level througheasier access to venturecapital, better dialoguewith regulatory agenciesand governmentsupport for R & D in Nanomedicine.Accelerate Nano-medicine research from lab to clinic andthen the market

• Move towards costeffective patient-individualisedtreatments, and point ofcare diagnostics

• Use experience withfirst generationanticancernanopharmaceuticals torapidly develop secondgeneration medicineswith increasedspecificity with lesstoxic side effects for awider range of targetdiseases

• Reduced health costsby earlier detection ofpredisposition allowinguse of preventativeintervention, and moreeffective monitoring ofchronic illness leadingto improved therapy

• Development of a new generation ofnanosized materialsand devices that can be used as a tool kit

• Design of innovativediagnostics andbiosensors

• Design ofnanopharmaceuticalsand implantabledevices for improveddrug delivery

• Design of vectorsable to - assist drugs to betterreach their target(transferring across biologicalbarriers)- ensure biotech drugsreach their intracellulartargets

• Development of nanomaterials ableto control biologicalsignalling and providea biomolecular displayfor tissue engineeringand to promote tissuerepair

Opportunities





Technology

3. EUROPEAN SITUATION AND FORWARD LOOK – SWOT ANALYSIS28

• EU and/or nationalbureaucracy limitingthe best use of funding for researchand innovation

• Continuedfragmentation of efforts in theNanomedicine field,particularly economic,political, andregulatory aspects

• Discrepanciesbetween promises and facts in funding

• Negative public andpolitical perception. A different perceptionby the public on risksof the use ofnanopharmaceuticalswas noted, comparedto the uses ofnanotechnology in hi-tech products; e.g. computers andmobile telephones

• Failure to respondquickly to the need formore multidisciplinarytraining targeted atNanomedicine, leadingto Inadequately trainedworkforce

• Increasing lack of science(under)graduates

• Too many youngresearchers leavingEurope, particularly toUSA via brain-drain

• Researchersbecoming unwilling to take on high riskprojects because of theneed to generate data(success) for subsequentproject evaluation

• Continued erosion ofthe Europeanpharmaceuticalindustry

• Pharmaceuticalcompaniesconcentrating theirresearch outsideEurope

• Overregulation and inadequatefunding for smallcompanies

• Difficulties inmanaging intellectualproperty with manydifferent national patentorganisations. Poorlycapitalised companiescan lose theirintellectual propertybase

• Inability to securesufficient funding (andtime) to commercialiseinnovative products

• Lack of scientificdissemination and truly interdisciplinaryexchange in the field of Nanomedicine

• Mismatch betweenstudies on toxicology of nanomaterials and Nanomedicineresearchers in certainsub-disciplines

• Failure to considerthe environmentalimpact of new materials

• Failure to considerthe safety of newmaterials in respect ofproposed applications

• Lack of a balancedunderstanding of the risk-benefit ofNanomedicine-relatedproducts in their manyforms and applications

Threats





Technology

29

4.1 General Recommendations

4.1.1. Priority areas in Nanomedicine for the next 5 years• Engineering technology for immobilising cells or

molecules on surfaces• Programmes to generate reproducible and reliable

platforms integrating micro- and nanotechnologies• Methods to deposit such platforms and such

components • Proactive risk management with an immediate

feedback to Nanomedicine development• Clinical applications• Development of satisfactory sensitivity of in vivo

methods• Developing of non-invasive in vivo diagnostic

systems• Implantable or injectable parenteral nanodevices

for diagnosis and therapy

4.1.2. Priority areas in Nanomedicine for the next 10 years• Understanding of the cell as a 3D complex system• Bioanalytical methods for single-molecule analy-

sis• Nanosensing of multiple, complicated analytics

for in vitro measurement of biochemical, genomicand proteomic networks, their dynamics and theirregulation

• Nanosensing in vivo with telemetrically controlled,functional, mobile sensors

• Rapid fingerprinting of all components in bloodsamples

4.1.3. Commercial Exploitation• European seed funds for nanotechnology applied

to medicine• Intellectual Property management• Improved interactions with the EU regulatory

system to promote rapid commercialisation ofinnovation

• Establishing incubators for innovative companiesin nanomedical applications

• New reference organisation (such as EMBO) innanobiotechnolgy/nanomedicine possibly withprestigious positions, scientific excellence, visi-

bility, and own journal• Support to clusters for internal cooperation and

European coordination

4.1.4. Interdisciplinary Education and Training• Trained people for technology management and

transfer (PhD + MBA)• Tailored education on management for scientists• Fellowships to support academics gaining experi-

ence in industry• Multidisciplinary training• Fellowships for complementary education for

scientists

4.2. Scientific Trends

4.2.1. Nanomaterials and NanodevicesGeneral directions should be:• optimisation of existing technologies to specific

Nanomedicine challenges• development of new multifunctional, spatially

ordered, architecturally varied systems for targeteddrug delivery

• enhancement of expertise in scale-up manufacture,characterisation, reproducibility, quality control,and cost-effectiveness

Specific directions should be:• new materials for sensing of multiple, complicated

analytes for in vitro measurement• new materials for clinical applications such as

tissue engineering, regenerative medicine and 3Ddisplay of multiple biomolecular signals

• telemetrically controlled, functional, mobile invivo sensors and devices

• construction of multifunctional, spatially ordered,architecturally varied systems for diagnosis andcombined drug delivery (theranostics)

• advancement of bioanalytical methods for single-molecule analysis

4.2.2. Nanoimaging and Analytical ToolsSpecific developments should include:short term• use and refinement of existing nanotechniques in

normal and pathological tissues for the under-

4. Recommendations and Suggested Actions

4. RECOMMENDATIONS AND SUGGESTED ACTIONS30

standing of initiation and progression of disease• development of novel nanotechniques for moni-

toring in real time cellular and molecular processesin vivo and for molecular imaging to study patho-logical processes in vivo, with improved sensitiv-ity and resolution

• identification of new biological targets for imag-ing, analytical tools and therapy

• translation of research based on molecular imag-ing using nanoscale tools from animal models toclinical applications

• closing of the gap between the molecular andcellular technologies and the clinical diagnosticnanotechnologies

Specific developments should include:longer term• development of a multimodal approach for nano-

imaging technologies• design of non-invasive in vivo analytical nanotools

with high reproducibility, sensitivity and reliabilityfor use in pre-symptom disease warning signal,simultaneous detection of several molecules,analysis of all sub-cellular components at themolecular level, and replacement of antibodies asdetection reagents by other analytical techniques

4.2.3. Novel Therapeutics and Drug DeliverySystemsSpecific developments should include:short term• application of nanotechnology to develop multi-

functional structured materials with targeting capa-bilities or functionalities allowing transport acrossbiological barriers

• nanostructured scaffolds (tissue engineering),stimuli-sensitive devices and physically targetedtreatments

• a focus on cancer, neurodegenerative and cardio-vascular diseases and on local-regional delivery(pulmonary/ocular/skin)

Specific developments should include:longer term• a synthetic, bioresponsive systems for intracellu-

lar delivery of macromolecular therapeutics andbioresponsive/self-regulated delivery systems(smart nanostructures such as biosensors coupledto delivery systems)

4.2.4. Clinical Applications and RegulatoryIssuesGeneral directions should be:• disease-oriented focus for Nanomedicine devel-

opment in specific clinical applications

• case-by-case approach for clinical and regulatoryevaluation of Nanomedicines

• highly prioritised communication and exchange ofinformation among academia, industry and regu-latory agencies with a multidisciplinary approach

4.2.5. ToxicologyGeneral directions should be:• improved understanding of toxicological implica-

tions of nanomedicines in relation to material prop-erties and proposed use by the potentially predis-posed, susceptible patient

• thorough consideration of the potential environ-mental impact, manufacturing processes and ulti-mate clinical applications in toxicological investi-gations for nanomedicines

• risk-benefit assessment for both acute and long-term effects of nanomedicines with special consid-eration on the nature of the target disease

• a shift from risk assessment to proactive riskmanagement at the earliest stage of new nanomed-icines discovery and development

4.3. Research Strategy and Policy

4.3.1. Organisation and FundingRecommendations• improved coordination and networking of research

activities and diverse range of funding sources atthe European, national and regional levels

• creation of new Nanomedicine-targeted fundingschemes to better facilitate both transdisciplinaryand interface research that is critical for success inNanomedicine

• establishment of European Centres of Excellencein the field of Nanomedicine

• modification of funding mechanisms for basictechnological research to permit academic-group-only applications

• development of funding procedures with sufficientscale and scope; for example with longer termfunding rather than continuous short-term fundingcycles, to enable research for seriously tacklinggoal-oriented problems

• establishment of economic and social benefits ofNanomedicine and communication of them tostakeholders and the public

Suggested Action• coordinated funding of basic research in Nano-

medicine through ESF EUROCORES and Euro-pean Commission FP7 instruments (e.g. ERA-Net)

4. RECOMMENDATIONS AND SUGGESTED ACTIONS 31

4.3.2. Commercial ExploitationRecommendations• establishment of a scheme supporting academic/

commercial ventures, such as a European versionof the Small Business Innovative Research programof the US National Institutes of Health

• involvement of clusters or highly selected teams,chosen for personal excellence or track record

• establishment of more manufacturing sites with‘Good Manufacturing Practice’ designation tosupport small and medium enterprises for trans-ferring projects more rapidly into clinical devel-opment

Suggested Actions• liaise with regulatory authority for Good Manu-

facture Practice designation• conduct policy study on the feasibility for a

European Small Business Innovative Researchprogramme

4.3.3. Interdisciplinary Education and TrainingRecommendations• establishment of formal interdisciplinary training

courses, mainly at the undergraduate level, cover-ing basic scientific disciplines such as molecularbiology, colloidal chemistry, cell physiology,surface chemistry, and membrane biophysics

• institution of new programmes, at master’s or earlypostgraduate level (with combined medical andscientific training), to support the rapidly devel-oping field of Nanomedicine

• encouragement of more interdisciplinary MD/PhDdegree programmes, with some provision fornanoscience, to provide core scientific training forboth scientists and clinicians in the longer term

Suggested Action• facilitate the establishment of interdisciplinary train-

ing courses, masters and MD/PhD programmes viaESF networking instrument (a la carte Programme),COST and European Commission instruments (e.g.Network of Excellence)

4.3.4. CommunicationRecommendations• promotion of more truly transdisciplinary confer-

ences focusing on the specific themes of Nano-medicine to facilitate better communicationbetween research disciplines

• encouragement of goal-oriented research partner-ships between large medical centres and univer-sity research groups

• clearer articulation and better communication ofthe benefits of embracing Nanomedicine and the

threats from inaction: the benefits consisting ofemployment potential and meeting the medicalneeds of the ageing population; and the threatsincluding missed economic opportunities

• engagement of the scientific community in regu-lar dialogue with the general public in order todiscover likely public concerns early, and contin-uation of dialogue to address and alleviate publicconcerns by the presentation of clear facts

• supply of non-specialist information on potentialbenefits of Nanomedicine to the general public ina timely fashion, with the emphasis on the fact thatNanomedicine is based on mimicking the eleganceof nature

Suggested Actions• organise truly transdisciplinary conferences using

the ESF Research Conference scheme or relatedschemes at the European Commission

• set up a communication entity, possibly in theform of a small enterprise, to report scientific find-ings and innovation to the public.

32

5. Bibliography

5.1. Key Reports onNanotechnology and Nanomedicine

• Baseline Scenarios for the Clean Air for Europe (CAFE)Programme (2004) International Institute for AppliedSystems Analysis, Laxenburg, Austria,www.iiasa.ac.at

• BECON Nanoscience and Nanotechnology:ShapingBiomedical Research (Symposium Report) (2000)National Institutes of Health, BioengineeringConsortiumhttp://grants.nih.gov/grants/becon/beconsymposia.htm

• Cancer NANOTECHNOLOGY PLAN:A strategic initiative to transform clinical oncology and basic research through the directed application of nanotechnology NCI, NIH, USA (2004)(http://nano.cancer.gov/alliance_cancer_nanotechnology_plan.pdf)report

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• European Science Foundation Policy Briefing, ESFScientific Forward Look on Nanomedicine (2005)www.esf.org

• Health Aspects of Air Pollution with Particulate Matter,Ozone and Nitrogen Dioxide (2003) WHO workinggroup, www.who.int/en/

• Industrial Application of Nanomaterials and Risks –chances and risks (2004). Technology analysis carriedout by VDI technologies division with support by theFederal Ministry of Education and Research (BMBF),Germany. www.bmbf.de

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• Nanotechnology: prospects and pitfalls,and Nanotechnology, Small matters many unknowns,a risk perception, Swiss Re (2004).publications.swissre.com

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• Small Dimension and Material Properties:A Definition of Nanotechnology by G. Schmid,M. Decker, H. Ernst, H. Fuchs, W. Grünwald,A. Grunwald, H. Hofmann, M. Mayor,W. Rathgeber, U. Simon, D. Wyrwa. Publisher:Europäische Akademie November (2003)http://www.europaeische-akademie-aw.de/pages/publikationen/graue_reihe.php

• Technology Platform on NanoMedicine Nanotechnologyfor Health. Vision Paper and Basis for a StrategicResearch Agenda for NanoMedicine (2005) inpreparation

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5.2. Key Literature onNanotechnology relating toMedicine

Selected references showing ongoing efforts in the area of “Nanomedicine”. This is not meant to be a comprehensive list.

General

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• M. Ferrari (2005) Cancer Nanotechnology: opportunitiesand challenges. Nature Reviews Cancer, 5, 161-171.

Analytical Tools and Sensors

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• M.C. Frost, M.E Meyerhoff (2002) Implantablechemical sensors for real-time clinical monitoring:progress and challenges. Current Opinion in ChemicalBiology, 6, 633-641.

• P.L.T.M. Frederix, T. Akiyamay, U. Staufery,Ch. Gerberz, D. Fotiadis, D.J. Muller, A. Engel (2003)Atomic force bio-analytics. Current Opinion inChemical Biology, 7, 641-647.

• N. Winegarden (2003) Commentary - Microarrays incancer: moving from hype to clinical reality. TheLancet, 362, 1428.

Imaging: from Molecules to Man

• M. Bohmer, J. Enderlein (2003) Fluorescencespectroscopy of single molecules under ambientconditions: Methodology and technology.ChemPhysChem, 4, 792-808.

• A. Engel and D. J. Müller (2000) Observing singlebiomolecules at work with the atomic force microscope.Nature Structural Biology, 7, 715-718.

• M. Dahan, S. Levi, C. Luccardini, P. Rostaing,B. Riveau, A. Triller (2003) Diffusion dynamics ofglycine receptors revealed by single–quantum dottracking. Science, 302, 442-445.

• Y.F. Dufrene (2003) Recent progress in the applicationof atomic force microscopy imaging and forcespectroscopy to microbiology. Current Opinion inMicrobiology, 6, 317–323.

• P. Hinterdorfer, W. Baumgartner, H.J. Gruber,K. Schilcher, H. Schindler (1996) Detection andlocalization of individual antibody-antigen recognitionevents by atomic force microscopy (ligand-receptorinteractionyhuman serum albumin-imaging-crosslinker).Proceedings of the National Academy of Sciences USA,93, 3477-3481.

• J.K.H. Horber, M.J. Miles (2003) Scanning ProbeEvolution in Biology. Science, 302, 1002-1005.

• Schafer, V. Shahin, L. Albermann, M.J. Hug,J. Reinhardt, H. Schillers, S. W. Schneider,H. Oberleithner (2002) Aldosterone signaling pathwayacross the nuclear envelope. Proceedings of theNational Academy of Sciences USA, 99, 7154-7159.

• G.J. Schultz, P. Hinterdorfer (2002) Single moleculefluorescence and force microscopy. ExperimentalGerontology, 37, 1493-1509.

• R. Weissleder, U. Mahmood (2001) Molecular Imaging.Radiology, 333, 219:316.

• R. Weissleder (2002) Scaling down imaging: molecularmapping of cancer in mice. Nature Reviews Cancer,2, 1-8.

Nanomaterials and Nanodevices

• F. Aulenta, W. Hayes, S. Rannard (2003) Dendrimers:a new class of nanoscopic containers and deliverydevices. European Polymer Journal, 39, 1741-1771.

• C.C. Berry, A.S.G. Curtis (2003) Functionalisation ofmagnetic nanoparticles for applications in biomedicine.Journal of Physics D-Applied Physics, 36, R198-R206.

• C.R. Martin, P. Kohli (2002) The emerging field ofnanotube biotechnology. Nature Reviews DrugDiscovery, 2, 29-37.

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Drug, Protein and Gene Delivery

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• R. Duncan (2003) The dawning era of polymertherapeutics. Nature Reviews Drug Discovery,2, 347-360.

• R. Duncan, L. Izzo (2005) Dendrimer biocompatibilityand toxicity. Advanced Drug Delivery Reviews, in press.

• A. Gabizon , H. Shmeeda, A.T. Horowitz, S.A. Zalipsky(2004) Tumor cell targeting of liposome-entrappeddrugs with phospholipid-anchored folic acid-PEGconjugates. Advanced Drug Delivery Reviews 56,1177-1192.

• K. Greish, J. Fang, T. Inutsuka, A. Nagamitsu, H. Maeda(2003) Macromolecular therapeutics: Advantages andprospects with special emphasis on solid tumourtargeting. Clinical Pharmacokinetics, 42, 1089-1105.

• J.M. Harris, R.B. Chess (2003) Effect of Pegylation onpharmaceuticals. Nature Reviews Drug Discovery,2, 214-221.

• A. Kichler (2004) Gene transfer with modifiedpolyethylenimines. The Journal of Gene Medicine,6, S3-S10.

• M.N.V.R. Kumar, M. Sameti, C. Kneuer, A. Lamprecht,C.-M. Lehr (2003) Polymeric Nanoparticles for Drugand Gene Delivery. Encyclopedia of Nanoscience andNanotechnology (Edited by H. S. Nalwa), Vol. X,pp. 1-19.

• P.S. Low, A.C. Anthony (2004) Folate receptor-targeteddrugs for cancer and inflammatory diseases. AdvancedDrug Delivery Reviews, 56, 1055-1058.

• T. Merdan, J. Kopecek, T. Kissel (2002) Prospects forcationic polymers in gene and oligonucleotide therapyagainst cancer. Advanced Drug Delivery Reviews,54, 715-758.

• S.M. Moghimi, A.C. Hunter, J.C. Murray (2005)Nanomedicine: current status and future prospects.The FASEB Journal, 19, 311-330.

• G.J. Nabel (2004) Genetic, cellular and immuneapproaches to disease therapy: past and future. NatureMedicine, 10, 135-141.

• D.W. Pack, A.S. Hoffman, S. Pun, P. S. Stayton (2005)Design and development of polymers for gene delivery.Nature Reviews Drug Discovery, 4, 581-593.

• A.C. Richards Grayson, I.S. Choi, B.M. Tyler,P.P. Wang, H. Brem, M.J. Cima, R. Langer (2003)Multi-pulse drug delivery from a resorbable polymericmicrochip device. Nature Materials, 2, 767-772.

• V. P. Torchilin (2005) Recent advances with liposomesas pharmaceutical carriers. Nature Reviews DrugDiscovery, 4, 145-160.

• J. K. Vasir, M. K. Reddy and V. D. Labhasetwar1 (2005)Nanosystems in drug targeting: Opportunities andchallenges. Current Nanoscience, 1, 47-64.

• Vauthier, C. Dubernet, E. Fattal, H. Pinto-Alphandary,P. Couvreur (2003) Poly(alkylcyanoacrylates) asbiodegradable materials for biomedical applications.Advanced Drug Delivery Reviews, 55, 519-548.

• E. Wagner (2004) Strategies to improve DNApolyplexes for in vivo gene transfer: Will ‘artificialviruses’ be the answer? Pharmaceutical Research, 21,8-14.

Applications in Tissue Engineering

• D.F. Emerich, C.G. Thanos (2003) Nanotechnology andmedicine. Expert Opinion on Biological Therapy,3, 655-663.

• T. Kubik, K. Bogunia-Kubik, M. Sugisaka (2005)Nanotechnology on duty in medical applications.Current Pharmaceutical Biotechnology, 6, 17-33.

• Z. Ma, M. Kotaki, R. Inai, S. Ramakrishna (2005)Potential of nanofiber matrix as tissue-engineeringscaffolds. Tissue Engineering, 11, 101-109.

• I. Martin, D. Wendt, M. Heberer (2004) The role ofbioreactors in tissue engineering. Trends inBiotechnology 22, 80-86.

• L.S. Nair, S. Bhattacharyya, C.T. Laurencin (2004)Development of novel tissue engineering scaffolds viaelectrospinning. Expert Opinion on Biological Therapy,4, 659-668.

• Y. Narita, K. Hata, H. Kagami, A. Usui, M. Ueda,Y. Ueda (2004) Novel pulse duplicating bioreactorsystem for tissue-engineered vascular construct. TissueEngineering, 10, 1224-3123.

5. BIBLIOGRAPHY 35

• K.C. Popat, E.E. Leary Swan, V. Mukhatyar,K.I. Chatvanichkul, G.K. Mor, C.A. Grimes, T.A. Desai(2005) Influence of nanoporous alumina membranes onlong-term osteoblast response. Biomaterials, 26,4516-4522.

• H. Shen, J. Tan, W.M. Saltzman (2004) Surface-mediated gene transfer from nanocomposites ofcontrolled texture. Nature Materials, 3, 569-574.

• M. Shin, O. Ishii, T. Sueda, J.P. Vacanti (2004)Contractile cardiac grafts using a novel nanofibrousmesh. Biomaterials, 25, 3717-3723.

• L.A. Smith, P.X. Ma (2004) Nano-fibrous scaffolds fortissue engineering. Colloids and Surfaces. B, Biointerfaces, 10, 125-131.

• Y. Tabata (2005) Nanomaterials of drug deliverysystems for tissue regeneration. Methods in MolecularBiology, 300, 81-100.

• C. Williams, T.M. Wick (2004) Perfusion bioreactor forsmall diameter tissue-engineered arteries. TissueEngineering, 10, 930-941.

• E.K. Yim, R.M. Reano, S.W. Pang, A.F. Yee, C.S. Chen,K.W. Leong (2005) Nanopattern-induced changes inmorphology and motility of smooth muscle cells.Biomaterials, 26, 5405-5413.

• S. Zhang (2003) Fabrication of novel biomaterialsthrough molecular self-assembly. Nature Biotechnology,21, 1171-1178.

Clinical, Regulatory and Toxicological Aspects

• P.J.A. Borm (2002) Particle toxicology: From coalmining to nanotechnology. Inhalation Toxicology,14, 311-324.

• P.J. Borm, W. Kreyling (2004) Toxicological hazards ofinhaled nanoparticles–potential implications for drugdelivery. Journal of Nanoscience and Nanotechnology,4, 521-531.

• V.L. Colvin (2003) The potential environmental impactof nanomaterials. Nature Biotechnology, 10, 1166-1170.

• R.D. Brook, B. Franklin, W. Cascio, Y. Hong,G. Howard, M. Lipsett, R. Luepker, M. Mittleman,J. Samet, S. C. Smith, Jr., I. Tager (2004) Air pollutionand cardiovascular disease: a statement for healthcareprofessionals from the Expert Panel on Population andPrevention Science of the American Heart Association.Circulation, 109, 2655-71.

• K. Donaldson, V. Stone, C. L. Tran, W. Kreyling,P. J. Borm (2004) Nanotoxicology. Occupational andEnvironmental Medicine, 61, 727-728.

• K. Donaldson, D. Brown, A. Clouter, R. Duffin,W. MacNee, L. Renwick, L. Tran, V. Stone (2002) The pulmonary toxicology of ultrafine particles. Journalof Aerosol Medicine, 15, 213-20.

• R. Duncan (2003) Polymer-Drug Conjugates. In:Handbook of Anticancer Drug Development, (Eds. D.Budman, H. Calvert, and E. Rowinsky), Lippincott,Williams & Wilkins, Philadelphia. pp 239-260.

• A. Gabizon, H. Shmeeda, Y. Barenholz (2003)Pharmacokinetics of Pegylated liposomal doxorubicin.Review of animal and human studies. ClinicalPharmacokinetics, 42, 419-436.

• W. Kreyling, M. Semmler, M. Moller (2004). Dosimetryand toxicology of ultrafine particles. Journal of AerosolMedicine, 17, 140-52.

• G. Oberdorster, E. Oberdorster, J. Oberdorster (2005)Nanotoxicology: an emerging discipline evolving fromstudies of ultrafine particles. Environmental HealthPerspectives, 113, 823-839.

• J.W. Park, C.C. Benz, F.J. Martin (2004) Futuredirections of liposome- and immunoliposome-basedcancer therapeutics. Seminars in Oncology, 31, 96-205.

5.3. Websites and GeneralInformation

It should be noted that many web sites containrelevant information but they are not necessarilydesignated “Nano”

• The world service for nanotechnology nanotechweb.org

• News.Nanoapex.com is one of the best nanotechnologynews services on the web news.nanoapex.com/

• Científica – the nanobusiness companyhttp://www.cientifica.com/

• Nanotechnology news at Chemical & Engineering NewsChemical & Engineering News - Nanotechnology

• European Nanotechnology Gatewayhttp://www.nanoforum.org/

• iNanowebsite containing links to several companies andinstitutions that could be helpful in the start-up phase of new companieshttp://www.inano.dk/sw179.asp

• Pronano Swedish site for the promotion of nanotechnology in industryhttp://www.pronano.se/

• The Institute of Nanotechnology provides news andbackground information on new developments in nanosciencewww.nano.org.uk

5. BIBLIOGRAPHY36

• Nanotechnology database, at Loyola College, Maryland,USAitri.loyola.edu/nanobase/

• The Foresight Institutewww.foresight.org/NanoRev/index.html

• Nanonordicwww.nanonordic.com/extra/page/

• The Royal Society: Nanotechnology and Nanosciencehttp://www.nanotec.org.uk/

Journals

It should be also noted that many journals contain relevant information but they are notnecessarily designated “Nano”.

• IEE Proceedings Nanobiotechnologywww.iee.org/proceedings/nbt

• For the latest articles in nanoscience andnanotechnology, visit the AIP/APS Virtual Journal ofNanoscale Science and Technology www.vjnano.org

• Chemical & Engineering News, October 16, 2000:Nanotechnologypubs.acs.org/cen/nanotechnology/7842/7842nanotechnology.html

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

• Nanotechnology focuses on the interdisciplinaryapproach to nanoscale sciencewww.iop.org/EJ/S/3/354/journal/0957-4484

• Scientific American : Nanotechnologyhttp://www.sciam.com/nanotech/www.sciam.com/nanotech

• International Journal of Nanomedicinehttp://www.dovepress.com/IJN.htm

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

• Particle and Fibre Toxicologywww.particleandfibretoxicology.com

• Journal of Nanoparticle Researchwww.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 Nanomedicinewww.dovepress.com/IJN_ed_profile.htm

• Journal of Nanotoxicologyhttp://www.tandf.co.uk/journals/titles/17435390.asp

North American Nanoinitiatives

• National Nanotechnology Initiative, the largestAmerican nanocooperation, USAwww.nano.gov

• NanoBioTechnology Center, a National ScienceFoundation Center, USAwww.nbtc.cornell.edu/

• The Canadian National Research Council’s NationalInstitute for Nanotechnologywww.nrc.ca/nanotech/home_e.html

• National Institute for Nanotechnology - UniversityAlberta; http://www.nint.ca/

• Pacific Northwest National Laboratory’s effort in nanosciencewww.pnl.gov/nano/index.html

• Center for Nanotechnology, University of Washingtonhttp://www.nano.washington.edu/

• Center for Biological and EnvironmentalNanotechnology, Rice University (CBEN)http://www.ruf.rice.edu/%7Ecben/

37

Appendix I

ESF Forward Look Workshop ParticipantsAmsterdam, Netherlands, 1-5 March 2004

Workshop on Analytical Techniques andDiagnostic Tools, Amsterdam, 1 March 2004

Dr Patrick Boisseau (Chair)CEA-Nano2Life17 rue des Martyrs38054 Grenoble Cedex 9 • [email protected]

Dr François BergerCentre Hospitalier UniversitaireRue des Carabins-Ancienne38043 Grenoble • [email protected]

Prof. H. Allen O. HillInorganic chemistry laboratoryUniversity of OxfordSouth Parks RoadOxford OX1 3QR • United [email protected]

Dr Jürgen SchnekenburgerGastroenterologische Molekulare Zellbiologie, UKMUniversity of MünsterDomagkstr. 3A48149 Münster • [email protected]

Prof. Yosi ShachamUniversity Research Institute for NanoScience andNanoTechnologyTel Aviv UniversityRamat Aviv, 69978 Tel Aviv • [email protected]

Dr Dimitrios StamouLaboratory of physical chemistry of polymers andmembranes (LCPPM)EPFL1051 ausanne • [email protected]

Workshop on Nanoimaging and Manipulation,Amsterdam, 2 March 2004

Prof. Jean-Louis Coatrieux (Chair)Lab. Traitement du Signal et de l’ImageUniversité de Rennes 1

Campus de Beaulieu35042 Rennes Cedex • [email protected]

Dr Andreas BrielSchering AGDrug Delivery Systems13342 Berlin • [email protected]

Prof. Salvatore CannistraroDipartimento di Scienze AmbientaliIstituto Nazionale per la Fisica della MateriaUniversità della Tuscia01100 Viterbo • [email protected]

Prof. Martyn DaviesLaboratory of Biophysics and Surface AnalysisSchool of Pharmacy, University of NottinghamUniversity ParkNottingham NG7 2RD • United [email protected]

Dr Sjaak DeckersMolecular Imaging and DiagnosticsPhilips Medical Systems Nederland BVP.O. Box 10.0005680 DA Best • [email protected]

Prof. Paul DietlInstitute of PhysiologyUniversity of InnsbruckFritz-Pregl-Str. 36020 Innsbruck • [email protected]

Rainer ErdmannPicoQuant GmbHRudower Chaussee 29 (IGZ)12489 Berlin • [email protected]

Dr Mauro GiaccaInternational Centre for Genetic Engineering andBiotechnology (ICGEB)Padriciano 9934012 Trieste • [email protected]

Dr Corinne MestaisCEA GrenobleDépartement Système pour l’Information et la Santé17, Rue des Martyrs38054 Grenoble Cedex 09 • [email protected]

6. Appendices

APPENDIX I38

Prof. Hans OberleithnerInstitute of PhysiologyUniversity of MünsterRobert-Koch-Str. 27a48149 Münster • [email protected]

Workshop on Nanomaterials and Nanodevices,Amsterdam, 3 March 2004

Prof. Jeffrey Alan Hubbell (Chair)Laboratoire de médecine régénérative et de pharmacobiologieEPFL1015 Lausanne • [email protected]

Prof. Wim Hennink (Co-chair)Department of PharmaceuticsUtrecht Institute for Pharmaceutical SciencesUtrecht University3508 TB Utrecht • [email protected]

Prof. João Pedro CondeDepartment of Materials EngineeringInstituto Superior TecnicoAv. Rovisco Pais 11096 Lisboa • [email protected]

Dr John W DaviesPolymer Laboratories LtdEssex RoadShropshireChurch Stretton SY6 6AX • United [email protected]

Prof. Helmuth MöhwaldMax-Planck-Institute of Colloids and InterfacesWissenschaftspark Golm14476 Potsdam • [email protected]

Prof. José RivasDpto. Física Aplicada, Campus Universitario SurUniversidad de Santiago de Compostela15782 Santiago de Compostela • [email protected]

Workshop on Drug Delivery and PharmaceuticalDevelopment, Amsterdam, 4 March 2004

Prof. María José Alonso (Chair)Department of Pharmaceutical TechnologyFaculty of PharmacyUniversity of Santiago de Compostela15782 Santiago de Compostela • [email protected]

Prof. Ruth Duncan (Co-chair)Centre for Polymer TherapeuticsWelsh School of PharmacyCardiff UniversityRedwood BuildingKing Edward VII AvenueCardiff CF10 3XF • United [email protected]

Prof. Daan CrommelinDepartment of PharmaceuticsUtrecht Institute for Pharmaceutical SciencesPO Box 800823508 TB Utrecht • [email protected]

Prof. Patrick CouvreurFaculté de PharmacieUniversite de Paris-Sud5 rue J-B Clement92296 Chatenay-Malabry • [email protected]

Prof. Mike EatonUCB-Celltech216 Bath RoadSlough, Berks SL1 4EN • United [email protected]

Prof. Thomas KisselInstitut für Pharmazeutische Technologie undBiopharmaziePhilipps-Universität MarburgKetzerbach 6335032 Marburg • [email protected]

Prof. Claus-Michael LehrDepartment of Biopharmaceutics and PharmaceuticalTechnologySaarland UniversityIm Stadtwald, Bldg. 8.166123 Saarbrucken • [email protected]

Prof. Egbert MeijerLaboratory of Macromolecular and Organic ChemistryEindhoven University of TechnologyDen Dolech 2 , STO 4.365600 MB Eindhoven • [email protected]

Workshop on Clinical Applications and Toxicology, Amsterdam, 5 March 2004

Dr Wolfgang Kreyling (Chair)GSF National Research Centre for Environment and HealthInstitut für InhalationsbiologieIngolstädter Landstrasse 185764 Neuherberg • [email protected]

APPENDIX II 39

Dr Paul J. A. BormCentre of Expertise in Life Sciences (CEL)Hogeschool ZuydNieuw Eyckholt 3006419 DJ Heerlen • [email protected]

Prof. Kenneth DonaldsonELEGI Colt LaboratorySchool of Clinical Sciences and Community Health,Medical SchoolUniversity of EdinburghWilkie Building, Teviot PlaceEdinburgh EH 8 9AG • United [email protected]

Prof. Alberto GabizonShaare Zedek Med. Ctr.Oncology InstitutePOB 3235Jerusalem 91031 • [email protected]

Dr Rogério GasparLaboratory of Pharmaceutical TechnologyFaculty of PharmacyUniversity of Coimbra3000 Coimbra • [email protected]

Dr Andreas JordanMagForce Applications Center of Biomedical NanotechnologyCampus Charite, CBN, Haus 30Spandauer Damm 13014050 Berlin • [email protected]

Appendix II

ESF Consensus Conference ParticipantsLe Bischenberg, France, 8-10 November 2004

Steering Committee

Prof. Ruth Duncan (Chair)Centre for Polymer TherapeuticsWelsh School of PharmacyCardiff UniversityRedwood BuildingKing Edward VII AvenueCardiff CF10 3XF • United [email protected]

Dr Wolgang Kreyling (Deputy-chair)GSF National Research Centre for Environment and HealthInstitut für InhalationsbiologieIngolstädter Landstrasse 185764 Neuherberg • [email protected]

Dr Patrick BoisseauCEA – Nano2Life17 rue des Martyrs38054 Grenoble Cedex 9 • [email protected]

Prof. Salvatore CannistraroDipartimento di Scienze AmbientaliInstituto Nationale per la Fiscica della MateriaUniversità della Tuscia01100 Viterbo • [email protected]

Prof. Jean-Louis CoatrieuxLab. Traitement du Signal et de l’ImageUniversité de Rennes 1Campus de Beaulieu35042 Rennes Cedex • [email protected]

Prof. Hans OberleithnerInstitute of PhysiologyUniversity of MünsterRobert-Koch-Str. 27a48149 Münster • [email protected]

ESF Member Organisations andRepresentatives/Political Bodies

Dr Janna de BoerThe Netherlands Organisation for Health Research and Development (NWO)P.O. Box 932452509 AE The Hague • [email protected]

Dr Oliver BujokVDI Technologiezentrum GmbHPhysikalische TechnologienGraf-Recke-STr. 8440239 Düsseldorf • [email protected]

Dr Jean ChabbalDept. Microtech. Biol.&HealthCEA-L2t17, Rue des Martyrs38054 Grenoble Cedex 09 • [email protected]

Dr Françoise CharbitCEA GrenobleLETI-DTBS17, Rue des Martyrs38054 Grenoble Cedex 09 • [email protected]

Dr Rosita CottoneMission Affaires Européennes on sabbatical of BMBF(Ministry of Research, Germany) Direction de la Technologie Ministère délégué à la Recherche1, rue Descartes75005 Paris • [email protected]

APPENDIX II40

Dr Julie DeaconUK Micro and Tanotechnology NetworkFarlan CottageLower RoadCookham, Berks SL6 9HJ • United [email protected]

Dr Nicole DéglonCEA/Service Hospitalier Frédéric Joliot4, place du Général Leclerc91401 Orsay Cedex France • [email protected]

Dr Luc DelattreDépartement de PharmaciePharmacie Galénique et MagistraleUniversité de LiègeAvenue de l’Hôpital, 1 – Bât. B364000 Liege 1 • [email protected]

Dr Franz DettenwangerVolkswagenStiftungKastanienallee 3530519 Hannover • [email protected]

Dr Mauro FerrariThe National Cancer Institute110U Davis Heart and Lung Research Institute31 Center Drive MSC 2580The Ohio State UniversityRoom 10A52473 West 12th AvenueColumbus OH 43210-1002 • [email protected]

Dr Valérie Lefèvre-SeguinDirection de la Recherche, Ministère délégué à la Recherche1, rue Descartes • 75005 Paris • [email protected]

Dr Corinne MestaisCEA GrenobleDépartement Système pour l’Information et la Santé17, Rue des Martyrs38054 Grenoble Cedex 09 • [email protected]

Prof. Julio San RomanCSICInstitute of PolymersJuan de la Cierva 328006 Madrid • [email protected]

Dr Christof SteinbachDechema e.V.Theodor-Heuss-Allee 2560486 Frankfurt a.M. • [email protected]

Prof. Manuel VázquezInstituto de Ciencia de Materiales de Madrid, CSICCampus de Cantoblanco28049 Madrid • [email protected]

Dr Peter VenturiniNational Institute of ChemistryHajdrihova 191000 Ljubljana • [email protected]

Dr Petra WolffBundesministerium für Bildung und Forschung (BMBF)Referat 511 NanomaterialienHeinemannstr. 253175 Bonn • [email protected]

Academic Experts

Prof. María José AlonsoDepartment of Pharmaceutical TechnologyFaculty of PharmacyUniversity of Santiago de Compostela15782 Santiago de Compostela • [email protected]

Dr Paul J.A. BormCentre of Expertise in Life Sciences (CEL)Hogeschool ZuydNieuw Eyckholt 3006419 DJ Heerlen • [email protected]

Prof. Hans BörnerMax Planck Institute of Colloids and InterfacesDepartment of Coloid ChemistryResearch Campus GolmAm Mühlenberg 114424 Potsdam • [email protected]

Dr Benoit DubertretESPCI, Laboratoire d’Optique PhysiqueCNRS UPRA000510, rue Vauquelin75231 Paris Cedex 10 • [email protected]

Prof. Alberto GabizonShaare Zedek Med. Ctr.Oncology InstitutePOB 3235Jerusalem 91031 • [email protected]

Prof. Varban GanevMedical University of Sofia2 Zdrave Street1431 Sofia • [email protected]

APPENDIX II 41

Dr Mauro GiaccaInternational Center for Genetic Engineering and Biotechnology (ICGEB)Padriciano 9934012 Trieste • [email protected]

Dr Robert M. HendersonDepartment of Pharmacology, University of CambridgeTennis Court RoadCambridge CB2 1PD • United [email protected]

Dr Peter HinterdorferInstitute for BiophysicsJohannes Kepler Universität LinzAltenbergerstr. 69A-4040 Linz • [email protected]

Prof. Thomas KisselInstitut für Pharmazeutische Technologie und BiopharmaziePhilipps-Universität MarburgKetzerbach 6335032 Marburg • [email protected]

Prof. Jørgen KjemsDepartment of Molecular BiologyUniversity of ArhusC.F.Mollers Alle, Build. 130DK-8000 Aarhus C • [email protected]

Prof. Harm-Anton KlokEcole polytechnique fédérale de Lausanne (EPFL)Institute de matériaux, Laboratoire de polymèresEcublensCH-1015 Lausanne • [email protected]

Prof. Jean-Marie LehnInstitut de Science et d’Ingénierie SupramoléculairesLaboratoire de Chimie Supramoléculaire ISIS/ULP8, allée Gaspard MongeBP 70028 • F-67083 Strasbourg [email protected]

Prof. Claus-Michael LehrDepartment of Biopharmaceutics and PharmaceuticalTechnologySaarland UniversityIm Stadtwald, Bldg. 8.166123 Saarbrucken • [email protected]

Prof. C.R. LoweInstitute of BiotechnologyUniversity of CambridgeTennis Court RoadCambridge CB2 1QT • United [email protected]

Prof. A.W. McCaskie Surgical&Reproductive SciencesMedical School, University of Newcastle upon TyneNewcastle upon Tyne NE2 4HH • United [email protected]

Prof. Helmuth MöhwaldMax-Planck-Institute of Colloids and InterfacesWissenschaftspark Golm14476 Potsdam • [email protected]

Prof. Lars MonteliusDivision of Solid State PhysicsDepartment of PhysicsLund UniversityBox 117SE-221 00 Lund • Sweden [email protected]

Prof. Roeland J.M. NolteDepartment of Organic ChemistryUniversity of NijmegenToernooiveld 1 - U 0526525 ED Nijmegen • [email protected]

Dr T.H. OosterkampLeiden Institute of PhysicsLeiden UniversityNiels Bohrweg 22333 CA Leiden • [email protected]

Dr Pierre PugetDépartement Systèmes pour l’information et la santé(DSIS)LETI - CEA Grenoble17, rue des Martyrs38054 Grenoble cedex 9 • [email protected]

Dr Andrea RavasioDepartment of PhysiologyUniversity of InnsbruckFritz-Pregl-Str. 36020 Innsbruck • [email protected]

Prof. Helmut RingsdorfUniversity of MainzRaum 00.125Düsenbergweg 10-1455128 Mainz • [email protected]

Dr Jürgen SchnekenburgerGastroenterologische Molekulare Zellbiologie, UKMUniversity of MünsterDomagkstr. 3A48149 Münster • [email protected]

APPENDIX II42

Dr Milada SirovaInstitute of Microbiology ASCRVidenska 1083142 20 Prague 4 • Czech [email protected]

Prof. K. UlbrichCzech Republic Academy of ScienceInstitute of Macromolecular ChemistryHeyrovského námestí 2CZ-162 06 Prague 6 • Czech [email protected]

Prof. Arto UrttiUniversity of KuopioDepartment of PharmaceuticsP.O.Box 1627FIN-70211 Kuopio • [email protected]

Prof. Ernst WagnerPharmaceutical BiotechnologyDepartment of PharmacyLudwig-Maximilians Universität München (LMU)Butenandtstr. 5-1381377 Munich • [email protected]

Dr Jaap WiltingUtrecht Institute Pharmaceutical SciencesUniversity of UtrechtSorbonnelaan 163585 CA Utrecht • [email protected]

Industrial & Regulatory Experts

Dr Andreas BrielSchering AGDrug Delivery Systems13342 Berlin • [email protected]

Dr John W DaviesPolymer Laboratories LtdEssex RoadChurch StrettonShropshire, SY6 6AX • United [email protected]

Dr Sjaak DeckersMolecular Imaging and DiagnosticsPhilips Medical Systems Nederland BVP.O. Box 10.000 • 5680 DA Best • [email protected]

Prof. Mike EatonUCB-Celltech216 Bath RoadSloughBerks SL1 4EN • United [email protected]

Rainer ErdmanPicoQuant GmbHRudower Chaussee 29 (IGZ)12489 Berlin • [email protected]

Dr Rogério GasparLaboratory of Pharmaceutical TechnologyFaculty of PharmacyUniversity of Coimbra3000 Coimbra • [email protected]

Dr Arne HengererSiemens Medical SolutionsMR MIKarl-Schall-STr. 491054 Erlangen • [email protected]

Dr Laurent LevyNanobiotixRue Pierre et Marie Curie - BP27/0131319 Labege Cedex • [email protected]

Dr Kristina RiehemannIntegrated Functional Genomics (IFG)University of Münstervon-Esmarch-Str. 5648149 Münster • [email protected]

Prof. Csaba Szántay Jr.Spectroscopic Research DivisionChemical Works of Gedeon Richter Ltd.H-1475 BudapestP.O.B. 27 • [email protected]

Nanotechnology Information Suppliers

Dr Ottila SaxlThe Institute of Nanotechnology6 The Alpha CentreUniversity of Stirling Innovation ParkStirling, FK9 4NF • United [email protected]

ESF/EMRC/COST

Prof. Luc P. BalantCOST TC Medicine & HealthDepartment of PsychiatryUniversity of Geneva2, Chemin du Petit-Bel-Air1225 Chene-Bourg • [email protected]

Dr Thomas BruhnInstitute of Experimental DermatologyUniversity of Münstervon-Esmarch-Str. 5848149 Münster • [email protected]

APPENDIX III 43

Nathalie GeyerEuropean Science Foundation1, quai Lezay MarnésiaBP 90015 • 67080 Strasbourg Cedex • [email protected]

Dr John MarksEuropean Science Foundation1, quai Lezay MarnésiaBP 90015 • 67080 Strasbourg Cedex • [email protected]

Prof. Mihail PascuESF-COST OfficeMedicine and Health; Biomaterials149, Avenue LouiseP.O. BOX 121050 Brussels • [email protected]

Prof. Clemens SorgInstitute of Experimental DermatologyUniversity of Münstervon-Esmarch-Str. 5848149 Münster • [email protected]

Dr Hui WangEuropean Science Foundation1, quai Lezay MarnésiaBP 90015 • 67080 Strasbourg Cedex • [email protected]

Appendix III

Projected Market for Nanomedicines

The market of nanomedicines is rapidly rising as new prod-ucts are being approved. It is expected that this market willreach a significant economic potential within 5 to 10 years.Currently, little data is available on the market of nanomed-icines in Europe.

Market size worldwide 2003 for medical devicesand pharmaceuticals* Medical devices €145 billionPharmaceuticals €390 billion

Expected market growth: 7-9% annually Within the market of pharmaceuticals, advanced drug deliv-ery systems account for approximately 11% market share(€42.9 billion). This market is expected to expand rapidly asonly a few products are currently in clinical application andmany more in clinical trials or in the process of beingapproved. As an example, the current estimates for

Doxil®/Caelyx® (PEGylated liposomal doxorubicin)are $300 million (€251.32 million) sales per annum

Ambisome® (liposomal amphotericin B) are > $100million (€83.77 million) sales per annum

* Vision paper and basis for a strategic research agenda for

NanoMedicine, European Technology

Platform on NanoMedicine - Nanotechnology for Health –

EU publication September 2005

Appendix IV

European Projects and Networks UndertakingNanomedicine Research

European Networks

EU funding opportunities in the NanotechnologyResearch Areawww.cordis.lu/nanotechnology/

Communication on nanotechnology from the EuropeanCommission, ‘Towards a European strategy onnanotechnology’www.cordis.lu/nanotechnology/src/communication.htm

Illustrated brochure entitled ‘Nanotechnology, Innovationfor tomorrow’s world’ ftp://ftp.cordis.lu/pub/nanotechnology/docs/nano_brochure_en.pdf

The PHANTOMS Nanoelectronics Network schemewww.phantomsnet.net

A general European site on European nanoscience andtechnology.www.nanoforum.org/

European National Nanocentres

The Swiss ‘National Centre for Nano Scale Science’ atUniversität Baselwww.nanoscience.unibas.ch/

Nanoscience @ Cambridge Universityhttp://www.nanoscience.cam.ac.uk/

London Centre for Nanotechnologyhttp://www.london-nano.ucl.ac.uk/

Nanolink at University of TwenteNanolinkwww.mesaplus.utwente.nl/nanolink/

Centre of Competence Nano-Scale Analysis in Hamburgwww.nanoscience.de/http://www.nanoanalytik-hamburg.de/shtml/index.shtmlhttp://www.nanoanalytik-hamburg.de/shtml/index.shtml

Centre for NanoScience based at Ludwig-Maximillians-Universität, Münchenwww.cens.de/

APPENDIX IV44

Centre of Competence NanoBioTechnology, Saarland,Germanywww.nanobionet.de/

Centre of Competence NANOCHEM, Saarbrücken,Germanywww.cc-nanochem.de

The German Ministry of Education and Researchsupports six national Competence Centreswww.nanonet.de/nanowork/indexe.php3

Nano-World, The Computer-Supported CooperativeLearning Environment on Nanophysics, a Swiss VirtualCampuswww.nanoworld.unibas.ch/zope/nano/en

Center for NanoMaterials at Technische UniversiteitEindhoven, Hollandwww.cnm.tue.nl

Center for Ultrastructure Research, Austriawww.boku.ac.at/zuf/

Institute of Nanotechnology at the ForschungszentrumKarlsruhehttp://hikwww1.fzk.de/int/english/welcome.html

DFG-Centrum für Funktionelle Nanostrukturenhttp://www.cfn.uni-karlsruhe.de/index.html

Nanostructures Laboratory at MFA Research Institute forTechnical Physics and materials sciencehttp://www.mfa.kfki.hu/int/nano/

Paul Scherrer Institut - Laboratory for Micro- andNanotechnologyhttp://lmn.web.psi.ch/index.html

Nano-Science Center at Københavns Universitethttp://www.nano.ku.dk/

MIC National Micro- and Nanotechnology ResearchCenter at DTUhttp://www.mic.dtu.dk/

NanoBIC - NanoBioCentrum at University of southernDenmarkhttp://www.sdu.dk/Nat/nanobic/index.php

European Projects

BIOMINObjectives: The aim of the project is to formnanostructure composites of biomaterials and inorganiccompounds for applications in, e.g. implants.Contact: Ralph ThomannEmail: [email protected]

BIOSMARTObjectives: To establish an infrastructure for coordinatingresearch into the design and application of biomimeticmaterials and smart materials with biorecognitionfunctions, including new porous biorecognition materialsfor tissue engineering.

Contact: Sergey PiletskyEmail: [email protected]

HEPROTEXObjectives: To develop a joint research infrastructure fordevelopment of protective textiles. With new innovationsin textiles, forms will become more widely used insurgical procedures than for just traditional uses such aswound care.Contact: Hilmar FuchsEmail: [email protected]

INCOMEDObjectives: The aim is to reduce 90% of implantcomplications, by way of an innovative method ofcoating objects with a thin layer of hydroxylapatite,bioactive glass or mixtures of both in order to givebiocompatible surfaces.Contact: Christoph SchultheissEmail: [email protected]

INTELLISCAF Objectives: The aim is to produce intelligent scaffoldsusing nanostructured particles and surfaces to givematerials which will help regenerate tissues such as boneor skin on their implantation.Contact: Soeren StjernqvistEmail: [email protected]

MENISCUS-REGENERATIOObjectives: The aim is to use tissue engineering toproduce an artificial meniscus with a structure similar tothe natural tissue.Contact: Claudio de LucaEmail: [email protected]

EU 6th Framework Programme

Search: http://eoi.cordis.lu/search_form.cfm

Microrobotnic surgical instrumentsProject Acronym: (none). Objectives: To develop microrobotic surgical instrumentsfor new types of surgery.Contact: Georges BogaertsEmail: [email protected]

MOBIASObjectives: To develop a way to manufacture implantsand scaffolds with several materials and to vary thecomposition throughout the structure, to give multiplefunctions. Contact: Gregory GibbonsEmail: [email protected]

NA.BIO.MATObjectives: The design and development of self-assembling biocompatible polymers, for applications in,e.g., tissue engineering. Contact: Gaio ParadossiEmail: [email protected]

APPENDIX V 45

NanoarchitectureObjectives: Nanostructuring modification of biomaterialsfor tissue engineering and other biomimetic applications.Contact: Vasif HasirciEmail: [email protected]

NanoBoneObjectives: To apply nanotechnology, in terms ofstructuring, to bone repair and regeneration.Contact: Fernando MonteiroEmail: [email protected]

NanostresObjectives: To use nanotechnology techniques to createimplants and implant technologies for skeletal tissues.Contact: Josep Anton PlanellEmail: [email protected]

NB-TISS-INTER-MEDObjectives: To redress the issue of the decreasingEuropean market share in medical devices.Contact: Ian McKayEmail: [email protected]

NMMAObjectives: To carry out interdisciplinary research (formedical applications) into the possibilitiesnanotechnology offers for shaping surface and internalstructure, and using molecular biology to controlinteractions between materials and cells.Contact: Krzysztof KurzydlowskiEmail: [email protected]

NONMETALLICIMPLANTSObjectives: To create new/improved polymer materialsfor implants and scaffolds, with the necessary structure tooptimise their function.Contact: Jan ChlopekEmail: [email protected]

SAM-MED-NETObjectives: To gain a better understanding of selfassembly mechanisms for applications in biomimeticmaterials (e.g. tissue engineering).Contact: Frederic CuisinierEmail: [email protected]

Appendix V

Nanomedicines in Routine Clinical Use or Clinical Development

Liposomal formulations in clinical use and clinical developmentProduct 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 antibodiesRituxan® CD20 inherent activity CD20+ve Non-Hodgkin’s

Lymphoma Herceptin® HER2 inherent activity HER2 +ve breast cancer Antibody-drug conjugatesMylotarg® CD33 calicheamicin Acute Myeloid LeukaemiaRadioimmunotherapeuticsTositumomab® CD20 [131I]iodide Non-Hodgkin’s Lymphoma-

targeted radiotherapy Zevalin® CD20 90Yttrium Non-Hodgkin’s Lymphoma-

targeted radiotherapyImmunotoxinsAnti-B4-blocked ricin CD19 blocked ricin Non-Hodgkin’s lymphoma

targeted immunotoxinAnti-Tac(Fv)-PE38 (LMB2) CD25 Pseudomonas Haematological malignancies

exotoxin fusion protein PEG-antiTNF Fab CDP870 TNFα Phase III Rheumatoid arthritis and

Crohn’s disease

APPENDIX V46

Nanoparticles as imaging agents and drug carriersProduct Compound Status Use

Imaging AgentsEndorem® superparamagnetic Market MRI agent

iron oxide nanoparticleGadomer® Dendrimer-based Phase III MRI agent-cardiovascular

MRI agent Drug deliveryAbraxane® Albumin nanoparticle Market Breast cancer

containing paclitaxel

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

Polymeric drugsPoly(alanine, lysine, Copaxone® Market Multiple sclerosisglutamic acid, tyrosine)Poly(allylamine) Renagel® Market End stage renal failureDextrin-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 intraperitoneallyPoly(I):Poly(C) Ampligen® Phase III Chronic fatigue immune

dysfunction (myalgic encephalomyelitis; ME)

Polyvalent, polylysine VivaGel™ Phase I/II Viral sexually transmitteddendrimer containing SPL7013 diseases, formulated

as a vaginal gel

Polymer-oligonucleotide conjugatesPEG-aptamer Macugen™ NDA filed Age-related macular degenerationPolymer-protein conjugatesPEG-adenosine deaminase Adagen® Market Severe combined immuno-

deficiency syndrome SMANCS Zinostatin Stimalmer® Market Cancer - hepatocellular

carcinomaPEG-L-asparaginase Oncaspar® Market Acute lymphoblastic leukamia PEG-a-interferon 2b PEG-intron™ Market Hepatitis C, also in clinical

development in cancer, multiple sclerosis, HIV/AIDS

PEG-a-interferon 2a PEG-Asys® Market Hepatitis CPEG-human growth hormone Pegvisomant® Market Acromegaly PEG-GCSF Neulasta™ Market Prevention of neutropenia

associated with cancer chemotherapy

PEG-antiTNF Fab CDP870 Phase III Rheumatoid arthritis andCrohn’s disease

Polymer-drug conjugatesPolyglutamate-paclitaxel CT-2103, XYOTAX™ Phase II/III Cancer -particularly lung cancer,

ovarian and oesophagealHPMA copolymer-doxorubicin PK1; FCE28068 Phase II Cancer -particularly lung and

breast cancerHPMA copolymer-doxorubicin- PK2; FCE28069 Phase I/II Cancer -particularly

galactosamine hepatocellular carcinoma HPMA copolymer-paclitaxel PNU166945 Phase I CancerHPMA copolymer camptothecin MAG-CPT / PNU166148 Phase I CancerHPMA copolymer platinate AP5280 Phase II CancerHPMA copolymer platinate AP5346 Phase I/II CancerPolyglutamate-camptothecin CT-2106 Phase I/II CancerPEG-camptothecin PROTHECAN™ Phase II Cancer

Polymeric micellesPEG-aspartic acid-doxorubicin NK911 Phase I Cancermicelle

APPENDIX VI 47

Appendix VI

European Companies Active in Nanomedicines’ Development

A list of some companies active in nanomedicines’development. This list is not meant to becomprehensive.

iNanowebsite containing links to several companies andinstitutions that could be helpful in the start-up phase ofnew companiesWebsite: http://www.inano.dk/sw179.asp

PronanoSwedish site for the promotion of nanotechnology inindustryWebsite: http://www.pronano.se/

Advanced Photonic Systems APhS GmbHAdvanced Photonic Systems manufactures lasers, lasersystems and components, with a focus on fast and ultrafast-pulsed lasers.Website: http://www.advanced-photonic-systems.com/

Bio-Gate Bioinnovative Materials GmbHBio-Gate develops and tests anti-infective materials usingnanosilver, for medicine and other industries.Website: http://www.bio-gate.de

DILAS, Diodenlaser GmbHDILAS designs and engineers various products (standardor custom designed) in the field of High Power DiodeLasersWebsite: http://www.dilas.de

JenLab GmbHJenLab uses femtosecond laser technology to developinstruments for biotechnology and biomedicalapplications. Website: http://www.jenlab.de

Kleindiek NanotechnikKleindiek Nanotechnik produces micro and nanopositioning systems, with high precision and resolution,combined with a large working range.Website: http://www.nanotechnik.com

NEWCO SurgicalNEWCO Surgical is a supplier of innovative surgicalinstruments and accessories throughout the UK.Website: www.newco.co.uk

Capsulution Nanoscience AGuses LBL-Technology® for making unique capsules, allowing the manufacture of extremely precisenano- and micron-sized capsules.Website: www.capsulution.com

Flamel Technologieshas developed Medusa which is nanoencapsulationtechnology to deliver native protein drugs.Website: www.flamel.com

ImaRx Therapeuticsuses SonoLysis technology which employs tiny microand nanobubbles injected into the bloodstream to enterinto regions of thrombosis. When external ultrasound isapplied, the microbubbles cavitate and dissolve bloodclots into smaller particles.Website: www.imarx.com

iMEDDis a biomedical company developing advanced drugdelivery systems based on MEMS technology. iMEDD’slead drug delivery platform, NanoGATE, is an implantthat uses membranes containing pores with nanometredimensions that control the diffusion of drugs at amolecular level.Website: www.imeddinc.com

LiPlasome Pharmahas developed a prodrug and drug delivery platform thatcan be used for targeted transport of anticancer drugs.Their prodrug and drug delivery technology is based onsmart lipid based nanocarriers (LiPlasomes) that can beapplied for targeted transport of anticancer drugs.Website: liplasome.com

MagForce Applicationsis a group of companies that have developed the magneticfluid hyperthermia method (MFH). This is a minimallyinvasive cancer therapy that attacks cancer at the cellularlevel whilst leaving healthy tissue largely unharmed. Themethod consists of two components; nanosized iron oxideparticles (MagForce) and an external magnetic fieldapplicator (MFH).Website: www.magforce.de

MagnaMedicsuses its SensithermA therapy to help combat AIDS. Theprinciple of the therapy is the selective overheating of thevirus and the infected cells by means of magneticnanoparticles. SensiTherm therapy is also used in thetreatment of liver tumours.Website: www.nanovip.com

Micromet AGis using antibodies to create novel drugs that preciselyand effectively combat human diseases such as cancer orrheumatoid arthritis.Website: www.micromet.de

Nanobiotixhas developed their NanoBiodrugs™ which are nano-particles with a diameter smaller than 100nm. The core ofthe nanoparticle is a NanoProdrug in an inactive form thatcan then be activated by external physical activation. Thisgenerates a local therapeutic effect destroying thepathological cells. Activation is achieved by a magneticfield similar to that of an MRI machine, or by laser.Website: www.nanobiotix.com

Nanogate Technologiesconcentrates on inorganic-organic nanocomposites aswell as self-organising nanostructures based on chemicalnanotechnologyWebsite: www.nanogate.de

APPENDIX VI48

Nanomix IncWebsite: nano.com

NanoPharm AGhas developed nanoparticles as a drug deliveryformulation using NANODEL technology. Drugs arebound to nanoparticles and then transported to theirspecific target. It is even possible to transport drugsacross the blood-brain barrier.Website: nanopharm.de

NOSENanomechanical olfactory sensors.Website: http://monet.unibas.ch/nose/

Novosom AGspecialises in the development and production ofliposomes, liposomal nanocapsules and liposomalvectors.Website: www.novosom.de

Pharmasol GmbHhas developed lipid nanoparticles as an alternativedelivery system to polymeric nanoparticles.Website: www.pharmasol-berlin.de

Psividia Ltdis a biomedical technology company which has produceda material designed to enable drug molecules to be heldin nanoscale pockets which release tiny pulses of a drugas the material dissolves. The rate of dissolution can becontrolled so that delivery can be achieved over days ormonths.Website: www.psividia.com

SkyePharmais a leading developer, manufacturer and provider of drugdelivery technologies. One of its technologies usesnanoparticles which allow targeted drug delivery in thelung.Website: www.skyepharma.com

Companies Active in Tissue Engineering

Alchimer SAAlchimer develops and produces coatings for biomedicalimplants and microelectronics.Website: http://www.alchimer.com/

BioTissue Technologies AGBioTissue produces autologous skin grafts, bone andcartilage implants.Website: www.biotissue-tec.com

GfE Medizintechnik GmbHGfE develops and produces titanium-coated (‘titanized’)implants.Website: http://www.gfe-online.de/opencms/opencms/gfe/en/mt/index.html

IIP-Technologies GmbHIIP has developed an artificial retina that can help restoresome sense of vision.Website: http://www.iip-tec.com/english/index.php4

Micromuscle ABMicromuscle develops and produces electroactivecomponents for medical devices.Website: http://www.micromuscle.com

pSiMedicapSiMedica has developed a form of silicon that isbiocompatible and biodegradable. BioSilicon can be usedin various medical applications.Website: http://www.psimedica.co.uk

TransTissue Technologies GmbHTransTissue creates replacement tissues such as bone andcartilage using tissue engineering.Website: http://www.transtissue.com

NAMOS GmbHNAMOS produces ‘intelligent’ surface coatings formaterials using nanotechnology.Website: http://www.namos.de/

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