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ThermosensitiveLiposomesModifiedwithPoly(N-isopropylacrylamide-co-propylacrylicacid)CopolymersforTriggeredReleaseofDoxorubicinTerenceTa,*AnthonyJ.Convertine,ChristopherR.Reyes,PatrickS.Stayton,andTyroneM.PorterDepartmentofBiomedicalEngineering,BostonUniversity,Boston,Massachusetts02215,DepartmentofBioengineering,UniversityofWashington,Seattle,Washington98195ReceivedMay6,2010;RevisedManuscriptReceivedJune25,2010Anovelpolymer-modifiedthermosensitiveliposome(pTSL)wasdevelopedforthedeliveryofDoxorubicin(DOX)forcancertherapy.Copolymerscontainingtemperature-responsiveN-isopropylacrylamide(NIPAAm)andpH-responsivepropylacrylicacid(PAA)weresynthesizedviareversibleaddition-fragmentationchaintransfer(RAFT)polymerization,yieldingcopolymerswithdualpH/temperature-dependentphasetransitionproperties.Whenattachedtoliposomes,thesecopolymersweremembrane-disruptiveinapH/temperature-dependentmanner.pTSLdemonstratedenhancedreleaseprofileandsignificantlylowerthermaldosethresholdwhencomparedtotraditionalthermosensitiveformulationsandwerestableinserumwithminimaldrugleakageovertime.Theseliposomesthushavethepotentialtodramaticallyreducetheriskofdamagetohealthytissuesthatisnormallyassociatedwithliposomalcancertherapy.IntroductionThermosensitiveliposomes(TSL)areapromisingandextensivelystudiedclassofliposomeswithtunabledrugreleaseproperties.TSLarecomposedoflipidbilayersthatundergotemperature-dependentphasetransitionsfromgeltoliquidphaseandarepermeableatelevatedtemperatures,resultinginrapidreleaseofencapsulateddruguponheating.1,2TSLsystemsdesignedforcancertherapyhavegainedconsiderablemomen-tum,buthavesufferedfromseveraldeficiencies,including(1)needforheatingbeyondconditionsthatcanbesafelytolerated1and(2)unstablecarriersthatleakdrugsprematurelyatphysi-ologicalconditions.3-6Thestandardmeasureofheatingdeliveredtotissueisthethermaldose,whichtakesaheattreatmentatonetemperatureandcalculatestheequivalentexposuretimeatareferencetemperatureof43°C:7wheret43°Cisthethermaldoseoftheexposureinequivalentminutesat43°C,∆tisthedurationofexposure(min),Tistheaveragetemperatureoftheexposureover∆t,andRisanempiricalconstant(R)0.5atTg43°C,0.25atT<43°C).Studieshaveshownthatthethermaldosethresholdfor100%necrosisinvarioustissuesrangesfrom240toaslowas50equivalentminat43°C.8,9Meshoreretal.(1983)foundthat,inporcinetissue,necrosisonsetoccurredatt43°C)0.5-30min,withmoderatedamageatt43°C)60-240min,andseveredamageatt43°C>240min.8TraditionalTSLrelease50%ofdrugatt43°C)5min.Theapplicationofthisthermaldosetoatumorwouldposeasignificantriskofnecrosistosurroundinghealthytissueduringheat-triggereddrugrelease.Thisdrawbackhasledtothedevelopmentoflysolipid-containingthermosensitiveliposomes(LTSL).1,2Lysolipidsfa-cilitatetheformationofdefectsandmembraneopeningsduringthephasetransition,increasingbilayerpermeabilityandcausingrapiddrugrelease.3,4However,lysolipidshavebeenshowntorapidlydesorbfromthebilayer,4likelyresultinginlossoftemperature-sensitivityandinstabilityinvivo.Indeed,prematureleakageofdruginvivo(50%ofencapsulateddrugat37°Cwithin5min,5∼70%within1h6)hasbeenobserved.Toaddresstheseissues,weintroduceanovelpolymer-modified,nonlysolipidTSL(pTSL)decoratedwithamembrane-disruptivecopolymerofN-isopropylacrylamide(NIPAAm)andpropylacrylicacid(PAA;Figure1).Thecopolymer,p(NIPAAm-co-PAA),isbasedonpoly(N-isopropylacrylamide)(pNIPAAm),akeym...