Nanobiopolymer for Direct Targeting and Inhibition of EGFR Expression in Triple Negative Breast Cancer 英文参考文献.docVIP

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Nanobiopolymer for Direct Targeting and Inhibition of EGFR Expression in Triple Negative Breast Cancer 英文参考文献.doc

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Nanobiopolymer for Direct Targeting and Inhibition of EGFR Expression in Triple Negative Breast Cancer 英文参考文献

NanobiopolymerforDirectTargetingandInhibitionof EGFRExpressioninTripleNegativeBreastCancer SatoshiInoue1,RameshwarPatil1,JosePortilla-Arias1,HuiDing1,BinduKonda1,AndresEspinoza1, DmitriyMongayt2,JanetL.Markman1,AdamElramsisy1,H.WestleyPhillips1,KeithL.Black1 ,Eggehard Holler1,JuliaY.Ljubimova1* 1Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, United States of America, 2Center for Pharmaceutical Biotechnology and Nanomedicine,NortheasternUniversity,Boston,Massachusetts,UnitedStatesofAmerica Abstract Treatmentoptionsfortriplenegativebreastcancer(TNBC)aregenerallylimitedtocytotoxicchemotherapy.Recently,anti- epidermal growth factor receptor (EGFR) therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugatebasedonapoly(b-L-malicacid)(PMLA)nanoplatformforTNBCtreatment.Thenanobioconjugatecarries anti-tumor nucleosome-specific monoclonal antibody (mAb) 2C5 to target breast cancer cells, anti-mouse transferrin receptor(TfR)antibodyfordrugdeliverythroughthehostendothelialsystem,andMorpholinoantisenseoligonucleotide (AON)toinhibitEGFRsynthesis.Thenanobioconjugatesvariantswere:(1)P(BioPolymer)withAON,2C5andanti-TfRfor tumorendothelialandcancercelltargeting,andEGFRsuppression(P/AON/2C5/TfR),and(2)PwithAONand2C5(P/AON/ 2C5).Controlsincluded(3)Pwith2C5butwithoutAON(P/2C5),(4)PBS,and(5)PwithPEGandleucineester(LOEt)for endosomal escape (P/mPEG/LOEt). Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulationofinjectednanobioconjugateslabeledwithAlexaFluor680wasexaminedbyXenogenIVIS200(liveimaging) andconfocalmicroscopyoftissuesections.LevelsofEGFR,phosphorylatedandtotalAktintumorsamplesweredetected by western blotting.In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFR synthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation. Significanttumorgrowthinhibitionwasobservedinmicetreatedwiththeleadnanob