搜索
AdeliverysystemspecificallyapproachingboneresorptionsurfacestofacilitatetherapeuticmodulationofmicroRNAsinosteoclastsJinLiua,b,c,d,e,1,LeiDanga,b,c,d,e,1,DefangLia,b,c,d,e,1,ChaoLianga,b,c,d,e,f,XiaojuanHea,b,g,HengWua,b,AirongQiane,f,ZhijunYanga,DorisW.T.Auh,MichaelW.L.Chiangh,Bao-TingZhangi,QuanbinHana,KevinK.M.Yuea,HongqiZhanga,ChangweiLvj,XiaohuaPank,JiakeXul,ZhaoxiangBiana,PengShangf,WeihongTanm,n,o,ZicaiLiangc,p,BaoshengGuoa,b,c,d,e,f,*,AipingLua,b,c,d,e,g,*,GeZhanga,b,c,d,e,f,*aInstituteforAdvancingTranslationalMedicineinBone&JointDiseases,SchoolofChineseMedicine,HongKongBaptistUniversity,HongKong,ChinabAcademicianChenXinziWorkroomforAdvancingTranslationalMedicineinBone&JointDiseases,KunshanRNAiInstitute,KunshanIndustrialTechnologyResearchInstitute,Kunshan,Jiangsu215347,ChinacInstituteofIntegratedBioinformaticMedicineandTranslationalSciences,HKBUShenzhenResearchInstituteandContinuingEducation,Shenzhen518057,ChinadShumYiuFoonShumBikChuenMemorialCentreforCancerandInflammationResearch,HKBUShenzhenResearchInstituteandContinuingEducation,Shenzhen518057,ChinaeHongKongBaptistUniversityeNorthwesternPolytechnicalUniversityJointResearchCentreforTranslationalMedicineonMusculoskeletalHealthinSpace,Shenzhen,518057,ChinafKeyLaboratoryforSpaceBioscienceandBiotechnology,InstituteofSpecialEnvironmentalBiophysics,SchoolofLifeScience,NorthwesternPolytechnicalUniversity,Xi'an,721000,ChinagInstituteofBasicResearchinClinicalMedicine,ChinaAcademyofChineseMedicalSciences,Beijing,100700,ChinahDepartmentofBiologyandChemistry,CityUniversityofHongKong,999077,HongKong,ChinaiSchoolofChineseMedicine,TheChineseUniversityofHongKong,HongKongSAR,999077,ChinajDepartmentofOrthopaedics,XijingHospital,TheFourthMilitaryMedicalUniversity,Xi'an,710032,ChinakDepartmentofOrthopaedics&Traumatology,ShenzhenPeople'sHospital,SecondMedicalCollegeofJi'nanUniversity,Shenzhen,518020,ChinalMolecularLab,SchoolofPathologyandLaboratoryMedicine,UniversityofWesternAustralia,Nedlands,WA6009,AustraliamDepartmentofChemistry,UniversityofFlorida,Gainesville,FA32611-7200,USAnDepartmentofPhysiologyandFunctionalGenomics,UniversityofFlorida,Gainesville,FA32611-7200,USAoCenterforResearchatBio/NanoInterface,ShandsCancerCenter,UniversityofFlorida,Gainesville,FA32611-7200,USApInstituteofMolecularMedicine,PekingUniversity,Beijing,100871,ChinaarticleinfoArticlehistory:Received10October2014Receivedinrevisedform28January2015Accepted1February2015AvailableonlineKeywords:TargeteddeliverysystemMicroRNAOsteoclastBoneresorptionabstractDysregulatedmicroRNAsinosteoclastscouldcausemanyskeletaldiseases.ThetherapeuticmanipulationofthesepathogenicmicroRNAsnecessitatesnovel,efficientdeliverysystemstofacilitatemicroRNAsmodulatorstargetingosteoclastswithminimaloff-targeteffects.Boneresorptionsurfacescharacterizedbyhighlycrystallizedhydroxyapatitearedominantlyoccupiedbyosteoclasts.Consideringthattheeightrepeatingsequencesofaspartate(D-Asp8)couldpreferablybindtohighlycrystallizedhydroxyapatite,wedevelopedatargetingsystembyconjugatingD-Asp8peptidewithliposomefordeliveringmicroRNAmodulatorsspecificallytoboneresorptionsurfacesandsubsequentlyencapsulatedantagomir-148a(amicroRNAmodulatorsuppressingtheosteoclastogenicmiR-148a),i.e.(D-Asp8)-liposome-antagomir-148a.OurresultsdemonstratedthatD-Asp8couldfacilitatetheenrichmentofantagomir-148aandthesubsequentdown-regulationofmiR-148ainosteoclastsinvivo,resultinginreducedboneresorptionandattenuateddeteriorationoftrabeculararchitectureinosteoporoticmice.Mechanistically,theosteoclast-targeteddeliverydependedontheinteractionbetweenboneresorptionsurfacesandD-Asp8.No*Correspondingauthors.InstituteforAdvancingTranslationalMedicineinBone&JointDiseases,SchoolofChineseMedicine,HongKongBaptistUniversity,HongKong,China.E-mailaddresses:borisguo@hkbu.edu.hk(B.Guo),aipinglu@hkbu.edu.hk(A.Lu),zhangge@hkbu.edu.hk(G.Zhang).1JinLiu,LeiDangandDefangLicontributedequallytothiswork.ContentslistsavailableatScienceDirectBiomaterialsjournalhomepage:://dx.doi.org/10.1016/j.biomaterials.2015.02.0070142-9612/©2015ElsevierLtd.Allrightsreserved.Biomaterials52(2015)148e160detectableliverandkidneytoxicitywasfoundinmiceaftersingle/multipledose(s)treatmentof(D-Asp8)-liposome-antagomir-148a.Theseresultsindicatedthat(D-Asp8)-liposomeasapromisingosteoclast-targetingdeliverysystemcouldfacilitateclinicaltranslationofmicroRNAmodulatorsintreatingthoseosteoclast-dysfunction-inducedskeletaldiseases.©2015ElsevierLtd.Allrightsreserved.1.IntroductionSkeletaldiseasesinducedbyosteoclastdysfunctionarestillgreatclinicalchallenges[1].IncreasingevidencesdemonstratedthataseriesofdysregulatedmiRNAswithinosteoclasts(e.g.miR-148a,miR-223,miR-21,miR-155,miR-335andmiR-29b)couldcontributetoosteoclastdysfunctionandsubsequentlycausedabnormalboneresorptioninskeletaldiseases,suchasmetabolicbonediseaseandprimary/metastaticbonetumor[2e6].ThemiRNAmodulators,includingangomir/antagomir,havebeenwidelyemployedtomodulateintracellularmiRNAs[7,8].However,systemicinjectionwithoutanytargete