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1、ALiposomalDrugPlatformOverridesPeptideLigandTargetingtoaCancerBiomarker,IrrespectiveofLigandAffinityorDensityBethanyPowellGray,MichaelJ.McGuire,KathlynnC.Brown*DepartmentofInternalMedicineandTheSimmonsComprehensiveCancerCenter,UniversityofTexasSouthwe
2、sternMedicalCenter,Dallas,Texas,UnitedStatesofAmericaAbstractOnemethodforimprovingcancertreatmentistheuseofnanoparticledrugsfunctionalizedwithtargetingligandsthatrecognizereceptorsexpressedselectivelybytumorcells.Intheorysuchtargetingligandsshouldspec
3、ificallydeliverthenanoparticledrugtothetumor,increasingdrugconcentrationinthetumoranddeliveringthedrugtoitssiteofactionwithinthetumortissue.However,theleakyvasculatureoftumorscombinedwithapoorlymphaticsystemallowsthepassiveaccumulation,andsubsequentre
4、tention,ofnanosizedmaterialsintumors.Furthermore,alargenanoparticlesizemayimpedetumorpenetration.Assuch,theroleofactivetargetinginnanoparticledeliveryiscontroversial,anditisdifficulttopredicthowatargetednanoparticledrugwillbehaveinvivo.Herewereportinv
5、ivostudiesforαvβ6-specificH2009.1peptidetargetedliposomaldoxorubicin,whichincreasedliposomaldeliveryandtoxicitytolungcancercellsinvitro.Wesystematicallyvariedligandaffinity,liganddensity,ligandstability,liposomedosage,andtumormodelstoassesstheroleofac
6、tivetargetingofliposomestoαvβ6.Indirectcontrasttotheinvitroresults,wedemonstratenodifferenceininvivotargetingorefficacyforH2009.1tetramericpeptideliposomaldoxorubicin,comparedtocontrolpeptideandnopeptideliposomes.Examiningliposomeaccumulationanddistri
7、butionwithinthetumordemonstratesthattheliposome,andnottheH2009.1peptide,drivestumoraccumulation,andthatbothtargetedH2009.1anduntargetedliposomesremaininperivascularregions,withlittletumorpenetration.ThusH2009.1targetedliposomesfailtoimprovedrugefficac
8、ybecausetheliposomedrugplatformpreventstheH2009.1peptidefrombothactivelytargetingthetumorandbindingtotumorcellsthroughoutthetumortissue.Therefore,usingahighaffinityandhighspecificityligandtargetinganover-expressedtumorbiomarkerdoesnotguarantee
