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干扰线粒体的TPGSPLGA纳米粒逆转多药耐药机制研究.docx

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干扰线粒体的TPGSPLGA纳米粒逆转多药耐药机制研究 Abstract: Multi-drugresistance(MDR)incancercellsisamajorobstacletoeffectivechemotherapy.Inrecentyears,studieshaveshownthatmitochondriaplayavitalroleinthedevelopmentofMDR.Therefore,interferingwithmitochondrialfunctionhasbecomeapromisingstrategytoovercomeMDR.Inthisstudy,wedevelopedTPGSPLGAnanocarriersthattargetandinterferewithmitochondria,effectivelyreversingMDRincancercells. Introduction: Drugresistanceisamajorobstacletothesuccessofcancerchemotherapy,andmulti-drugresistance(MDR)isthemostcommonandseriousformofdrugresistance.ThemechanismofMDRdevelopmentiscomplex,includingincreaseddrugefflux,decreaseddruguptake,andaltereddrugmetabolism.Inrecentyears,studieshaveshownthatmitochondriaplayavitalroleinthedevelopmentofMDR.Therefore,interferingwithmitochondrialfunctionhasbecomeapromisingstrategytoovercomeMDR. TPGS,D-α-tocopherylpolyethyleneglycol1000succinate,isabiodegradable,amphiphilicpolymerthathasbeenwidelyusedasadrugdeliverycarrierduetoitsexcellentbiocompatibilityandabilitytoovercomemultidrugresistance.Poly(lactic-co-glycolicacid)(PLGA)isanotherbiodegradablepolymerthathasbeenwidelyusedindrugdeliveryduetoitsexcellentbiocompatibilityandbiodegradability.Inthisstudy,weusedTPGSPLGAnanocarrierstotargetandinterferewithmitochondria,effectivelyreversingMDRincancercells. MaterialsandMethods: TPGSPLGAnanocarrierswerepreparedusingananoprecipitationmethod.Thesize,zetapotential,anddrugloadingcapacitywerecharacterized.ThecellularuptakeandintracellularlocalizationofTPGSPLGAnanocarrierswereevaluatedusingconfocalmicroscopy.TheeffectofTPGSPLGAnanocarriersonmitochondrialfunctionwasevaluatedusingamitochondrialmembranepotentialassay.ThereversaleffectofTPGSPLGAnanocarriersonMDRwasevaluatedusingMTTassaysandflowcytometry. Results: TPGSPLGAnanocarriersweresuccessfullypreparedwithanaveragesizeof160nm,azetapotentialof-18mV,andadrugloadingcapacityof5.38%.ConfocalmicroscopyshowedthatTPGSPLGAnanocarrierswereeffectivelyinternalizedbycancercellsandlocalizedinmitochondria.TPGSP