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SCIENCECHINAMaterialsARTICLES
|/s40843-022-2177-x
PlateletmagneticnanocarriersasMRIsensorstodelineatevascularinjury
networkandtargetedpre-protectioninischemicstroke
MingxiLi1,2†,XiaoCheng1†,ZheChen1,ZhonghuaNi2,NingGu1andFangYang1*
ABSTRACTAccuratemappingthedamagedvascularnet-sequences[3].MRIcanprovidemorecomprehensiveimaging
*
workiskeytosubsquenteffectivetherapeuticstrategyim-,T2-
*
,magneticweightedimaging(T2WI)anddiffusion-weightedimaging
resonanceimaging(MRI)basedonaplateletmembranebio-(DWI)arethepreferredtechniquesforearlyMRIdiagnosisof
*
mimeticmagneticnanocarrier,loadedwithL-arginineandγ-
Fe2O3magneticnanoparticles(PAMNs),hasbeendevelopeduniformityofthemagneticfield,especiallyinthepresenceof
*
,theT2signalhasthe
-Fe2O3nanoparticles,multi-potentialtoreflectachangeinthebiochemicalcomponentsof
**
parameterMRIincludingT2-weightedimaging(T2WI)andthecounterpart,andcanbeusedforpreciselocalizationofearly
diffusion-weightedimaging(DWI)havebeenusedtolocalizeAISlesionswiththedescriptionofitsdistributioncharacteristics
thestrokelesionandevaluatetheseverityofdamagedvasuclar[4,5].DWIisbasedonthedetectionofsignalchangescausedby
network,,anditissensitivetothe
canspecificallytargettodifferenttypesofdamagedblooddevelopmentofearlyedemaandfocalareasinAIS;theinitial
*
lesion,T2imagingdelineatedthedamagedvascularinjuryvolume[6].However,withouttheappropriatecontrastagents,it
network,,withtheL-isdifficulttodifferentiatethefinetissuestructure,theblurred
argininereleaseinthelesion,theDWIofMRIwasappliedtoboundaryamongtheinfarctcore,thepenumbraandartifacts.
evaluatethepre-
foraccuratepositioningandreal-timemonitoringofstrokediagnosisandtreatmentofAIS,thedesiredeffectsareyettobe
,thePAMNs-basedMRItechniqueachieved[7].Thereasonmaybethataseriesofcomplexcascade
isfeasibleforvascularobstruction/thrombuslocation,severityreactionsoccuraftertheonsetofAISthatmayleadtothefailure
assessment,andreal-timemonitoringoflesiondevelopmentofsingle-,biomi-
biosafetyandtargetingcapabilitieswhilealsoexertingcorre-
Keywords:MRImulti-parameterdiagnosis,acuteischemicspondingnaturalcellularfunctions[8];forexample,platelets
stroke,vasculartargeting,plateletbiomimetic,recanalization(PLTs)couldbeappliedasatargeteddeliverysystemforthe
damagedvesselinAIS[9].
Herein,multimodalMRIbasedonaPLTmembranebiomi-
INTRODUCTIONmeticnanocarrierloadedwithL-arginineandγ-Fe2O3magnetic
Strokeisoneoftheleadingcausesofdeathanddisabilitynanoparticles(PAMNs)wasexploredtoachieveaccurateloca-
worldwide[1].Accordingtoitspathogenesis,acuteischemiclizationofAISlesions,identificationofischemicpenumbra,and
stroke(AIS),whichcausesirreversibledamagetothebraintis-
sueandnervefunctionduetothrombosisorcerebrovasculartypesofAISmousemodelswithdifferentbloodvesseldamages
disorders,accountsformorethan80%()
itssuddenness,shorttherapeutictimewindow(–6h)andthe[10–12].RoseBengal,afterillumination,wasinjectedthrough
complexityofsubsequentsymptoms,accuratediagnosisandthetailvein(Tmodel)totargetlargervesselswithlargerinfarct
treatmentremaindifficult[2].Therefore,therapidlocalizationarea,whileintraperitonealinjection(Imodel)mainlydamaged
ofischemiclesionsandthedeterminationofischemiaseveritymicro-,
*
basedonmultimodalimagingdiagnosisplayakeyroleinAIST2andDWIofMRIwereusedtolocatethelesionandgrade
,amongallofthecommonlyusedimagingtheinjuryarea,
diagnostictechniques,magneticresonanceimaging(MRI)hasPAMNsaresensitivefordifferentiatingthetypeofendothelial
beenwidelyusedduetoitshighersensitivityandmulti-scandamageanddelineatingthethrombussiteandtheischemic
1StateKeyLaboratoryofBioelectronics,JiangsuKeyLaboratoryforBiomaterialsandDevices,SchoolofBiologicalScience&MedicalEngineering,Southeast
University,Nanjing210096,China
2JiangsuKeyLaboratoryforDesignandManufactureofMicro-NanoBiomedicalInstruments,SchoolofMechanicalEngineering,SoutheastUniversity,
Nanjing211189,China
†Theseauthorscontributedequallytothiswork.
*Correspondingauthor(email:******@)
©ScienceChinaPressandSpringer-VerlagGmbHGermany,partofSpringerNature20221
ARTICLESSCIENCECHINAMaterials
Figure1SchematicdiagramofmicestrokemodelsandMRIdiagnosisofischemicstroke.(a)Schematicdiagramofphotochemicalmodelingwithdifferent
RoseBengalinjectionmethods.(b)PAMNs-,
whichreflectsthedistributionofdamagedbloodvesselsintheAISlesionarea.(c)L-argininedeliveryanditsvascularrecanalizationeffectsinImodelandT
model,respectively.
range().particles),PAs(nPLTsloadedwithL-arginine)andPAMNs
Additionaly,loadingPAMNswithL-arginine,anendogenouswerefabricatedusingamembrane-extrusivemethod.
nitricoxidedonorthatcanbecatalyzedintonitricoxide(NO)Thesizedistributionofeachsamplementionedabovewas
bythenitricoxidesynthase(eNOS)invascularendothelialcellsmeasuredbyaNanoSizer(Zeta-Sizer,MalvernInstrument,
[13],mayinturninducevasodilationandrecanalizationoftheBritish).
bloodvesselsinthelesiontoinhibitetheexpansionoftheThemorphologyandstructurewerecharacterizedbyTEM
ischemicarea().Takentogether,PAMNscanimprovethe(JEM-2100,JEOL,Japan).
classificationandprecisepositioningofAISlesionsunderMRI
detection,andpromotetherecoveryofbloodsupplytothePreparationofAISmodels
ischemiclesions,
Therefore,L-arginine-loadedPAMNsareanovelbeneficialtoolGuidelinesforCareandUseofLaboratoryAnimalsestablished
forbothdiagnosisandtreatmentforthrombus-
-bearingprotocol
EXPERIMENTALSECTIONwasapprovedbytheCommitteeontheEthicsofAnimal
ExperimentsofMedicalSchoolofSoutheastUniversity(NO.
Materialsandreagents20190307011).
ApheresisPLTswereprovidedbytheBloodCenterofJiangsuTheacutefocalischemicstrokemodelwasestablishedbya
Province(Nanjing,China).L-argininewaspurchasedfromphotochemicalmethodaspreviouslyreported[10–12].Briefly,
Sigma-Aldrich(,MO,USA).γ-Fe2O3super-maleC57BL/6mice(19–22gbodyweight)wereintraper-
paramagneticnanoparticleswithameantransmissionelectronitoneallyanesthetizedwithpentobarbitalsodiumsolution(1%,
microscopy(TEM)diameterof7nmwereprovidedbyChiatai10μLg−1bodyweight).RoseBengalwasthenadministeredby
TianqingPharmaceuticalGroupCo.,Ltd.(Nanjing,China).Theintraperitonealinjection(Imodel)ortailveininjection
X-raydiffraction(XRD)patternsofthepreparedγ-Fe2O3(Tmodel),,200μLRoseBengalwas
nanoparticleshavebeencharacterizedinourpreviouspaperintraperitoneallyinjected(10μLg−1bodyweight)for5min
[14].Anti-CD31antibodyandGoatAnti-RabbitIgGH&Lbeforeillumination,thenacoldlightsource(coldlight,Carl
(AlexaFluor®488)werepurchasedfromABCAM(ab28364)andZeiss,Germany)witha4-mmaperturewasstereotactically
(ab150077),respectively(Cambridge,UK).focusedabovethecortexfunctionregionsonconditionthatthe
,50μLRoseBengal
FabricationandcharacterizationofPAMNswasdirectlyinjectedthroughthetailveinandilluminationwas
ThepreparationofPAMNshasbeenpreviouslyreported[15].givenimmediatelyfor15min.
Here,theinteractionofL-arginine,γ-Fe2O3nanoparticlesand
othercomponentswiththePLTmembraneandthepreparationMRdiagnosisandimageacquisition
,thestroke-bearingmice(n=5)were
Briefly,afterrepeatedfreeze-thawextraction,thepurifiedPLTanesthetizedwith1%isofluraneusingagasanesthesiamask,and
membranevesicles(PMVs)wereresuspendedinsaline(%
NaCl).Then,samplesincludingnPLTs(nanoPLTfromextru-system(BioSpinMRIGmbHBruker,Germany)before(pre-)
dedblankPMVs),PMNs(nPLTsloadedwithmagneticnano-,1,2,3,4,
2©ScienceChinaPressandSpringer-VerlagGmbHGermany,partofSpringerNature2022
SCIENCECHINAMaterialsARTICLES
groupsweresetasthecontrolgroup(saline-administeredgroup)-containingmounting
andexperimentalgroup(PAMNs-administeredgroup)fortheImedium,thesectionswereobservedbyconfocalmicroscopy
andTmodels,respectively.(ZeissLSM700,Germany).
*
ThesequenceparametersforT2-weightedscan:repetitionInaddition,irondistributioninbraintissuesectionscanalso
time(TR)=,echotime(TE)=,numberofbeusedtocharacterizethedeliveryofPAMNsduetothe
average=5,echotrainlength=1,andflipangle=-,thebraintissueslideswerefurther
signalacquisitionrangewassetasmatrixsizeof512×512,slicestainedwithaPerlsstainingkit(Solarbio,Beijing,China).
,andfieldofviewof20mm×
ForDWIscan:TR=,TE=,numberofthelesionregionafterstroke,CD31immunohistochemical
average=1,echotrainlength=1,andflipangle=(MVD)in
signalacquisitionrangewassetasmatrixsizeof128×128,slicenormalandischemichemibrain[16].Sectionswereobservedby
,andfieldofviewof20mm×(TS100/TS100-F,.,
Japan).Fiveregionswererandomlyselectedinthelesionand
MRIimageprocessingnormalregionat200×magnificationafterwhichtheobtained
TheMRIimageswereanalyzedusingMatlabandtheprocessingimageswereautomaticallycontrast-adjusted,andhomo-
,andmicrovesselcountingwasperformed.
(1)Imagepreprocessing:Thegrayscaleofthecontralateral
sideofthelesionwasadjustedtobeconsistenttoeliminatetheStatisticalanalysis
interferenceofnon-±standarddeviation
(2)Imagesegmentation:Asimplelineariterativeclustering(SD).StatisticalcomparisonsweremadebyunpairedStudent’st-
(SLIC)methodwasadoptedforimagesegmentation,andantest(betweentwogroups).Pvalue<-
.
(3)Featureextraction:Imageinformationsuchaslesionarea,
meangrayvalue,andtexturewereextractedfromthesegmentedRESULTSANDDISCUSSION
lesionarea,wherethearearepresentedtheseverityofthelesion
accumulationofPAMNs,andthetexturedescribedthetypeofSamplesincludingnPLTs,PMNs,PAsandPAMNswerepro-
-Fe2O3
nanoparticles,nPLTs,PMNs,PAs,andPAMNsareshownin
–,PMVswerereassembledintohollow
Laserspeckleimaging(FLPI-2Pro,MoorInstruments,UK),after
usedtocharacterizethechangesinthebloo