Boisseau Nanomedicine CRAS

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ComptesRendusdel AcadmiedesSciences

Nanomedicine,NanotechnologyinmedicineNanomdecineetnanotechnologiespourlamdecine

PatrickBOISSEAU*1,BertrandLOUBATON2

1Chairman,WorkingGrouponNanoDiagnostics,ETPNanomedicineCEALeti,CampusMinatec,17ruedesmartyrs,F38054GrenobleCedex9,France

[email protected]

2ChairmanETPNanomedicine,GeneralElectricHealthcare,Pharmaceutical&AcademicResearchCollaboration,Velizy,

France

Resum:

La nanomdecine est un domaine relativement rcent des sciences et techniques. Sadfinition sembleparfois imprcise etdiffrentes interprtations sontdonnes ce terme,notammententrelEuropeetlesEtatsUnis.

En interagissant avec des molcules biologiques donc lchelle nanomtrique, lesnanotechnologies ouvrent un vaste champ dapplication et de recherche. Les interactionsentre assemblagesmolculaires synthtiquesoudispositifsnanomtriques etbiomolcules

peuventseconcevoirtantdanslemilieuextracellulairequlintrieurdescellulesducorpshumain.Lchellenanomtriquepermetdexploiterdespropritsphysiquesdiffrentesdecellesobserveslchellemicroscopiquetellesquunrapportsurface/volumeimportantparexemple.

Lesapplicationsendiagnostiquetudiessontapplicablestantpourlediagnostiqueinvitroque pour le diagnostique in vivo. In vitro, les particules synthtiss et les dispositifs demanipulation ou dtection permettent la reconnaissance, la capture, la concentration debiomolcules.Invivo,lesassemblagesmolculairessynthtiquessontessentiellementconuscommeagentdecontrastepourlimagerie.

Un second domaine de la nanomdecine prsentant un fort dveloppement est celuidesnanomdicamentsodesnanoparticulessynthtiquessontconuespourlavectorisationet la dlivrance de principes actifs pharmaceutiques. Le recours ces vecteurs permetdamliorer la biodistribution des mdicaments, concentre leur ciblage vers les tissuspathologiquesetprotgelestissussains.Un troisime domaine dapplication est celui de la mdecine rgnrative o lesnanotechnologiespermettentdeconcevoirdesmatriauxbiocompatiblesdestinsausupportdecroissancedescellulesutilisesenthrapiecellulaire.

Lapplicationdesnanotechnologies lamdecinesoulvedesproblmesnouveauxdepar

certains nouveaux usages quelles permettent, par exemple: la puissance nouvelle dudiagnostiqueestellegrableparlecorpsmdical?Quesignifietraiterunpatientsanssigne

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clinique? Que devientmme la notion de patient en labsence de signes cliniques? Lananomdecine peut potentiellement contribuer au dveloppement dune mdecinepersonnalise o un diagnostique personnel permettrait de prescrire une thrapiepersonnaliseefficace.

Il existedansdenombreuxpaysun cadre rglementaire existantqui couvre les rglesdebasedescuritetdefficacitdesnanotechnologiesmdicales,quilsagissedassemblagesmolculairesoudedispositifsmdicaux.Maisunbesoindeprciservoirede fairevoluercertainsaspectsdecesrglementationsmobilisentdenombreuxexperts.

LaFranceestunpaysoledveloppementdesnanotechnologiesmdicalesestsignificatif,linstar de lAllemagne, du RoyaumeUni ou de lEspagne, en ce qui concerne lUnionEuropenne.Lacommunautscientifiqueyestactiveetdespartenairesindustrielsdetoutetailleyoprent,mmesiletransfertdetechnologiesverslindustrienestpasaussiefficacequenAmriqueduNord.

Keywords: nanomedicine; nanotechnology; drug delivery; diagnostic; regenerativemedicine;theranostic

Motscls:nanomdecine;nanotechnologie;vectorisationdemdicaments; diagnostique;mdecinergnrative;thranostique.

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Abstract:

Nanomedicine is a relatively new field of science and technology. It looks sometimes illdefined and interpretations of that term may vary, especiallybetween Europe and theUnitedStates.

Byinteractingwithbiologicalmolecules,thereforeatnanoscale,nanotechnologyopensupavastfieldofresearchandapplication.Interactionsbetweenartificialmolecularassembliesornanodevices andbiomolecules canbe understoodboth in the extracellularmedium andinsidethehumancells.Operatingatnanoscaleallowtoexploitphysicalpropertiesdifferentfromthoseobservedatmicroscalesuchasthevolume/surfaceratio.

Theinvestigateddiagnosticapplicationscanbeconsideredforinvitroaswellasforinvivodiagnosis.Invitro,thesynthesizedparticlesandmanipulationordetectiondevicesallowfortherecognition,capture,andconcentrationofbiomolecules.Invivo,thesyntheticmolecularassembliesaremainlydesignedasacontrastagentforimaging.

Asecondareaexhibitingastrongdevelopmentisthe nanodrugs wherenanoparticlesaredesigned for targeted drug delivery. The use of such carriers improves the drugbiodistribution,targetingactivemoleculestodiseasedtissueswhileprotectinghealthytissue.

A third area of application is regenerative medicine where nanotechnology allowsdevelopingbiocompatiblematerialswhichsupportgrowthofcellsusedincelltherapy.

Theapplicationofnanotechnologytomedicineraisesnewissuesbecauseofnewusestheyallow,forinstance: Isthepowerofthesenewdiagnosticsmanageablebythemedical

profession?Whatmeanstreatingapatientwithoutanyclinicalsigns?Nanomedicinecancontributetothedevelopmentofapersonalizedmedicinebothfordiagnosisandtherapy.

Thereexistsinmanycountriesexistingregulatoryframeworksaddressingthebasicrulesofsafetyandeffectivenessofnanotechnologybasedmedicine,whethermolecularassembliesormedicaldevices. Butthereisaneedtoclarifyortomodifytheseregulationswhichmobilizemanyexperts.

France is a countrywhere themedicaldevelopmentofnanotechnology is significant, likeGermany,theUnitedKingdomorSpain,asregardstheEuropeanUnion.Thereisanactive

scientific communityand industrialpartnersofallsizes,even if the technology transfer toindustryisnotaseffectiveasinNorthAmerica.

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1 0BDefinitionThere is no nanomedicine, there is nanotechnology in medicine. Even if the expressionnanomedicinehasbeenwidelyused for a coupleofyears, it ismoreproper to refer to

nanotechnologyenabledmedicine indifferentsubareasofmedicinesuchasdiagnostics,therapyormonitoring.

The definition of nanomedicine is slightly different onboth sides of theAtlanticOcean.While theUSNationalNanotech Initiative clearly refers to the nanoscale, the EuropeanScienceFoundationandtheEuropeanTechnologyPlatformonNanomedicinedontrefertoit:

TheUSNationalNanotechInitiativeNanotechnology is the understanding and control of matter at dimensionsbetween

approximately1and

100

nanometres,

where

unique

phenomena

enable

novel

applications. Encompassing nanoscale science, engineering, and technology,nanotechnology involves imaging,measuring,modelling, andmanipulatingmatter atthislengthscale.Nanomedicineistheapplicationofnanotechnologytomedicine.

TheEuropeanScienceFoundationThe field of nanomedicine is the science and technology of diagnosing, treating andpreventing disease and traumatic injury of relieving pain, and of preserving andimprovinghumanhealth,usingmoleculartoolsandmolecularknowledgeofthehumanbodyD1D.

TheEuropeanTechnologyPlatformonNanomedicineNanomedicine isdefinedas theapplicationofnanotechnology tohealth. Itexploits theimprovedandoftennovelphysical, chemical,andbiologicalpropertiesofmaterialsatthenanometric scale.Nanomedicinehaspotential impacton theprevention, earlyandreliablediagnosisandtreatmentofdiseasesD2

However, nanomedicine is more an academic concept than an industrial one. Medicalindustry is looking forsolutions forpatientsregardless the involved technology.Thereforenanomedicine is now sometimes classified under advanced medical technologies byindustry.Nevertheless,thetermnanomedicineisusedinthischapter,foreasiness.

Themainapplicationareasofnanomedicineare: deliveryofpharmaceuticals invitro,onvivoandinvivodiagnostics,includingimaging regenerativemedicine implanteddevices

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2 1BHistoryThefirstresultsrelated to thedevelopmentofnanomedicinecouldbeidentifiedin the late60satETHZurich

D

3D.

The significant technological and industrialdevelopmentofnanomedicine ismore recent,

justacoupleofdecadeorso.Ithasbeenmarkedbysomelargeinitiativeswhichpavedthewayforitsdevelopment.

Intheearly2000s,boththescientistoptimismandthechallengeswhichcouldbeaddressedby nanotechnology have prompted governmental science and funding organisations toundertakestrategicreviewsof thecurrentstatusofnanomedicine, theirprimaryobjectivesbeing to assess potential opportunities forbetter healthcare as well as the riskbenefitanalysisofthesenewtechnologies,andtodetermineprioritiesforfuturefunding.Inearly2003,theEuropeanScienceFoundationlauncheditsForwardlookonnanomedicine.At that time, therewas an increasing optimism that nanotechnology applied tomedicine

wouldbring significant advances in the diagnosis and treatment of diseases. This firstforesight study focusedonmedicalapplicationsofnanosciencesandnanotechnology.TheForwardLook involvedover 100 leadingEuropean expertsandallowed todetermine thecurrentstatusof thefieldand tofosterdebatesonstrategicpolicy issues.Apolicybriefingwas published on 23rd February 2005 which summarised the recommendations of theForwardLook.

InJune2003,theUKGovernmentcommissionedtheRoyalSociety,theUKnationalacademyofscience,andtheRoyalAcademyofEngineering,theUKnationalacademyofengineering,to carry out an independent study of likely developments and investigate whether

nanotechnologymightraiseorislikelytoraisenewethical,healthandsafetyorsocialissueswhich arenot coveredby current regulation.The Hfinal reportHwaspublished inJuly 2004with21recommendationsforasure,safeandresponsibledevelopmentofnanotechnologyD4D.

In2004,TheCommissionoftheEuropeanCommunitiesreleaseditscommunicationontheEuropeanstrategy fornanotechnology

D

5D. In thesame time, theHighLevelGroupEuropean

TechnologyPlatformNanomedicinewaslaunchedinOctober2004undertheinitiativeoftheEuropean Commission. This group of 40 experts from industry, research centres andacademia convened to prepare the vision regarding future research priorities innanomedicine.InSeptember2005,itsVisionPaperandBasisforaStrategicResearchAgenda

forNanomedicinewas released,asa firststep towards settingupaEuropeanTechnologyPlatform onNanomedicine, aiming at strengthening Europe position and improving thequalityoflifeandhealthcareofEuropeancitizens.

Morerecently,in2007,theEuropeanFoundationforClinicalNanomedicinewasestablishedin Basel (Switzerland). This foundation is a nonprofit institution aiming at advancingmedicineforthebenefitofindividualsandsocietythroughtheapplicationofnanosciences.Aiming at prevention, diagnosis, and therapy through nanomedicine as well as atexplorationofitsimplications,theFoundationreachesitsgoalsthroughsupportofclinicallyfocussed researchandof interactionand information flowbetween clinicians, researchers,

thepublic,andotherstakeholders.Therecognitionofthelargefutureimpactofnanosciences

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onmedicineand theobservedrapidadvanceofmedicalapplicationsofnanoscienceshavebeenthemainreasonsforthecreationoftheFoundation.

OntheothersideoftheAtlanticOcean,theNationalInstitutesofHealth(NIH)releasedtheirfirst roadmaponnanomedicine in2004D6D.Asa followup, theNIHestablished in2005and

2006anationalnetworkof HeightNanomedicineDevelopmentCentresH,whichservedas theintellectualandtechnologicalcentrepieceoftheNIHNanomedicineRoadmapInitiative.ThegoaloftheCommonFundsNanomedicineprogram,aspartoftheNationalHealthInstitutesNanomedicine Roadmap is to determine how cellularmachines operate at the nanoscaleleveland thenuse thesedesignprinciples todevelopand engineernew technologies anddevicesforrepairingtissueorpreventingandcuringdisease.In 2004, the National Cancer Institute (NCI), as part of NIH, launched the CancerNanotechnologyPlan,astrategicinitiativetotransformclinicaloncologyandbasicresearchthroughthedirectedapplicationofnanotechnologyD7D.TheNCIAllianceforNanotechnologyinCancerisengagedineffortstoharnessthepowerofnanotechnologytoradicallychange

the way we diagnose, treat and prevent cancer. This alliance is a comprehensive,systematized initiativeencompassing thepublicandprivatesectors,designed toacceleratetheapplicationofnanotechnologytocancer.

3 2BNanotechnologyinmedicine:theidealscaleTheaimofnanomedicinemaybebroadlydefinedasthecomprehensivemonitoring,control,construction, repair, defence and improvement of all humanbiological systems,workingfromthemolecularlevelusingengineereddevicesandnanostructures,ultimatelytoachievemedicalbenefits.Inthiscontext,nanoscaleshouldbetakentoincludeactivecomponentsor

objects in the size range from one nanometre to hundreds of nanometres. Thesemaybeincludedinamicrodevice(thathaveamacrointerface)orinabiologicalenvironment.Thefocus,however, isalwaysonnanointeractionswithin the frameworkofa largerdeviceordirectlywithinasubcellular(orcellular)system.Nanosciencesandnanotechnologiesimplystudyingandworkingwithmatteratultrasmallscale.Onenanometre isonemillionthof amillimetre and a singlehumanhair is around80,000nanometresthick.Thereforenanomedicineoperatesatthesamesizescaleabout100nanometresor less thatbiologicalmoleculesandstructures inside livingcellsoperate.Atypical protein size liesbetween 3 to 10 nanometres (nm), while redblood cells are astandardsizeofabout60008000nm.

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Fig.1:Scaleofsize.Howsmallissmall

Thenanoparticulate systemshavea size ranging froma fewnanometres, likemicelles, toseveral hundreds of nanometres like liposomes. For instance, drug delivery systems canreadily interactwithbiomolecules located onboth the cell surface and inside.Thusnanodrug delivery systems can not only transport encapsulated or grafted smallchemotherapeuticdrugs,witha sizeof less thanadozensofnanometres,butalsodelivertheminsidecellsoncetheyhavepenetratedthem. Suchsystemscanalsobedecoratedwithfragments of antibodies on their surface to target specific tissues, thus improving thespecificityofthedrugdelivery.

4 3BIsthenanoscalereallyadequateformedicaltechnologies?Somephysicallawsaredifferentatnanoscale,andthismaybefavourableornotformedicalapplications:

The surface/volume ratio ofparticlesbecomesvery largewhen sizedecreases, so thatnanoparticleshaveahuge surface suitable for chemical interactionswithbiomoleculesforinstance.Moreover,(bio)chemicalreactiontimearemuchshorter(itdecreasessharplywithsamplesize)andaccordinglyanalyticaldevicesarefasterandmoresensitive.

Theultra small sizeof the sensingpartofa (macro ormicro)analyticaldevice,withnanopillars,nanobeads, canbepossiblyexploited fordeviceminiaturization.Smallerdevicesofferalowerinvasivenessandcanevenbeimplantedwithinthebody.

Anotheradvantageoftheultraminiaturisationofthesensingpartliesintheultrasmallsizeof thebiologicalsamplerequiredformeasurement.Thisbecomesakeyfeature foranalysingraresampleslikesomebiopsies.

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Fig2:NanopillarsinaBioChipLabmicroreactor.Credit:CEALeti

On the contrary,measuring low concentrations ofbiologicalmolecules like somebiomarkers in large samples like blood droplets requires preliminary steps forconcentratingthesemolecules.Inageneralway,biosampleslikeurine,blood,sweator tear aremicrometric; thus several samplepreparation steps are requiredbeforeanalysis.

Viscositybecomesmore effective at the nanoscale. The interaction with capillarywallsbecomesmoreimportant,andtheviscosityeffectdominatesthatofgravity.Theconsequenceisthatmakesnanofluidicsmorecomplexthanmicrofluidics.

5 4BMedicaldiagnostics5.1 12BInvitrodiagnosticD8Invitrodiagnosisformedicalapplicationshastraditionallybeenalaborioustask;bloodandotherbodyfluidsortissuesamplesaresenttoalaboratoryforananalysis,whichcouldtakehours,daysorevenweeks,dependingontheusedtechnique,andishighlylabourintensive.Themanydisadvantagesincludesampledeterioration,cost,lengthywaitingtimes(evenforurgent cases), inaccurate results for small sample quantities, difficulties in integratingparameters obtainedby awide variety ofmethods and poor standardisation of samplecollection.Steadily,miniaturisation,parallelisationandintegrationofdifferentfunctionsonasingledevice,basedon techniquesderived from theelectronics industry,have led to the

development of a new generation ofdevices that are smaller, faster and cheaper,do notrequirespecialskills,andprovideaccuratereadings.Theseanalyticaldevicesrequiremuchsmallersamplesandwilldelivermorecomplete(andmoreaccurate)biologicaldatafromasinglemeasurement.Therequirementforsmallersamplesalsomeanslessinvasiveandlesstraumaticmethodsofextraction.Nanotechnologyenables further refinementofdiagnostic techniques, leading tohigh throughput screening (to test one sample for numerous diseases, or screen largenumbersofsamplesforonedisease)andultimatelypointofcare(POC)diagnostics.

An invitro diagnostic tool canbe a singlebiosensor, or an integrated device containing

manybiosensors.Abiosensor is a sensor that contains abiological element, such as anenzyme, capable of recognising and signalling (through somebiochemical change) the

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presence,activityorconcentrationofaspecificbiologicalmoleculeinsolution.Atransduceris used to convert the biochemical signal into a quantifiable signal. Key attributes ofbiosensorsaretheirspecificityandsensitivity.

Techniques derived from the electronics industry have enabled the miniaturisation of

biosensors, allowing for smaller samples and highly integrated sensor arrays,which takedifferentmeasurements in parallel from a single sample. Higher specificity reduces theinvasiveness of the diagnostic tools and simultaneously increases significantly theireffectivenessintermsofprovidingbiologicalinformationsuchasphenotypes,genotypesorproteomes.

Fig. 3:Inchecklabonchipplatform,Credit:STMicro

Several complex preparation and analytical steps canbe incorporated into labonachipdevices, which can mix, process and separate fluids, realising sample analysis andidentification.Integrateddevicescanmeasuretenstothousandsofsignalsfromonesample,thusprovidingthegeneralpractitionerorthesurgeonwithmuchmorecomplementarydatafromhispatients sample. Somedevices fordiagnosticshavebeendeveloped tomeasurepartsof thegenomeorproteomeusingDNA fragmentsorantibodiesas sensingelementsandarethuscalledgeneorproteinchips.Cellsonchipsusecellsastheirsensingelements,employedinmanycasesforpathogenortoxicologyscreening.Integrated devices canbe used in the early diagnosis of disease and formonitoring the

progressoftherapy.

Newadvancementsinmicrofluidicstechnologiesshowgreatpromisetowardstherealisationof a fully integrateddevice thatdirectlydelivers fulldata for amedicaldiagnosis from asinglesample.Recentdevelopmentsaimatdevelopinginvitrodiagnostictoolstobeusedinastandardclinicalenvironmentore.g.aspointofcaredevices.

Improvementsofspecificationsofinvitrodiagnosticdevicesthankstonanotechnologiescanbe envisaged in two major application areas: Point of care (POC) analysis and centralanalytical labs.Ononehand,miniaturisation, integration andmultiplexingwouldbe key

featuresforPOCdevices.Ontheotherhand,centralanalyticallabsinhospitalsneedhighlyautomatedsystemwithhigh throughput.Howeverat themomentpointofcare isnot the

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main focus of In vitro diagnostic (IVD) industrywhich concentrates and earns themostmoney in central clinical labs. However, in the long term the capacity of central labdiagnosticswill probably saturate,whichwill likely result in an increased need for POCdiagnostics.The trend towards simplediagnostics tests in theGeneralPractitionersofficeand ultimately the home of the patientbecomes inevitable. This trend however requires

morerobustsystems,easy tooperatewithout technical training,offering fastresponseandthedeliveryofeasilyanalysabledatatothepractitioner.

5.2 13BInvivodiagnosticInvivo diagnostics refers in general to imaging techniques,but also covers implantabledevices.Nanoimagingincludesseveralapproachesusingtechniquesforthestudyofinvivomoleculareventsandmoleculesmanipulation. Imaging techniquescoveradvancedopticalimaging and spectroscopy, nuclear imagingwith radioactive tracers,magnetic resonanceimaging,ultrasound,opticalandXray imaging,allofwhichdependonidentifying tracers

orcontrastagentsthathavebeenintroducedintothebodytomarkthediseasesiteThegoalofinvivodiagnosticsresearchistocreatehighlysensitive,highlyreliabledetectionagentsthatcanalsodeliverandmonitortherapy.Thisisthefind,fightandfollowconceptof early diagnosis, therapy and therapy control that is encompassed in the concept oftheranostics.With this strategy, the tissue of interest can firstlybe imaged, using targetspecificcontrastnanostructures.Then,combinedwithapharmacologicallyactiveagent,thesame targetingstrategycanbeusedforapplying therapy.Finally,monitoringof treatmenteffectsispossiblebysequentialimaging.

5.2.1 19BImagingMedical imaginghasadvanced from amarginal role inhealthcare tobecomean essentialdiagnostictooloverthelast25years.Molecularimagingandimageguidedtherapyisnowabasic tool formonitoringdisease and indeveloping almost all the applications of invivonanomedicine.Originally, imaging techniquescouldonlydetectchangesin theappearanceoftissueswhensymptomswererelativelyadvanced.Later,contrastagentswereintroducedtomore easily identify andmap the locus of disease. Today, through the application ofnanotechnology,both imaging tools and marker/contrast agents arebeing dramaticallyrefinedtowardstheendgoalsofdetectingdiseaseasearlyaspossible,eventuallyatthelevelofasinglecell,andmonitoringthetherapyeffectiveness.Targetedmolecular imaging is important forawiderangeofdiagnosticpurposes,suchas

the identificationof the locusof inflammation, the localizationand stagingof tumors, thevisualisationofvascularstructuresorspecificdiseasestatesandtheexaminationofanatomy.It isalso importantforresearchoncontrolleddrugrelease, inassessingdrugdistributions,andfortheearlydetectionofunexpectedandpotentiallydangerousdrugaccumulationsTheconvergenceofnanotechnologyandmedicalimagingopensthedoorstoarevolutioninmolecular imaging (also called nanoimaging) in the foreseeable future, leading to thedetectionofasinglemoleculeorasinglecellinacomplexbiologicalenvironment.

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Fig4.DiffusionMagneticResonanceImagingofhumanbrain.Credit:CEA

Current imagingmethods canonly readilydetect cancersonce theyhave causedavisiblechange to a tissue,bywhich time thousands of cellswill have proliferated and perhapsmetastasized.And evenwhen visible, the tumornaturemalignant orbenign and thecharacteristics thatmightmake it responsive to a particular treatmentmustbe assessed

throughbiopsies. Imagine instead ifcancerousorevenprecancerouscellscouldsomehowbetaggedfordetectionbyconventionalscanningdevices.Twothingswouldbenecessaryfirstsomethingthatspecificallyidentifiesacancerouscellandsecondsomethingthatenablesit tobeseenandbothcanbeachieved throughnanotechnology.Forexample,antibodiesthat identifyspecificreceptors found tobeoverexpressed incancerouscellscanbecoatedontonanoparticlessuchasmetaloxideswhichproduceahighcontrastsignalonMagneticResonance Images (MRI)orComputedTomography (CT)scans.Once inside thebody, theantibodiesonthesenanoparticleswillbindselectivelytocancerouscells,effectivelylightingthemupfor thescanner.Similarly,goldparticlescouldbeused toenhance lightscatteringforendoscopy techniques likecolonoscopies.Nanotechnologywillenable thevisualization

ofmolecularmarkersthatidentifyspecificstagesandtypesofcancers,allowingphysicianstoseecellsandmoleculesundetectablethroughconventionalimaging.

5.2.2 20BImplants,sensorsImplantableDevicesforInvivoDiagnostics

Nanotechnology also has many implications for in vivo diagnostic devices such as theswallowableimagingpillandnewendoscopicinstruments.Monitoring of circulatingmolecules is of great interest for some chronicdiseases such asdiabetesorAIDS.Continuous,smartmeasurementofglucoseorbloodmarkersofinfectionconstitutes a realmarket for implantable devices.Miniaturisation for lower invasiveness,

combinedwithsurfacefunctionalisationandthe biologicalisationof instrumentswillhelpincreasetheiracceptanceinthebody.Autonomouspower,selfdiagnosis,remotecontrolandexternaltransmissionofdataareotherconsiderationsinthedevelopmentofthesedevices.Nanosensors, forexampleused incatheters,willalsoprovidedata tosurgeons.Nanoscaleentitiescouldidentifypathology/defects;andthesubsequentremovalorcorrectionoflesionsbynanomanipulationcouldalsosetafuturevision.

Nanoharvestingofbiomarkers

Researchers attempting to identify diseaserelated biomarkers in blood face two majorproblems, each ofwhich the new polymerbased nanoparticles appear to overcome.One

issue is that two proteinsalbumin and immunoglobulinaccount for 90 percent of themolecules inblood,whereasanypotentialbiomarkersare likely tobepresentatonly trace

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levels.Furthermore,manybloodbornemoleculesadheretothesetwomajorproteins,sothatanyefforttoremovetheseprevalentproteinstomaximizeananalyticalsignalfromthetracesubstances is likely to also eliminate the potentialbiomarkers. In addition,many of thepotentialbiomarkersarelikelytobeproteins,butenzymespresentinbloodbegindegradingtheseproteinsalmostimmediatelyafterbloodisremovedfrombody.

Nanoparticles can be modified to render surfaces selective for targeted molecularinteractions.Asthe

Hbiomarker

Hpopulationspresentinbloodwillbemorefullycharacterized,

nanoparticle harvesting platforms will have significant potential for improving diseasedetectionatanearly,moretreatablestage.

Nanobiopsy

Braintumoursareoftenthehardestcancerstodiagnoseinthehumanbody.Fordiagnosisinother tissues,biopsies allow to determinewhether a tumour isbenign ormalignant.Butremovingbrain tissueshouldbeavoideddue to thespecificityof thisorgan.However, thedecreased invasiveness enabledby nanotechnology offer an alternative. In order tomap

brain tumours, a novel techniquebased on a nano patterned pen hasbeendeveloped tocollectproteinsandcellsbysurfaceadhesion.Thisisdonethroughtheuseofanendoscopicpenwhich is inserted through thebrain. Then a small amount of floating cells andbiomolecules is removed from the targetarea in thebrain,without removingbrain tissue.However,becauseoftheextremelydelicatenatureofthebrain,preciseplacementofthetipofthepenbystereotaxicmethodsisvitaltoensurethesampleisremovedwithoutcausingharmtopotentiallyhealthytissuesurroundingit.

Fig5:Protool,harvestingdeviceforcollectingcellsandbiomoleculesinthebrain.Credit:CEALeti

6 5BNanoPharmaceuticalsThescopeofpharmacypractice includesmore traditional rolessuchascompoundinganddispensing pharmaceutical drugs.Most of pathologies are treatedby dispensing drugs.Someof themaresmallchemicalmoleculeswhileothersarebiologicalones.However theuse of systemic drug administration may generate some side effects. Thereforeimprovements of drug administration, especially for injectable drugs, are looked forbypharma industryandbypatients.Encapsulationofdrugs incarriers isapossibility,whichhasbeenexplored forseveral tensofyears.Nanotechnologyoffersmeans toaim therapies

directly and selectively at diseased tissues or cells, with application in cancer or

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inflammation for instance.Thebehaviourofnanomaterialsused for invivoadministrationshouldbedemonstratedwhethertheyarebiocompatible,orbiodegradable.

6.1 14BNanoparticulateDrugDeliverySystemsIn theshortandmedium term, themainuseofnanoparticlemedicinalproducts (NMP) isvectorizationofactiveprinciples,corresponding toseveralproductsalreadymarketed likeDoxil.ormorerecentlyAbraxane.Generallythreevectorgenerationsareconsidered:

Firstgenerationvectors:nanospheres andnanocapsules (thebestknown andmostaccessible),

Secondgenerationvectors:nanoparticles coatedwithhydrophilicpolymerssuchaspolyethyleneglycol(PEG),PEGylatednanoparticles

Thirdgenerationvectors, stillunderdevelopment, combiningabiodegradable coreandapolymerenvelope(PEG)withamembranerecognitionligand.

Today,mostcurrentresearchprojectsinnanodeliverysystemsarefocusedonthethirdtype.

Fig6:Lipidotslipidnanoparticlescontainingvariousorganicdyesformolecularimaging.Credit:

CEALeti

Conventional chemotherapy employsdrugs thatareknown tokill cancer cells effectively.Butthesecytotoxicdrugskillhealthycellsinadditiontotumorcells,leadingtoadversesideeffects suchasnausea,neuropathy,hairloss, fatigue,and compromised immune function.Nanoparticles canbe used as drug carriers for chemotherapeutics to delivermedication

directlytothetumorwhilesparinghealthytissueD9D.Nanocarrierspresentseveraladvantagesoverconventionalchemotherapy.Theycan:

Protectdrugsfrombeingdegradedinthebodybeforetheyreachtheirtarget. Enhancedrugabsorptionintotumorsandthecancerouscellsthemselves. Allow forbetter control over the timing and distribution of drugs to the tissue,

makingiteasierforoncologiststoassesshowwelltheywork. Preventdrugsfrominteractingwithnormalcells,thusavoidingsideeffects.

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Fig7:Lipidotsfordrugdeliveryandmolecularimaging.Credit:CEALeti

PassiveTargeting

There are now several nanocarrierbased drugs on the market, which rely on passivetargeting through a process known as enhanced permeability and retention. Because oftheirsizeandsurfaceproperties,certainnanoparticlescanescapethroughbloodvesselwallsinto tissues. Inaddition, tumors tend tohave leakybloodvesselsanddefective lymphaticdrainage, causingnanoparticles toaccumulate in them, thereby concentrating theattachedcytotoxicdrugwhereitsneeded,protectinghealthytissueandgreatlyreducingadversesideeffects.Another strategy for passive targeting consists in usingmyeloid cells likemacrophageswhichabsorbnanoparticlesandconcentratetheminthesitetobetreated,likeaTrojanhorse.

ActiveTargeting

Onthehorizonarenanoparticlesthatwillactivelytargetdrugstocancerouscells,basedonthemolecules that they express on their surface.Molecules thatbind particular cellularreceptorscanbeattachedtoananoparticlesothatitspecificallytargetscellsexpressingthisreceptor. Active targeting can evenbe used tobring drugs into the cancerous cell,byinducing thecell toabsorb thenanocarrier.Active targetingcanbecombinedwithpassivetargetingtofurtherreduceinteractionofcarrieddrugswithhealthytissue.Nanotechnologyenabledactiveandpassivetargetingcanalsoincreasetheefficiencyofachemotherapeutic,achievingmoresignificanttumorreductionwithlowerdrugdoses.

Destructionfromwithin

Moving away from conventional chemotherapeutic agents that activate normalmolecularmechanisms to induce cell death, researchers are exploring ways to physically destroycancerouscellsfromwithin.Onesuchtechnologynanoshellsisbeingusedinlaboratoryto thermallydestroy tumorsfromthe inside.Nanoshellscanbedesignedtoabsorb lightatdifferentwavelengths, generating heat (hyperthermia).Once the cancer cells take up thenanoshells(viaactive targeting),scientistsapplynearinfrared light that isabsorbedby thenanoshells,creatinganintenseheatinsidethetumorthatselectivelykillstumorcellswithoutdisturbingneighbouringhealthycells.Similarly,newtargetedmagneticnanoparticlesarein

developmentthatwillbothbevisiblethroughMagneticResonanceImaging(MRI)andcanalsodestroycellsbyhyperthermia.

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6.2 15BDrugDelivery(mechanical)DevicesImplanteddrugdeliverydevicesDDDcantakebenefitofnanotechnology.ExamplesareDebioStarorNanopump,fabricatedbytheSwisscompanyDebiotechD10D.TheNanopumpisaminiaturizeddrugdeliverypumpbasedonMEMS chipswhich canbe implanted foraccurate dosing of various therapeutic compoundswith dedicated delivery profiles. TheNanopump has been tested for instance for insulin delivery. The precision ofnanofabricationandmicro techniquesenabledesignand fabricationofultra smalldeviceswith reservoirs, actuators, pumps to control accurately the release of pharmaceuticalingredients.Somepartsofthesemicrosystemsareatthenanoscale.Duetotheirsmallsizeandlowinvasiveness,thesedrugdeliverydevicescanbeimplantedwithinthebody,eveninthebrain.

Fig8:DELICEminiaturisedpumptechnologyfordrugdelivery.Credit:CEALeti

6.3 16BTheranostics,combinedtechniquesNanobiotechnologyofferssignificantinputstotheimprovementofdetectiondevicesandofthe taggingofdisease indicatorsadministered invivo,whichwill lead toadvancement inimaging.Potentdrivingforcesincludesynergies,suchasthosebetweeninvitrodiagnostics(probesandmarkers)and invivo imaging techniquesand thosebetweencontrastagents /

probe development (in drug delivery and/or toxicology studies) and imaging technology(medical instrumentation).The combinationof invitrodiagnostics techniquesand invivonanoimagingcouldleadtotargetedtumordisruptionorremoval:Taggingtumorcellswithfunctionalized nanoparticles,which react to external stimuli, allows for insitu, localizedsurgery (breaking up or heating of particlesby laser,magnetic fields,microwaves, etc.)withoutinvasivenesswithinthehumanbody.Thecapacityofsomenanoparticlestocarrycontrastagentsanddrugsopensnewwaysfortherapy.Theranostic,usedasa combinationof therapyanddiagnostics, canbe envisageddifferently.Imagingcanbeusedtotracethedeliveryofdrugwithinthebody.Butimagingcanalsobeused toactivate thedrug release fromoutside,byan external stimulus,.Such

externalstimuli

can

be

laser

light,

temperature

or

ultrasounds

for

instance.

All

in

all,

the

smartprobesrepresentnewconceptsforclinicalpractice.

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7 6BRegenerativemedicineRegenerativemedicineistheprocessofcreatingliving,functionaltissues,torepairorreplace

tissueororgan function lostdue toage,disease,damage,or congenitaldefects.This fieldholds thepromiseofregeneratingdamaged tissuesandorgans in thebodybystimulatingpreviously irreparable organs to healby themselves. Regenerative medicine could alsoempowers physicians to grow tissues and organs in laboratory and safely implant themwhen thebody cannot healby itselfD11D. Regeneration of tissues canbe achievedby thecombinationoflivingcells,whichwillprovidebiologicalfunctionality,andmaterials,whichactasscaffoldstosupportcellproliferation.The vision for nanoassisted regenerative medicine is the development of costeffectivediseasemodifying therapies that will allow for insitu tissue regeneration. Theimplementation of this approach involves not only a deeper understanding of thebasic

biology of tissue regeneration wound healing, in its widest sense but also thedevelopmentofeffectivestrategiesandtoolstoinitiateandcontroltheregenerativeprocess.

7.117BStemcells

Combinatorial extracellularmatrixmicronanoarrays, generatedby softlithography, havegreatpotentialinstudyingandcontrollingthebehaviourofstemcells.Nanomaterialbasedgene delivery formanipulating stem cells has a vital role in recognizing the potential ofregenerativemedicineD12D.

Themajorgoalofongoingandfutureeffortsinregenerativemedicinewillbetoeffectively

exploittheenormousnewlydiscoveredselfrepairpotentialthathasbeenobservedinadultstem cells. Given the logistical complexities and the costs associatedwith todays tissueengineering therapies, which are based on the autologous reimplantation of cultureexpandeddifferentiatedcells,nextgeneration therapieswillneed tobuildon theprogressmadewith tissueengineering inunderstanding thehugepotential for cellbased therapieswhich involve undifferentiated cells. Nanotechnology will aid in pursuing two mainobjectives:

1. Identifying signalling systems in order to leverage the selfhealing potential ofendogenousadultstemcells

2. Developingefficienttargetingsystemsforadultstemcelltherapies.

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Fig9:FigurefromN.Jessel INSERMU977,Strasbourg,France:A. A.Manufactureofthe(Poly(caprolactone)PCLmembranebyelectrospining;

scalebar1 mB. B.Invivoboneinduction:Osteopontinexpression(ingreen)onPCLmembrane

Scalebar:20 m.

Onepossible application for future regenerativemedicine strategies is to avoidhaving topreseed ananostructuredbiomaterial scaffold ormatrixwith thepatientsown cells,butrather tohave thebiomaterials loadedwith essential signallingmolecules targeting adultprogenitorcellsintheimplantsite.Thus,understandinghowadulthumanstemcellsreacttosuchnanostructuresdependingonthesiteoftissueregenerationwillbeaconditionsinequanonforspecificapplications.Cellbasedtherapiesshouldbeaimedatefficientharvestingofadult stem cells, toallow forabriefpreimplantation, cultivation stage,or,preferably, forimmediateintraoperativeadministrationusinganintelligentbiomaterialasabiointeractivedelivery vehicle.Ofhuge impactwould alsobe the ability to implant cellfree intelligent,bioactivematerials that would effectively provide signalling to leverage the selfhealingpotentialofthepatientsownstemcellsD13D.

7.2 18BBiomaterialsMammaliancellsbehave invivo inresponse to thebiologicalsignals theyreceivefrom thesurroundingenvironment,whichisstructuredbynanometrescaledcomponents.Therefore,

materialsusedinrepairingthehumanbodyhavetoreproducethecorrectsignalsthatguidethe cells towards a desirablebehaviour.Nanotechnology is not only an excellent tool toproducematerial structures thatmimic thebiological onesbut also holds the promise ofproviding efficient delivery systems. The application of nanotechnology to regenerativemedicine is awide topic. It covers the fabricationofmaterials, such asnanoparticles andscaffolds for tissue engineering, and surface nanopatterning to elicit specific biologicalresponsesfromthehosttissueD14D.

Futurebiomaterials must simultaneously enhance tissue regeneration while minimizingimmuneresponsesandinhibitinginfection.Whilepromotersoftissueengineeringpromised

todevelopmaterials thatcan triggertissueregenerationfor theentirebody,suchpromiseshave yet not become reality. However, tissue engineering experienced recently great

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progress due to the emergence of nanotechnology. Specifically, it has now been wellestablished that enhanced tissue regeneration canbe achieved on almost any surfacebyemployingnovelnanotexturedsurface features.Numerousstudieshavereported thatuseofnanotechnologyallowstoacceleratevariousregenerativetherapies,suchasthoseforthebone,vascular,heart,cartilage,bladderandbraintissue.Variousnanostructuredpolymers

andmetals(alloys)havebeeninvestigatedfortheirbio(andcyto)compatibilitypropertiesD15D.

To apply nanotechnology to stem cell biology several conditions must be fulfilled:nanomaterialsmustbedesignedtointeractwithproteinsandcellswithoutperturbingtheirbiologicalactivities;nanomaterialsmustmaintaintheirphysicalpropertiesafterthesurfaceconjugationchemistry;andnanomaterialsmustbebiocompatibleandnontoxicD16D.

Accesstonanotechnologyhasofferedacompletelynewperspectivetothematerialscientisttomimicthedifferenttypesofextracellularmatricespresentintissues.Techniquesarenowavailable which can produce macromolecular structures of nanometre size, with finely

controlled composition and architecture.Conventionalpolymer chemistry, combinedwithnovelmethodologies suchas electrospinning,phase separation,directpatterningand selfassembly, havebeen used to manufacture a range of structures, such as nanofibres ofdifferent andwell defined diameters and various surfacemorphologies, nanofibrous andporous scaffolds, nanowires and nanoguides, nanospheres, nano trees (e.g.dendrimers),nanocompositesandothermacromolecularstructuresIn conclusion, nanotechnology can assist in the development ofbiomimetic, intelligentbiomaterials, which are designed to positively react to changes in their immediateenvironment and stimulate specific regenerative events at themolecular level in order togeneratehealthytissues.

8 7BEthicsNanotechnologyoffersgreatpromiseformedicine,butmuchofthisliesinthefuture.Thisfutureorientationhasmadenanotechnologyvulnerabletothecurrenttrendofoverclaiminginscience,either thepotentialbenefitorharm.There isaneed tobecarefulaboutplacingprematureweightonspeculativehopesorconcernsaboutnanotechnologiesraisedaheadofevidence.Foresightingofbreakthroughtechnologies isnotoriouslydifficult,andcarriestherisk that early public engagementmay promote either public assurance or concern overwrongissues.

Nanotechnology as an enabling technology for many future medical applications raisesissues such as sensitivity of genetic information, the gapbetweendiagnosis and therapy,health care resources and tensions between holistic and functional medicine. As well,nanotechnologywilladdanewpossibilitiesattheinterfacebetween bio(human)andnonbio(machine)suchasbrainchipsorimplants,whichmayeventuallyraisenewethicalissuesspecifictonanomedicine.ThisrequirescarefulanalysisofethicalaspectsinviewofexistingstandardsandregulationssetbyethicscommitteesattheEuropeanscale.At the same time,newnanomedical inventionshave tobe evaluatedwith respect tonewethicalaspectsbyethical,legalandsocialaspects specialists.Thekeypointinthisregardisan early proactive analysis of new technological developments to identify and discuss

possible issues as soon as possible.This requires a close collaboration and colearning oftechnologydevelopers and ethics specialists assistedby communication experts to ensure

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openandefficient informationof thepublicaboutethicalaspectsrelated tonanomedicine.This coevolutionwill ensure a socially and ethically accepteddevelopmentof innovativediagnosticandtherapeutictoolsinnanomedicine.Fromtheaboveitisclearthatanindepthethicalanalysisisnecessaryinthisfield.Suchananalysisshouldbebasedonthefollowingprinciples.

HumanDignityandthederivedethicalprinciplesof: Noninstrumentalisation:Theethicalrequirementofnotusingindividualsmerelyas

ameansbutalwaysasanendoftheirown. Privacy:Theethicalprincipleofnotinvadingapersonsrighttoprivacy. Nondiscrimination: People deserve equal treatment, unless there are reasons thatjustifydifferenceintreatment.Itisawidelyacceptedprincipleandinthiscontextitprimarilyrelatestothedistributionofhealthcareresources.

InformedConsent:Theethicalprinciplethatpatientsarenotexposedtotreatmentorresearchwithouttheirfreeandinformedconsent.

Equity:Theethicalprinciple thateverybodyshouldhave fairaccess to thebenefitsunderconsideration.

ThePrecautionaryPrinciple:ThisprincipleentailsthemoraldutyofcontinuousriskassessmentwithregardtothenotfullyforeseeableimpactofnewtechnologiesasinthecaseofICTimplantsinthehumanbody.

The last of these principles (the Precautionary Principle) is particularly important in thisparticularcontext.Theethicalanalysisshouldalsodealwithvalueconflicts.Therecouldexistsconflictbetweenpersonal freedom to use ones economic resources to obtain advanced treatment such as

nanomedicineandwhatsocietyatlargeconsidersdesirableorethicallyacceptable.Concernforeconomiccompetitivenessandothereconomicvalues(economicgrowth)maycomeintoconflictwithrespectforhumandignity.Unrestrictedfreedomofsomemayendangerhealthand safety of others. Therefore abalance has tobe struckbetween values that are alllegitimateinourculture.

9 8BRegulation,approvalEuropeanMedicinesAgency

The current regulatory framework based on benefit/risk approach and including risk

management plan and environmental risk assessment, is adequate for the currentdevelopmentandevaluationofcurrentnanoapplicationinpharmaceuticals.Currentregulatoryexperienceallowstheassessmentofmanyaspectsofnanomedicines,butthere is a scientific gap between the current knowledge and the more advanced andemergingnanomedicines.Thisgap isanopportunityforscientificresearchD17D.It isexpectedthatnewmethodswillbeimplementedtocomplementtherelevantexistingguidelinesandnewfeatureswillbeassessedastheyemerge.

AgenceFranaisedeScuritSanitairedesProduitsdeSantWorkingGrouponnon

clinicalinnovation

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AFSSAPSF1Fhasreleasedin2009apositionpaperapprovedbytheExpertsoftheReflexionGrouponneworientationsonevaluatingnonclinicalsafetyofHealthproductsF2F.AccordingtothisexpertgroupF3F,andasindicatedabove,...generalscientificand/orregulatorydatarelatedtothetoxicologicalevaluationofnanoparticlemedicinalproducts(NMP)arecurrentlylacking

Howevertheconventionaltoxicologicalapproachproposedbycurrentguidelinesformedicinal

productsingeneralhasbeenacceptedupuntilnowforapprovedNMPsorNMPscurrentlyunder

evaluationbyhealthauthorities.However,somecriticismshavebeenraisedconcerningthecurrently

availablemethodsofexperimentalevaluationthatareconsideredtonotadequatelyassessthe

propertiesofnanoparticleproductsConsequently,likecertainconsumergroupsintheUSA,we

mayneedtorecommendthedevelopmentofcompletelynewregulationsbasedonadaptedsafety

assessmenttestsfornanomaterials,includingNMPs.Thismaximalistproposalistotallyidealistic

andscientificallyunjustifiedaccordingtotheverygreatmajorityofthescientificcommunity.How

manyyearsfordevelopmentandvalidationwouldbenecessarytoachievesucharesult?Thismajor

revisionalsodoesnotappeartobejustifiedbytheavailablescientificdata.Somemanufacturersand

mostoftheAFSSAPStaskforcealsoconsiderthattoxicologicalevaluationofNMPsshouldnotbe

appreciablydifferentfromconventionalevaluation,butwithcertainspecificadaptations.Theplan

adoptedforelaborationoftheserecommendationsisbasedonthislatterapproach,i.e.adaptthesafety

assessmentstrategy,whennecessary,withoutmodifyingthebasicprinciplesD18D.

USFoodandDrugAdministration(FDA)

AccordingtoFDA:Nanomedicineisreallynodifferentthananyothernewtechnologythatwouldbe incorporated into FDAproducts. Sowith that inmind,wefeel comfortable using ourpresent

regulatoryframework.However,wefeltthere isneedforguidancetohelpthis industryas itmoves

forward.Werecognizedaneedforadditionalinformationinvariousareas,suchasbiosafety.FDAand

otheragenciesareworkingtogetheronthat.Butfornow,wejustdonotseetheneedforregulations

writtenspecificallyfornanoengineeredmaterialsintheproductsFDAregulates(2008)D19D.The existing regulatoryframework can accommodate the types of nanoparticle therapeutics under

developmentandwhenneeded,adapttoaddressnewchallenges.Currentpublishedguidancemaybe

applicable to nanoparticle therapeutics. Staff is working on addressing the need for guidance

documents that address nanorelated issues aswell as the regulatory science to bring to bear this

emergingtechnology(2010)D20D.

10 9BTheindustrialperspectiveNanomedicineisnolongerrestrictedtoanacademicconcept.Thatisnowalsoanindustrial

reality, amarketwith approvedproducts anddevices.Nanomedicine is a large industry,withsalesreaching6.8billiondollarsin2004,andwithover200companiesand38productsworldwide.Aminimumof3.8billiondollarsinnanotechnologyR&Disbeinginvestedeveryyear.HU]UH Asthenanomedicineindustrykeepsongrowing,itisexpectedtosignificantlyimpacteconomy.

1AgenceFranaisedeScuritSanitairedesProduitsdeSant(FrenchHealthProductsSafety

Agency)2GroupedeRflexionsurlesNouvellesOrientationsenMatiredvaluationNoncliniquedelaScuritdesProduitsdeSantdelAfssaps

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Tradename company Yearapproved

Ativepharmaceuticalingredient

Indication Nanotechnology

Visudyne 2000 Verteporfin Photodynamlictherapy

foragerelatedmaculardegeneration

Liposome

Doxil/Caelyx 1995 Doxorubicin Antineoplastic PEGylatedliposomeAmBisome 1990 AmphotericinB Fungalinfections Liposome

Abelcet 1995 AmphotericinB Fungalinfections LiposomeDefinity 2001 Octofluoro

propaneLiposome

Myocet 2001 Doxorubicin LiposomeDepoCyte 1999 Cytarabine Lymphomatous

meningitisLiposome

DepoDur 2004 Morphine LiposomeDaunoxome 1996 Daunirubicin Antineoplastic LiposomeOctocogalfa 2009 FactorVIII LiposomeAbraxane Abraxis

Biosciences2005 paclitaxel Metastaticbreastcancer Albuminbound

nanoparticlesRapamune Wyeth 2000 Rapamycin Immunosuppresant NanocrystalElanEmend Merck 2003 Aprepitant Antiemetic NanocrystalElanTricor Abbott 2004 Fenofibrate Hypercholesterolemia NanocrystalElanMegaceES ParPharmaCo 2005 Megestrol Antianoretic NanocrystalElanTriglide ScielePharmaInc. 2005 Fenofibrate Hypercholesterolemia IDPPSkyepharma

nanocrystalMepact Mifamurtide LiposomeAmphotec 1996 Fungalinfections MicelleEstrasorb 2003 Vasomotorsymptoms

associatedwithmenopause

Micelle

Taxotere 1996 Antineoplastic MicelleSomatulinedepot

2007 Acromegaly Nanotube

Ferahemeinjection

2009 TreatmentofirondeficiencyanemiainpatientwithChronicKidneyDisease

SPIO

Table14: ListofdrugsapprovedbyFDA.Source:AdaptedfromUSFDAandEMA

Only a few studies provide clear estimates of nanomedicine market., Drug deliveryrepresents the largest application area, while the biomaterials are the fastestgrowingapplicationsegmentovertheyears2006through2015.Howeverthenanomedicinemarketishighly fragmented and is characterized by the presence of several niche players. Thefollowingplayersareamongthelargestonesormostactiveonesinnanomedicine:

NanosphereInc. ParPharmaceuticalCompaniesInc. AMAGPharmaceuticalInc. ElanCorporationPLC LifeTechnologiesCorporation

AbraxisBioScienceInc.(nowCelGene) FlamelTechnologiesS.A.

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OxonicaPlc WyethPharmaceuticalsInc MagForceGmbH NanoBiotix ArrowheadResearchCorporationD21

Theglobalnanomedicinemarketwasvaluedat$53billionin2009,andisforecasttoincreaseatacompoundannualgrowthrate(CAGR)of13.5%toreachmorethan$100billionin2014.Nanomedicalproductsforcancerareoneofthelargestmarketsegments,worthnearly$20billionin2009.Thissectorisexpectedtoincreaseatacompoundannualgrowthrate(CAGR)of 11% to reach $33billion in 2014. Nanomedicine for central nervous system relatedindicationsisanothermajormarketsector,valuedatnearly$11billionin2009andexpectedtoreach$18billionby2014,an11.1%compoundannualgrowthrate(CAGR).D22

Althoughthenumberofnanotechbasedmedicinesmaylooklimited,asignificantnumberofclinical trials involvingtheuseofnanoparticles,87precisely,are listed in theUSNIHdatabase

HUwww.clinicaltrials.gov

UH,especially inphase Iandphase II. It isexpected that some if

themwillreachtheapprovalstageandthenthemarket inafewyears, thus increasingthenumberofsuccessfulnanopharmaceuticals.

Thedominantmodelfor theinnovationchain innanobiotechisof typeAwherediscoverymadeinacademiclabsistransferredtospinofforhightechSMEsaddressingnichemarkets,validatingtheconceptandinitiatingthefirstclinicaltrials,sometimesuptostageIIa.Then

largecompaniestakeovertheseSMEswithinnovativeandvalidateddevices,moleculesorconcepts.

AcademiaSME

Spin-off

Large

company

Clinical trials

Largecompany

MAR

KET

A)A)

B)B)

Academia

Fig10:innovationchainofnanomedicine.Credit:personaldata

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TheNanomedicineEuropeanTechnologyPlatform(ETP)establishedin2005isaninitiativeled by industry and set up together with the European Commission, addressing theapplicationofnanotechnologytoachievebreakthroughsinhealthcare.TheETPsupportsitsmembersincoordinatingtheirjointresearcheffortsandimprovingcommunicationamongstthemaswellas towards theEuropeanCommissionand theEuropeanMemberStates.The

NanomedicineETPpromotes thedevelopmentof thenanomedicine industry inEurope, inliaisingindustry,academiaandhospitalsfortranslatingnanomedicineresearchfrombenchtobedside.Itsrolebecomesevenmoreimportantinthecontextofopeninnovation.

Nanomedicine isarecentsetof technologies.Researchsignificantlystartedabout tenyearsagoonly.Itisusuallyconsideredthattheaveragedevelopmenttimeforanyhightechrangesfrom10to15years.Thereforenanomedicineisnotdevelopingmoreslowlythanotherhightechnology. Some large companies are however sometimes reluctant to invest intonanomedicineR&Dprojectsbecausetherearestillsomeuncertaintiesabouttheregulationtobeappliedtothiskindoftechniques.Inaddition,poorsocialacceptanceofnanotechnologies

ingeneral,and oppositionexpressed in some countriesagainst inorganicnanoparticles isnot favourable to investment, even though nanomedicine ismuchbetter acceptedby thegeneralpublicthanuseofnanotechnologiesinmanufacturedproducts.TheexampleoftheFrenchpublicdebateonnanotechnologyin20092010highlightsthispointofviewD23D.

11 10BFrenchstakeholdersinnanomedicineNanomedicine is an active area in the French academia and in the small businesscommunity.Sincetheearly2000s,researchinstitutes,universities,somehospitalsandafewyearslater,SMEsandsomelargecompanieshaveshownstronginterestinnanomedicineby

participating tovariousEuropeanandnational initiatives.Itcanbesaid that today thatallstakeholderareinvolved.

Ministries

Nanotechnologyhasbeen considered formanyyearsasa strategicpriorityby theFrenchMinistriesofResearch and Industry.Research innanotechnology is a strategicpriority insome universities and several research organisations. Since 2003, a network of nanotechfacilities hasbeen supportedby French government to facilitate access of academia orindustrytonanotechnology.Morerecently,inMay2009,anadditionalefforttosupporttechtransferto industryhasbeeninvestedbytheMinistryofResearchby investing70millions

Eurosinthreemajorcentres:Saclay,GrenobleandToulouse.Research in nanosciences and nanotechnology in France represents approximately 5300scientistsand243labs.Franceisrankedatthe2ndor3rdpositioninEuropebyitsnumberofpublicationswhile it isranked6th in theworldbehind theUnitedKingdom,GermanyandChina.

A public debate hasbeen organised in late 2009 and 2010 about public acceptance andperceptionofnanotechnologyD24D.Ithadthreeobjectives:

1. Informthepublicaboutnanosciencesandnanotechnology2. Listentoquestions,reactions,statementbythepublic3.

Publishallwhathasbeendiscussedandpresentedoverthefourmonthsperiod.

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Its important to note that while there was some strong opposition to the use ofnanotechnologies inproducts like food,ormanufacturedproducts,nanomedicine ismuchbetter perceived. Nanomedicine, even if it leads to the use some nano components, isconsideredaspartof themedicalprogressand researchshouldbepursued, inconformitywiththelegalandregulatoryframework.

AVIESANITMOTS

Setup inApril2009, theFrenchNationalAlliance forLifeSciencesandHealth (Aviesan)groups together themain stakeholders of life andhealth sciences in France.AVIESAN isconsideredastheorganisationwhereacademiaandcliniciansarebestrepresentedtodiscussabout research.Among the ten thematic institutesof thisAlliance, the Institute forHealthTechnologiescoordinatesresearchinthefieldoftechnologiesthatareessentialtobiomedicalprogress inboth fundamental and clinical terms. As such, it started a working groupdedicatedtonanomedicinein2010.

Companies

ThereisnodedicateddatabaseordirectoryofFrenchcompaniesinvolvedinnanomedicine.In fact,very fewcompaniesconsider themselvesasnanomedicinecompanieswithsomeexceptionlikeNanobiotix,developingNanoXray.Nanomedicineisratherconsideredasanadvancedmedical technology.Therefore fewcompaniesare labelling theirproductnanoevenifitfitswiththedefinitionofnanotechnology,likeAbraxaneforinstance.However, the database Biotechnology in FranceD25D lists approximately 50 companiesbutmuchlessshouldbereallyconsideredasnanomedicinecompanieslike:

BioAlliancePharma BioMrieux CarlinaTechnologies Cezanne Cytoo Diatos Etypharm FlamelTechnologies Fluoptics

Genoptics Guerbet Imstar InoDiag Medsqual NanoH NanoBioTix (nonexhaustivelist)

Agencies

The FrenchMedicineAgencyAFSSAPS is responsible for the clearance of nanomedicineproductslikeanyotherdrugormedicaldevice.AworkinggroupfromAFSSAPSreleasedin2009recommendationsfortoxicologicalevaluationofnanoparticlemedicinalproducts.

TheFrenchNationalResearchAgencyANRissupportingnanomedicinerelatedresearchinseveral funding programmes.Except in the 20102011 programme Investissements dAvenir(French National recovery plan), no funding programme is fully dedicated tonanobiotechnology andnanomedicine as such.However,nanomedicine related topics areeligible and supported under several programmes like pNano, BiotecS, TecSan,Emergence.TheFrenchNationalResearchAgencyANRisalsosupportingtheFrenchlabs

participatingtoERANETEuroNanoMedprojects,from2010.

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12 11BConclusionLikemosthightechnologiesandtakingintoaccountthehighregulationofmedicalsector,ittakes 1015 years to any advanced medical technology before reaching the market.Consideringsignificanteffortsputinnanomedicinerelatedbasicresearchintheearly2000s,

it is expected that a significant number of approved nanodrugs or nanodevices willbeapprovedintheearly2010s.Sofar22nanodrugsareapprovedbyFDA,andmanymoreareunder clinical trials phase II or even III. The same situation occurs in Europe withapproximately25ongoingclinicaltrialsin2010D26D.Inthesametime,moreSMEsandspinoffcompanies targetmedical applications using nanotechnologies, sometimes nichemarkets,contributing to the validation of innovative concepts. It is easy forecasting that largecompanies, like pharma, imaging or diagnostics companies will help some of the mostpromising companies to reach the market. Then we will see what the real medicalapplications are forwhich nanotechnologybrings a real added value in a cost effectivemanner.

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1EuropeanScienceFoundation:Nanomedicine,anESFEuropeanMedicalResearchCouncils(EMRC)ForwardLookreport,2005.

2EuropeanTechnologyPlatformonNanomedicine,NanotechnologyforHealth:Visionpaperandbasisforastrategicresearchagendafornanomedicine,September2005,ECPublicationoffice.

3KreuterJ.Nanoparticlesahistoricalperspective.HUIntJPharm.UH2007Feb22;331(1):110

4UKRoyalSocietyandRoyalAcademyofEngineering(2004)Reportonnanoscienceandnanotechnologies:opportunitiesanduncertainties,(HUwww.nanotec.org.ukUH)

5CommissionoftheEuropeanCommunitiesCommunication(2004)TowardsaEuropeanStrategyforNanotechnology,EU,DGResearch,Brussels(HUwww.cordis.lu/nanotechnologyUH).

6NationalInstitutesofHealth:NIHroadmap:nanomedicine(2004),NIH,USA(HUhttp://nihroadmap.nih.govUH)

7NationalInstitutesofHealthNationalCancerInstitute(2004)CancerNanotechnologyPlan:astrategicinitiativetotransformclinicaloncologyandbasicresearchthroughthedirectedapplicationofnanotechnology,NCI,NIH,USA(HUhttp://nano.cancer.gov/alliance_cancer_nanotechnology_plan.pdfUH)

8NanotechnologyImprovingHealthcarethroughInvitroBiosensorsandIntegratedDevicesandInvivoImplantableDevicesandMedicalImaging,AZoNanotechnologyArticle,(HUhttp://www.azonano.com/Details.asp?ArticleID=1701#_Invitro_DiagnosticsUH)

9ChristineVauthierEtPatrickCouvreur:Nanotechnologiespourlathrapieetlediagnostic.(2008)NM4010, Lestechniquesdelingnieur.

10Debiotech:DebioSTARTMimplantabledrugdeliverytechnologyforthesustaineddeliveryofpharmaceuticalcompounds.(HUhttp://www.debiotech.com/products/drugdd/debiostar.htmlUH)

11Regenerativemedicine,NIHFactsheets,September2006.HUhttp://www.nih.gov/about/researchresultsforthepublic/Regen.pdfUH

12Regenerativemedicine,NIHFactsheets,September2006.HUhttp://www.nih.gov/about/researchresultsforthepublic/Regen.pdfUH

13ETPNanomedicine:Nanomedicine,NanotechnologyforHealth.StrategicResearchAgenda,2006

14ElisabethEngel,AlexandraMichiardi,MelbaNavarro,DamienLacroixandJosepA.Planell.Nanotechnologyinregenerativemedicine:thematerialsside.TrendsinBiotechnology,HVolume26,Issue1H,3947,1January2008

15HKhangDH,HCarpenterJH,HChunYWH,HParetaRH,HWebsterTJH.Nanotechnologyforregenerativemedicine.HBiomedMicrodevices.H2010Aug;12(4):57587

16AnnirudhSolanki,JohnD.Kim&KimBumLee.Nanotechnologyforregenerativemedicine:nanomaterialsforstemcellsimaging.Nanomedicine(2008)3(4),567578

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17MarisaPapaluca:Wayforward.(2010),EMAfirstinternationalworkshoponnanomedicines.

18AFSSAPS:Recommendationsfortoxicologicalevaluationofnanoparticlemedicinalproducts.(2009)

19BarbaraJ.Culliton.IsSpecialFDARegulationOfNanomedicineNeeded?AConversationWithNorrisE.Alderson.HHealthAffairsH,27,no.4(2008):20CarlosPena:aFDAperspectiveonnanomedicine,currentinitiativesintheUS.(2010),EMAfirstinternationalworkshoponnanomedicine

21GlobalIndustryAnalystsInc..Nanomedicine:aglobalstrategicbusinessreport(2009)

22BCCResearch.NanotechnologyinMedicalApplications:TheGlobalMarket(2010)

23Commissionparticuliredudbatpublicnanotechnologies.DebatpublicsurlesnanotechnologiesHUhttp://www.debatpublicnano.org/U

24NanoInnov:unplanenfaveurdesnanotechnologies.Dossierdepresse.MinistredelenseignementSuprieuretdelaRecherche.5mai2009(HUhttp://www.enseignementsuprecherche.gouv.fr/cid25281/nanoinnovunplanenfaveurdesnanotechnologies.htmlUH)

25BiotechnologiesFrance:Basededonnesnationaledesbiotechnologies,HUhttp://www.biotechnologiefrance.org/UH

26BeatLoeffler,PatrickHunzicker,CLINAM,Privatecommunication,2010.

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Boisseau Nanomedicine CRAS