JournalofControlledRelease90(2003)363–374www.elsevier.com/locate/jconrelPoly(L-histidine)–PEGblockcopolymermicellesandpH-induceddestabilizationEunSeongLeea,b,HyunJoonShinb,KunNaa,YouHanBaea,*aDepartmentofPharmaceuticsandPharmaceuticalChemistry,UniversityofUtah,421WakaraWay,Suite315,SaltLakeCity,UT84108,USAbCenterforBiomaterialsandBiotechnology,DepartmentofMaterialsandEngineering,KwangjuInstituteofScienceandTechnology,1Oryong-dong,Buk-gu,Gwangju500-712,SouthKoreaReceived13January2003;accepted22April2003AbstractPoly(L-histidine)–poly(ethyleneglycol)diblockcopolymers(polyHis–b–PEG)werepreparedandusedfortheconstruc-tionofpolymericmicellesrespondingtolocalpHchangesinthebody.PolyHiswassynthesizedbyringopeningpolymerizationofL-histidineN-carboxyanhydride,theimidazoleaminegroupofwhichwasprotectedbythedinitrophenylgroup.Theresultingpolymer(Mn:5,000g/mole)wascoupledtopoly(ethyleneglycol)(Mn:2,000g/mole)viaanamidelinkageusingthedicyclohexylcarbodiimideandN-hydroxysuccinimide-mediatedreaction.TheblockcopolymerindimethylsulfoxideformedpolymericmicellesondiafiltrationagainstaboratebufferatpH8.Dynamiclightscatteringandatomicforcemicroscopyshowedthemicelleswerespherical,diameter|114nm,withaunimodaldistribution.Thecriticalmicelleconcentration(CMC)atpH8.0was2.3mg/l.TheCMCincreasedmarkedlyondecreasingthepHofthediafiltrationmediumbelow7.2.MicellespreparedatpH8.0weregraduallydestabilizedbelowpH7.4,asevidencedbyaslightincreaseinlighttransmittance,analterationinsizedistribution,andadecreaseinthepyrenefluorescenceintensity.ItwasconcludedthattheionizationofthepolyHisblockformingthemicellecoredeterminedthepH-dependentCMCandstability.AfterfurtheroptimizationofthepH-sensitivity,pH-sensitivemicellesareexpectedtohaveapplicationforsolidtumortreatment,exploitingthefactthatmostsolidtumorshaveanacidicextracellularpH.2003ElsevierB.V.Allrightsreserved.Keywords:Poly(L-histidine);PEG;pH-sensitivemicelle;Blockcopolymer;ExtracellulartumorpH1.IntroductionpKbvalueandpH-solub