纳米技术在阿尔茨海默病药物治疗中的应用-机遇与挑战-高小玲

2015102··：，，（，200025）：；；：R749.16：A：1673-6087（2015）02-0095-04DOI:10.16138/j.1673-6087.2015.02.006（Alzheimer’sdisease,AD）AloisAlzheimer。1906，AD。，AD。AD：AD，。，AD。，：、（bloodbrainbarrier）。，AD。AD，。ADADβ（amyloidβ，Aβ），，AD。ADAD，AD。AD。、AβAD，AβAβAD[1]。，Aβ；AD，Aβ，、τ、，，。，AβAD，，。、。AD。，[2]。AD、，，AD。、，AD，，、、[3]。Aβ，；，。、，AD[4]。，、、DNA，。、AD2。AD1%，；AD99%，65[5-6]。2AD，AD（amyloidpre-cursorprotein,APP)、(presenilin，PSEN)1PSEN2，Aβ95··JInternMedConceptsPract2015,Vol.10,No.2；ADE(apolipoproteinE,ApoE）、α2-。ApoEε4AD。AD，AD。，AD。、，。，，、、、、，（neu-rovascularunit,NVU）[7]。，，（ATP）[ATP-bindingcassette(ABC)transporters][8]，、，。P-(P-glycoprotein,P-gp)、(multidrugresistancerelatedproteins,MRPs)(breastcancerresistanceprotein,BCRP)。，；98%[9]，。，AD[10]，，，。，AD。、，2，。1.：、、[11]。，，、。，，，AD，。2.：，、；，。。、，，。。，[12]。，，。AD，、，。，、、、、。AD，。：200nm，；；，；，，。，、、、、、，、[13]。AD。、AβAβ，Aβ96··2015102，Aβ、Aβ、Aβ。Aββ-APP1（β-siteAPP-cleavingenzyme1,BACE1）γ-APPAPP，2Aβ。BACE1RNA（shortinterferingRNA，siRNA），siRNA、。，Alvarez-Erviti[14]（rabiesviralglycoprotein，RVG）（exosome）BACE1siRNA。BACE1siRNA，。AβAD，，AD99%ADAβ。，AβAD。，、AβApoE[15]。，AβAβ，AD。，AD（Aβ、Aβ、τ），AD，AD。、AD，、AD[16]。Ismail[17]（rivastigmine），。。、，，、。，AD。，Aβ、、[18]。AD。，，。，Liu[19]2--N-（2’-）-3--4-（MAEHP）Apo，Aβ，Aβ。，，。、，，AD，[20]。，AD。，，，，。，Mittal[21]80-（PLGA）。，。AD，。，，、、、[22]。；，；，。，AD，，，，，。，。AD，，。，AD，，。，AD，97··JInternMedConceptsPract2015,Vol.10,No.2。[][1]HardyJ,SelkoeDJ.TheamyloidhypothesisofAlzheimer’sdisease:progressandproblemsontheroadtotherapeutics[J].Science,2002,297(5580):353-356.[2]BartusRT.Onneurodegenerativediseases,models,andtreatmentstrategies:lessonslearnedandlessonsforgottenagenerationfollowingthecholinergichypothesis[J].ExpNeurol,2000,163(2):495-529.[3]TiimanA,PalumaaP,T觛uguV.ThemissinglinkintheamyloidcascadeofAlzheimer’sdisease—metalions[J].NeurochemInt,2013,62(4):367-378.[4]PadurariuM,CiobicaA,LefterR,etal.TheoxidativestresshypothesisinAlzheimer’sdisease[J].PsychiatrDanub,2013,25(4):401-409.[5]McIlroySP,VahidassrMD,SavageDA,etal.RiskofAlzheimer’sdiseaseisassociatedwithaverylow-densitylipoproteinreceptorgenotypeinNorthernIreland[J].AmJMedGenet,1999,88(2):140-144.[6]PriceDL,SisodiaSS.MutantgenesinfamilialAlzheimer’sdiseaseandtransgenicmodels[J].AnnuRevNeurosci,1998,21:479-505.[7]RonaldsonPT,DavisTP.Blood-brainbarrierintegrityandglialsupport:mechanismsthatcanbetargetedfornoveltherapeuticapproachesinstroke[J].CurrPharmDes,2012,18(25):3624-3644.[8]MahringerA,OttM,ReimoldI,etal.TheABCoftheblood-brainbarrier—regulationofdrugeffluxpumps[J].CurrPharmDes,2011,17(26):2762-2770.[9]PardridgeWM.Crossingtheblood-brainbarrier:arewegettingitright?[J].DrugDiscovToday,2001,6(1):1-2.[10]EricksonMA,BanksWA.Blood-brainbarrierdysfunc-tionasacauseandconsequenceofAlzheimer’sdisease[J].JCerebBloodFlowMetab,2013,33(10):1500-1513.[11]GabathulerR.Approachestotransporttherapeuticdrugsacrosstheblood-brainbarriertotreatbraindiseases[J].NeurobiolDis,2010,37(1):48-57.[12]KaratasH,AktasY,Gursoy-OzdemirY,etal.Ananomedicinetransportsapeptidecaspase-3inhibitoracrosstheblood-brainbarrierandprovidesneuroprotec-tion[J].JNeurosci,2009,29(44):13761-13769.[13]FazilM,Shadab,BabootaS,etal.NanotherapeuticsforAlzheimer’sdisease(AD):past,presentandfuture[J].JDrugTarget,2012,20(2):97-113.[14]Alvarez-ErvitiL,SeowY,YinH,etal.DeliveryofsiRNAtothemousebrainbysystemicinjectionoftar-getedexosomes[J].NatBiotechnol,2011,29(4):341-345.[15]SongQ,HuangM,YaoL,etal.Lipoprotein-basednanoparticlesrescuethememorylossofmicewithAlzheimer’sdiseasebyacceleratingtheclearanceofamyloid-β[J].ACSNano,2014,8(3):2345-2359.[16]StandridgeJB.PharmacotherapeuticapproachestothetreatmentofAlzheimer’sdisease[J].ClinTher,2004,26(5):615-630.[17]IsmailMF,ElmeshadAN,SalemNA.Potentialtherapeu-ticeffectofnanobasedformulationofrivastigmineonratmodelofAlzheimer’sdisease[J].IntJNanomedicine,2013,8:393-406.[18]BologninS,MessoriL,DragoD,etal.Aluminum,cop-per,ironandzincdifferentiallyalteramyloid-Aβ(1-42)aggregationandtoxicity[J].IntJBiochemCellBiol,2011,43(6):877-885.[19]LiuG,MenP,KudoW,etal.Nanoparticle-chelatorcon-jugatesasinhibitorsofamyloid-βaggregationandneuro-toxicity:anoveltherapeuticapproachforAlzheimerdis-ease[J].NeurosciLett,2009,455(3):187-190.[20]CraigMC,MurphyDG.Alzheimer’sdiseaseinwomen[J].BestPractResClinObstetGynaecol,2009,23(1):53-61.[21]MittalG,CarswellH,BrettR,etal.Developmentande-valuationofpolymernanoparticlesfororaldeliveryofestradioltoratbraininamodelofAlzheimer’spathology[J].JControlRelease,2011,150(2):220-228.[22]BrambillaD,LeDroumaguetB,NicolasJ,etal.Nan-otechnologiesforAlzheimer’sdisease:diagnosis,therapy,andsafetyissues[J].2011,7(5):521-540.（：2015-02-16）（：）98··