纳米药物体内过程介绍

Deliveryofnanomedicinestoextracellularandintracellularcompartmentsofasolidtumor胥洪鹃2011-7-11Keywordsdrugdeliveryinterstitialtransportintracellulartraffickingendosomalescapeendocytosisnanoparticles（NP)Introduction•1.NPofferasuitablemeansfordeliveryingdiagnostic,imagingortherapeuticagents.•2.TheutilityofNPdependsontheirabilitytoreachtheirsitesofaction•3.Thepotentialtargetsitesincludetumorvasculature,tuomrinterstitium,cellmembrane,andintracellularcompartments.•4.DeliveryofNPfromtheinjectionsitetovarioustargetsiteswithinasolidtumorinvolvesmultiplekineticsteps.DeliveryofnanoparticlestoorganlevelBarriestogenetransfer2DeliveryofNPtoasolidtumors•NParedistributedtodifferentorgans/elimination/removedbythecells•ThedeliveryofNPtoasolidtumorisdeterminedbyphysiologicalfactorsandthephysico-chemicalpropertiesofNP2.1DistributionandretentionofNPintumorsaftersystemicdelivery•Inasolidtumor,NPleavetheintravascularspacewithinavesseltoentertheinterstitium.•Diffusionisdrivenbyconcentrationgradients•Transvascularfluidtransportisdrivenbypressuregradients2.1.1Tumorbloodflowandbloodvasculature•Bloodflowwithinatissueisdeterminedbythearteriole-venule(A-V)pressuredifferenceandflowresistance.•Bloodvesseldistributionwithinatumordependsonthetumorsizeandthelocationswithinatumor.•Tumorbloodvesselsaregenerallyleakyduetodiscontinuityoftheendothelium.•Asolidtumorcomprisesthreeregions:•a:avascular-necroticregionwithnovasculature•b:semi-necroticregioncontainingcapillares•c:stablyperfusedregioncontaingmanyvenousvesselsandfewarterolarvesselsTheseintratumoralvasculatureheterogeneitiescontributetounevendrugdistributionTumorvsnormaltissues1.tumorbloodvesselsaregenerallymoreheterogeneousindistribution,density,lengthanddiameter,andarelargerinsizeandmorepermeable.2.theaveragebloodflowintumorsislowerthaninnormaltissues3.tumorvesselsaremoreleakywithporesizesexceeding100nm4.lackoffunctionallymphaticdrainageintumors2.3ExperimentalapproachesandNPformulationdesigns•1.PassivetargetingviaEPReffect:effectofparticlesizeEPRispredominantforcompandswithmolecularweightslargerthan40KDEPRisaffectedbythetumorsizewithagreaterEPRinsmallertumorsThevesselporesizeinamajorityofexperimentaltumorsrangesgrom380nmto780nm2.3.2SurfacemodificationofNPtoconferstealthproperty•SurfacemodificationhasbeenusedtominimizeRESentrapmentandtoincreasethebloodcirculationtimeThedegreeofpegylationaffectsthestealthpropertiesofNP.PegylationdecreasesthetransportofNPintumorinterstitiumanddecreasethecellularinternalization2.3.3Targetingtheacidicmicroenvionmentintumormatrix•Solidtumors,inpart,duetothehighglycolysis,usuallyshowsacidicpH•pHgradientaffectstheionizationandintratumoraldistributionandcellularuptakeofionizabledrugsinatumor.•NPcomprisingpH-sensitivepolymersaretargetthetumorextracellularmatrixortopromotethereleaseoftheircontents2.3.4Targetingtumorvasculaturebyelectrostaticinteraction•TheluminalendothelialmembraneinvesselisnegativelychargedandthereforecanbetargedbycationicNPthroughelectrostaticinteractions.•However,becausethenegativechargeonluminalendothelialmembraneisalsofoundinnormaltissues,thismadeoftargetingisquantiativeratherthanqualitative•GreatertumorselectivityisachievedbyconjugatingNPwithtumorendotheliumspecificligands.3.Interstitialtransport(sub-organlevel)Afterenteringatumorviabloodcirculation,amoleculeistransportedacrosstheinterstitialspacetoreachindividualtumorcellsThetransportprocessesforsmallmoleculesreleasedfromNPisbydifussionandconvection,andNPreliesmoreonconvection.BarrierstoNPtransportintumorinterstitium,andtheexperimentalapproachestoovercomesuchbaarriersareasfollows3.1barrierstoconvectivetransvascularandinterstitialtranport•ThehighIFPandthelackofafunctionallymphaticsystemreducesthefluidflowandconvectiontransport.AgentsareusedtolowertumorIFPReducethedensityoftumorcellIFP:interstitialfluidpressure3.2Extracellularmatrix(ECM)•Thefibrousproteinsandpolysaccharidesarethebarrierstotransport.•EnzymesthatdegradetumorECMmaterialspromoteintra-tumoraldispersionofNP.Bindingbarrier4.NPcellularandsubcellularcompartmentstargeting•TrantportofNPinacellinvolvesseveralprocesses:•(1)attachmentofNPtocellmembranethroughbindingtonon-specificornonspecificbindingsites•(2)internalizationofNPthroughendocytosis•(3)entrapmentofNPinendosomes,caveosomesormacropinosomes•(4)releaseofNPfromthesestructures•(5)NPtransportincytosolanduptakebyotherintracellularcytoplasmicorganelles•(6)transportofNPintothenucleus4.1targetingthecellmembrane•non-specificbindingPositivesurfacechargePegylation,inpartbydesreasingthepositivecharge,inhibitsNPbindingtocellsurface.•Specifictargeting•ligandsareinternalizaedbytheclathrin-mediatedendocytosis•thedensityofligandsonparticalsurface,cellselectivity,stability,andbypassMDR4.2Internalization/endocytosis4.3Escapefromendosomestocytosol•agentsuesdtopromoteNPescape/releasefromendosomespHsensitivepeptidespHbufferingpolymersfusogeniclipids4.4Deliverytonucleus•Passivecytosol-necleustransportusestheaqueouschannelofNPC.•Activeenergy-dependentnucleartransportrequiresthepresenceofspecif