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7/30/2019 Boisseau Nanomedicine CRAS
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Nanomedicine,NanotechnologyinmedicineNanomdecineetnanotechnologiespourlamdecine
PatrickBOISSEAU*1,BertrandLOUBATON2
1Chairman,WorkingGrouponNanoDiagnostics,ETPNanomedicineCEALeti,CampusMinatec,17ruedesmartyrs,F38054GrenobleCedex9,France
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
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