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Mitochondria-TargetingNanoplatformwithFluorescentCarbonDotsforLongTimeImagingandMagneticField-EnhancedCellularUptakeYeZhang,†YajingShen,†XiyaoTeng,†ManqingYan,†HongBi,*,†,‡andPauloCesarMorais§,⊥†CollegeofChemistryandChemicalEngineering,AnhuiUniversity,Hefei230601,China‡InstituteofHealthSciences,AnhuiUniversity,Hefei230601,China§SchoolofAutomation,HuazhongUniversityofScienceTechnology,Wuhan430074,China⊥InstitutodeFísica,UniversidadedeBrasília,Brasília,FederalDistrict70910-900,Brazil*SSupportingInformationABSTRACT:Inthisstudy,abiocompatiblenanoplatformhasbeenconstructedonthebasisofmagneticmesoporoussilicananoparticles(Fe3O4@mSiO2)viasurfacemodificationoftriphenylphospine(TPP)andthenconjugationwithfluores-centcarbondots(CDs).Theas-preparedFe3O4@mSiO2−TPP/CDsnanoplatformshowsaverylowcytotoxicityandapoptosisrateinvariouscelllinessuchasA549,CHO,HeLa,SH-SY5Y,HFF,andHMEC-1.Moreimportantly,thisnanoplatformintegrateslongtimecellimaging,mitochon-dria-targeting,andmagneticfield-enhancedcellularuptakefunctionalitiesintoanall-in-onesystem.Time-dependentmitochondrialcolocalizationinallofthecelllineshasbeenprovedbyusingconfocallaserscanningmicroscopyandflowcytometry,whilethemulticoloredfluorescenceoftheFe3O4@mSiO2−TPP/CDscouldremainbrightandstableaftercoincubationfor24h.Inaddition,thecellularuptakeefficiencycouldbeenhancedinashorttimeasastaticmagneticfieldof0.30TwasappliedtothecoincubationsystemofA549andHFFcelllines.Thisbionanoplatformmayhavepotentialapplicationsintargeteddrugdeliveryformitochondriadiseasesaswellasearlycancerdiagnosisandtreatment.KEYWORDS:mitochondrialtargeting,carbondots,magneticfield,cellularuptake,bioimaging,nanoplatform■INTRODUCTIONThedevelopmentoftherapeuticapproachesforcancertreatmentdemandinghigherefficacyhasfosteredtheengineer-ingofmultifunctionalnanosystems.Abiocompatiblemulti-functionalnanosystem,usuallycalledabionanoplatform,aimstoconstructnewapproachestointegratecancertreatment,imaging,anddrugdeliveryfunctionalitiesinanall-in-onesystem.1,2Intheevolutionofbionanoplatformsengineering,superparamagneticFe3O4nanoparticles(NPs)areprobablyoneofthemostappealingcandidates,giventhesuccessofT2asacontrastagentformagneticresonanceimaging(MRI),aswellassuperparamagnetismformagnetic-targeteddrugdeliveryandmagnetohyperthermia(MHT)therapy.3,4Conjugatedwithfluorescentquantumdotsorphotosensitivereagents,theFe3O4NPs-basedbionanoplatformcancombineadualimagingprobeforcancer5withmagneticallyguideddrugdelivery,6targetedchemotherapy,7orphotodynamictherapy(PDT),8andphotothermaltherapy.9Inthepastdecades,mesoporoussilicananoparticles(MSNs)areknowntohavelittleornotoxicityduetofavorablebiocompatibilityofsilicon.Moreover,surfacemodifiedorend-cappedMSNsareexcellentnanopalt-formsfortargetingdrugdeliveryandchemotherapy,owingtotheirdistinctivemesoporousstructure,largesurfacearea,tunableporesize,facilefunctionalizationchemistry,andgoodbiocompatibility.10−12Particularly,theengineereddesignofamesoporoussilicashellonamagnetitenanocrystalcore(Fe3O4@mSiO2)endowstheas-constructednanoplatformwithmultifunctionalitiesincludingMRI,fluorescenceimaging,andmagnetictargeted-drugdelivery.13Inaddition,magneticNPsunderanappliedmagneticfieldcoulddirectcancer-targetingdrugdelivery,14enhanceTcellactivationsoastostimulateantitumoractivity,15promotecellsorting,16andmodulatecellularuptake.17ThoughthemechanismandexactprocessofmagneticNPscellularuptakeassistedbyanappliedmagneticfieldisstillunclear,mostoftheresearchregardingthemultifunctionalFe3O4@mSiO2NPshasfocusedoncombiningdrugdeliverysystem(DDS)withbiosensing18orMRIfunctionalities.19Recently,advancesinbiomedicalnanotechnologymakesubcellular-targetedtherapyanemergingimportantareaforcancertreatment.Comparedtotherandominteractionofdrugswithintracellularsiteofaction,thetherapeuticoutcomesReceived:January14,2015Accepted:April27,2015ResearchArticle©XXXXAmericanChemicalSocietyADOI:10.1021/acsami.5b00405ACSAppl.Mater.InterfacesXXXX,XXX,XXX−XXXcouldbeenhancedmanyfoldifpharmaceuticalagentscanbespecificallydirectedtowardthetargetedorganelle,i.e.,pro-apoptoticcompoundstomitochondria.20,21Ingeneral,theadvantagesoforganelletargetingconstructioninchemotherapyaretoachieveahigherdrugefficacyaswellasaminimumsideeffect.Themitochondrionisadouble-membraneofphospho-lipidbilayerenvelopedcytoplasmicorganellethatpossessesitsowninternalgenome.Themitochondriaareindispensableforprovidingenergyforthesurvivalofeukaryoticcellsandtocontroltheactivationofprogrammedcelldeath(so-calledapoptosis)mechanismbyregulatingthetranslocationofpro-apoptoticproteinsfromthemitochondrialintermembranespacetothecytosol.22Therefore,themitochondrionisrecognizedasanimportanttherapeutictargetincancertherapy,andmanyresearchershaveattemptedtodesignmitochondria-targetedpharmaceuticalsanddrugcarriers.23−25Triphenyl-phosphonium(TPP)isarepresentativelipophiliccationicspeciesthatcanselectivelyaccumulateinthemitochondriabyreducingthefreeenergychangewhilemovingfromanaqueoustothehydrophobicenvironmentinresponsetothemitochondrialmembranepotentialofabout−180to−200mV.26Throu