CCS

SelectivelyDegradableCoreCross-LinkedStarPolymers

JamesT.WiltshireandGregG.Qiao*

PolymerScienceGroup,DepartmentofChemicalandBiomolecularEngineering,TheUniVersityofMelbourne,ParkVille,Victoria3010,Australia

ReceiVedSeptember22,2006;ReVisedManuscriptReceiVedOctober23,2006

ABSTRACT:Arangeofselectivelydegradablecorecross-linkedstar(CCS)polymersweresynthesizedviaacombinationofatomtransferradicalpolymerization(ATRP)andring-openingpolymerization(ROP)usingthe“armfirst”method.Themultifunctionalinitiator2-hydroxyethyl2′-methyl-2′-bromopropionatewasusedtosynthesizedegradablepoly(󰀁-caprolactone)(PCL)andnondegradablepolystyrene(PSt)andpoly(methylmethacrylate)(PMMA)macroinitiatorswhichweresubsequentlycross-linkedtogenerateCCSpolymers.Byusingnondegradable(divinylbenzene(DVB),ethyleneglycoldimethacrylate(EGDMA))anddegradable(4,4′-bioxepanyl-7,7′-dione(BOD),2,2-bis(󰀁-caprolactone-4-yl)propane(BCP))monomerstocross-linkthedifferentmacroinitiators,arangeofCCSpolymersweresynthesizedwhereeitherthearmorthecoredomaincanbeselectivelydegraded.PCL/DVBandPCL/EGDMAarm-degradableCCSpolymersweresynthesizedundervariousconditionstodeterminetheoptimalreactionconditionswithhydrolysisyieldingDVBandEGDMAcores,forwhichthehydrodynamicdiameterwasdetermined.HydrolysisofPCL/PMMA/EGDMAmiktoarmCCSpolymerresultedinCCSpolymerwithareducednumberofarms,whereasPSt/BODcore-degradableCCSpolymeryieldedtheoriginallinearPStarmsuponhydrolysis.PCL/BODandPCL/BCPfullydegradableCCSpolymerswerealsosynthesizedandshowntobecompletelydegradableuponhydrolysisoftheesterlinkagestogeneratesmall-chainacidunits.

Introduction

Corecross-linkedstar(CCS)polymers1haveauniquethree-dimensionalarchitecturethatconsistsofacross-linkedcoresurroundedbyanumberofradiatinglineararms.2,3Synthesisofthisclassofpolymerisusuallycarriedoutinatwo-stepprocessknownasthe“armfirst”approachwherelivinglineararmscapableoffurtherchainextensionareinitiallysynthesized.Theseterminallyreactivelinearpolymerchainsaresubsequentlyusedtoinitiatethepolymerizationofacross-linkablemonomersuchthattheactivearmendsarecoupledtogethertoformstar-shapedpolymerwithacross-linkedcore.Controlledradicalpolymerizationtechniquessuchasnitroxide-mediatedradicalpolymerization(NMP),4atomtransferradicalpolymerization(ATRP),5,6andreverseaddition-fragmentationchaintransfer(RAFT)7polymerizationaretypicallyemployedtosynthesizeCCSpolymers,resultinginahighdegreeofstructuralcontrolandnarrowmolecularweightdistribution.

CCSpolymersrepresentaninterestingclassofmacromoleculeduetothefactthattheyareofveryhighmolecularweightbuthaveasolubilityandviscositysimilartolinearorbranchedpolymersofrelativelylowmolecularweight.8Thecombinationofuniquerheologicalpropertiesandtheabilitytoemploycontrolledpolymerizationtechniquestoobtainwell-definedstructureshasrecentlyledtoincreasinginteresttowardthisclassofmacromolecule.AwiderangeofpotentialapplicationsforCCSpolymershavearisensuchasindrugdelivery,9membraneformation,5andpaintadditiveapplications.10CCSpolymersalsohavepotentialforapplicationastemplatesforsilicatematerialswithlowdielectricconstants.11

ThestructuralarchitectureofCCSpolymersissuchthatitcanbedividedintotwoseparatedomains,thatofthearmandthecore.Thisallowsfortheselectiveincorporationofadegradablefunctionalityintoeitherofthesedomains,therebygeneratingdegradableCCSpolymerwhereeitherthearmsor

*Correspondingauthor.E-mail:gregghq@unimelb.edu.au.

thecorecanbeselectivelytargetedfordegradation.WerecentlypublishedashortcommunicationonthesynthesisoffullydegradableCCSpolymer12(botharmandcoremoieties)usingatwo-stepone-potprocessentirelybasedonring-openingpolymerization(ROP)oflactone-basedmonomers.HerewereportthesynthesisofarangeofCCSpolymerswithdegradablefunctionalitysuchthatdifferentdomainscanbeselectivelydegradedtoproduceeitherarm-degradable,partiallyarm-degradable,core-degradable,orfullydegradableCCSpolymer.TheselectivelydegradableCCSpolymersreportedhererepresentanimportantdevelopmentinthequesttobetterunderstandtheabsolutemorphologyofthisuniqueclassofmacromolecule,particularlyinrelationtotherelativesizeandnatureofthecore.TheyalsoincreasethescopeofpotentialapplicationsforCCSpolymers,includinguseasatemplatefornanoporousmaterialsorasdrugcarrierswherethecoredomaincouldbeselectivelydegradedtoreleaseencapsulateddruginacontrolledfashion.ExperimentalSection

Materials.2-Bromoisobutyrylbromide(98%),anisole(anhy-drous,99.7%),copper(I)bromide(CuBr,98%),2,2′-bipyridine(bpy,99%),ethyleneglycol(>99%),stannous2-ethylhexanoate(Sn-(Oct)2,95%),andureahydrogenperoxideadduct(98%)werepurchasedfromAldrichandusedasreceived.Formicacid(99%,AjaxFinechem),4,4′-bicyclohexanone(LombScientific),and2,2-bis(4-oxocyclohexyl)propane(LombScientific)werealsousedasreceived.Tetrahydrofuran(THF)andtolueneweredistilledfromsodiumbenzophenoneketylandsodiummetalunderargonandstoredover4Åmolecularsieves.Butanol(Merck)and󰀁-capro-lactone(CL,99+%)(Aldrich)weredriedoverCaH2for24handdistilledunderhighvacuumpriortouse.Methylmethacrylate(MMA,99%),styrene(St,99%),ethyleneglycoldimethacrylate(EGDMA,98%),divinylbenzene(DVB,80%mixtureofisomers),andN,N,N′,N′,N′′-pentamethyldiethylenetriamine(PMDETA,99%)wereallpurchasedfromAldrichandwashedthreetimeswith5%w/waqueousNaOH,oncewithwater,thendistilledfromcalciumhydride,andstoredat-5°C.p-Toluenesulfonylchloride(TsCl,

10.1021/ma0622027CCC:$33.50©2006AmericanChemicalSociety

PublishedonWeb12/06/2006

Macromolecules,Vol.39,No.26,2006

99+%)(Aldrich)wasdissolvedinminimumchloroform,dilutedwithpetroleumether(bp40-60°C),clarifiedwithcharcoal,filtered,concentrated,andcollectedbyfiltration.

Instrumentation.SizeexclusionchromatographywasperformedonaShimadzusystemwithaWyattDAWNDSPmultianglelaserlightscatteringdetector(690nm,30mW)andaWyattOPTILABEOSinterferometricrefractometer(690nm).THFwasusedastheeluentwiththreePhenomenexphenogelcolumns(500,104,and106Åporosity;5µmbeadsize)operatedat1mL/minwiththecolumntemperaturesetat30°C.Astrasoftware(WyattTechnologyCorp.)wasusedtoprocessthedatausingknowndn/dcvaluestodeterminethemolecularweightoranassumptionof100%massrecoveryofthepolymerwherethedn/dcvaluewasunknown.1HNMRspectrawerecollectedindeuteratedchloroform(unlessotherwisestated)usingaVarianUnityPlus400MHzspectrometer.MonomerconversionwasdeterminedbygaschromatographyusingaShimadzuGC17-AgaschromatographequippedwithaDB-5capillarycolumn(30m,5%phenylsiloxane)andcoupledtoaGCMS-QP5000massspectrometer.DynamiclightscatteringmeasurementswereperformedusingaMalvernHPPSparticlesizerwitha3.0mWHe-Nelaseroperatedat633nm.Analysiswasperformedatanangleof173°andaconstanttemperatureof25°C.Synthesisof2-Hydroxyethyl2′-Methyl-2′-bromopropionate.2-Bromoisobutyrylbromide(5.45g,23.7mmol)wasaddedintoamolarexcess(25times)ofethyleneglycol(33mL,593mmol)andstirredfor16hat0°C.Themixturewasthendissolvedinwaterandextractedwithdichloromethane.TheorganicphasewaswashedwithasaturatedaqueoussodiumbicarbonatesolutionfollowedbywateranddriedwithMgSO4.Thesolventwasdistilledoffunderreducedpressuretoyieldacolorlessliquid(3.90g,78%).1HNMR(400MHz,CDCl3),δ(ppm):1.95(s,6H,-C(CH3)2),2.17-COOC(s,H1H,-OH),3.87(t,2H,-CH2OH),4.31(t,2H,2-).

Synthesisof4,4′-Bioxepanyl-7,7′-dione(BOD).Asolutionofureahydrogenperoxide(CO(NH2)2‚H2O2)(10.0g,106mmol)in50mLofformicacid(99%)wasstirredat23°Cfor90min.4,4′-Bicyclohexanone(5.0g,25.7mmol)wasthenslowlyaddedover5-10minandstirredforafurther4h.200mLofwaterwasaddedtothemixturefollowedbyextractionwithchloroform.Theorganicfractionswerecollected,washedwithasaturatedaqueoussodiumbicarbonatesolution,anddriedwithNa2SO4.Theorganicfractionwasconcentrated,andthesolventwasremovedunderreducedpressuretoyieldawhitepowder(3.50g,60%).1HNMR(400MHz,CDCl3),δ(ppm):4.34(R,R)4.17(S,R)(t,2H,-CH2-OOC-),2.73(R,R)2.60(S,R)(t,2H,-CH2COO-),1.93-1.83(m,2H,-CH2CH2OOC-),1.70-1.60(m,2H,-CH2CH2COO-),1.49(q,1H,-CHCH2-).

Synthesisof2,2-Bis(󰀁-caprolactone-4-yl)propane(BCP).Asolutionofureahydrogenperoxide(CO(NH2)2‚H2O2)(8.16g,86.7mmol)in50mLofformicacid(99%)wasstirredat23°Cfor90min.2,2-Bis(4-oxocyclohexyl)propane(5.0g,21.2mmol)wasthenslowlyaddedover5-10minandstirredforafurther5h.200mLofwaterwasaddedtothemixturefollowedbyextractionwithchloroform.Theorganicfractionswerecollected,washedwithasaturatedaqueoussodiumbicarbonatesolution,anddriedwithNa2SO4.Theorganicfractionwasconcentrated,andthesolventwasremovedunderreducedpressuretoyieldawhitepowder(4.72g,83%).1HNMR(400MHz,CDCl3),δ(ppm):4.35(R,R)4.15(S,R)(t,2H,-CH2OOC-),2.73(R,R)2.57(S,R)(t,2H,-CH2-COO-CH-),2.01-1.90(m,2H,-CH2CH2OOC-),1.66-1.52(m,2H,2CH2COO-),1.40(q,1H,-CHCH2-),0.80(t,3H,-CCH3).SynthesisofPCL-BrMacroinitiator.Inatypicalreactionaround-bottomflaskwaschargedwithamixtureofCL(10g,87.6mmol),Sn(Oct)2(2.366g,5.84mmol),and2-hydroxyethyl2′-methyl-2′-bromopropionate(2.465g,11.7mmol).AcondenserandCaCl2dryingtubewereattachedtotheflaskwhichwasheatedat130°C.After24hthereactionsolutionwasdilutedwithTHFandprecipitatedintocoldmethanolwiththeprecipitatebeingcollectedbyfiltrationanddriedfor16hinadesiccatortoyield

DegradableCoreCross-LinkedStarPolymers9019

PCL-Br)1.12).

macroinitiator(yield:8.73g;Mn)2700g/mol,Mw/MnSynthesisofPMMA-ClMacroinitiator.AmixtureofMMA(1.95mL,18.2mmol),CuBr(0.093g,0.650mmol),bpy(0.305g,1.95mmol),TsCl(0.124g,0.650mmol),andanisole(2.60mL)wasaddedtoaSchlenkflaskanddegassedbythreefreeze-pump-thawcycles.Theflaskwasthenbackfilledwithargonandimmersedinanoilbathat100°C.After48h(87%MMAconversion)thereactionwasstoppedviaexposuretoairanddilutedwithTHFbeforebeingpassedthroughacolumnofbasicaluminatoremovethecoppercomplex.Thesolutionwasthenconcentratedandprecipitatedintocoldmethanolwiththeprecipitatebeingcollectedbyfiltrationanddriedfor16hinadesiccatortoyieldPMMA-Clmacroinitiator(yield:1.51g;Mn)7500g/mol,Mw/Mn)1.08).SynthesisofPSt-OHMacroinitiator.AmixtureofSt(3.26mL,28.4mmol),CuBr(0.068g,0.474mmol),bpy(0.222g,1.42mmol),and2-hydroxyethyl2′-methyl-2′-bromopropionate(0.10g,0.474mmol)wasaddedtoaSchlenkflaskanddegassedbythreefreeze-pump-thawcycles.Theflaskwasthenbackfilledwithargonandimmersedinanoilbathat80°Cfor16h.ThereactionwasstoppedviaexposuretoairanddilutedwithTHFbeforebeingpassedthroughacolumnofbasicaluminatoremovethecoppercomplex.Thesolutionwasthenconcentratedandprecipitatedintocoldmethanolwiththeprecipitatebeingcollectedbyfiltrationanddriedfor16hinadesiccatortoaffordPSt-OHmacroinitiator(yield:1.90g;Mn)10700g/mol,Mw/Mn)1.09).

SynthesisofArm-DegradableCCSPolymer.InatypicalreactionPCL-Brmacroinitiator(0.3g,0.132mmol;Mn)2300g/mol)wasreactedwithamixtureofCuBr(0.025g,0.172mmol),PMDETA(36.0µL,0.172mmol),EGDMA(0.622mL,3.30mmol),andanisole(26mL)inaSchlenkflaskanddegassedbythreefreeze-pump-thawcycles.Theflaskwasthenbackfilledwithargonandimmersedinanoilbathat100°C.After65h(93%EGDMAconversion)thereactionwasstoppedviaexposuretoairanddilutedwithTHFbeforebeingpassedthroughacolumnofbasicaluminatoremovethecoppercomplex.Thesolutionwasthenconcentratedandprecipitatedintomethanolwiththeprecipitatebeingcollectedbyfiltrationanddriedundervacuum.

SynthesisofPartiallyArm-DegradableCCSPolymer.AmixtureofPCL-Brmacroinitiator(0.250g,0.110mmol;Mn)2300g/mol)andPMMA-Clmacroinitiator(0.825g,0.110mmol;Mn)7500g/mol)wasreactedwithCuBr(0.025g,0.172mmol),PMDETA(36.0µL,0.172mmol),EGDMA(0.374mL,1.98mmol),andanisole(17mL)inaSchlenkflask.Theflaskwasdegassedbythreefreeze-pump-thawcyclesandbackfilledwithargonbeforebeingimmersedinanoilbathat100°C.After68h(80%EGDMAconversion)thereactionwasstoppedviaexposuretoairanddilutedwithTHFbeforebeingpassedthroughacolumnofbasicaluminatoremovethecoppercomplex.Thesolutionwasthenconcentratedandprecipitatedintomethanolwiththeprecipitatebeingcollectedbyfiltrationanddriedundervacuum.

SynthesisofCore-DegradableCCSPolymer.PSt-OHmac-roinitiator(1.52g,0.142mmol;Mn)10700g/mol)wasreactedwithamixtureofSn(Oct)2(23.0µL,0.071mmol),BOD(0.321g,1.42mmol),andtoluene(7.1mL)inadryround-bottomflaskat110°CwithacondenserandCaCl2dryingtubeattached.After48h(87%BODconversion)thereactionsolutionwasfilteredandprecipitatedintomethanolwiththeprecipitatebeingcollectedbyfiltrationanddriedundervacuum.

SynthesisofFullyDegradableCCSPolymer.CL(2.0g,17.5mmol)wasaddedtoamixtureoftoluene(17.5mL),butanol(30.8µL,0.337mmol),andSn(Oct)2(54.5µL,0.169mmol).AcondenserandCaCl2dryingtubewereattachedtotheflask,whichwasthenheated5300at110g/mol)°Cwithasolutionstirring.ofAfterBOD24(0.762h(CLg,conversion3.37mmol)>99%;Mn)in3mLofchloroformwasinjectedintothereactionmixture([BOD]/[PCL])10)andlefttoreactforafurther16h(86%BODconversion).Thereactionmixturewasthencooled,andthesolventwasremovedunderreducedpressurewiththecrudepolymerbeingdissolvedinTHFandprecipitatedintomethanol.Theprecipitatewascollectedbyfiltrationanddriedundervacuum.Similarreaction

9020WiltshireandQiaoMacromolecules,Vol.39,No.26,2006

Scheme1.GeneralizedSchematicofSelectivelyDegradableCoreCross-LinkedStar(CCS)PolymerFormationandSubsequent

HydrolysisToRemovetheLabileComponent

conditionswereemployedforsynthesisofBCP/PCL-basedCCSpolymerwithBCPreplacingBODsuchthat[BCP]/[PCL])10.

Hydrolysis.Inatypicalhydrolysisreaction40mgofdegradablepolymerwasdissolvedin4mLofTHF,towhichwasadded0.3mLofH2Oand0.1mLof12MHCl.Hydrolysiswascarriedoutat60°Cfor24h.Forreactionswheredegradationwasmonitoredusing1HNMR,THFandH2Owerereplacedwithdeuteratedsolvents(CD3COCD3andD2O,respectively).

ResultsandDiscussion

TheincorporationofadegradablefunctionalityintoCCSpolymerscanbeachievedbycombiningcontrolledradicalpolymerizationtechniques,suchasATRP,ofnondegradablemonomerswithring-openingpolymerization(ROP)oflactone-basedmonomers.TheROPmethodallowsforthesynthesisofCCSpolymerswithpolyester-basedstructures(armand/orcoremoieties)whichcanthereforebedegradedundercontrolledconditions13-15viahydrolysisoftheesterlinkagesinthepolymer.SinceROPisacontrolledpolymerizationtechnique,itsusetosynthesizeselectivelydegradableCCSpolymersresultsinwell-definedstructureswithnarrowpolydispersitiescompa-rabletotraditionalnondegradableCCSpolymerssynthesizedbyATRP,NMP,orRAFTpolymerization.

Bycombiningtheuseofdegradableandnondegradablemonomers,itispossibletosynthesizearangeofCCSpolymerswithdegradablefunctionalitysuchthatdifferentdomainsoftheCCSpolymercanbeselectivelydegradedtoproducearm-degradableCCS,partiallyarm-degradableCCS,core-degradableCCS,andfullydegradableCCSpolymer(Scheme1).ThisisachievedbymakinguseofanactivatedbrominecontainingalcoholwhichcanactasaduelinitiatorsuitableforinitiatingATRPofnondegradablemonomers(methylmethacrylate,styrene)fromtheactivatedbromineendgrouporROPof

degradablemonomers(󰀁-caprolactone)fromthehydroxylendgroup.Thisallowsforthesynthesisofdegradableandnonde-gradablelivinglineararmswhichcanbecross-linkedthroughoneactiveendgroup,eitherbyATRPofnondegradablecross-linker(divinylbenzene,ethyleneglycoldimethacrylate)orROPofdegradablecross-linker(4,4′-bioxepanyl-7,7′-dione,2,2-bis-(󰀁-caprolactone-4-yl)propane).Byusingdifferentcombinationsofdegradableandnondegradablearmsandcross-linkers,itispossibletosynthesizearangeofselectivelydegradableCCSpolymerswhichcanbestructurallymodifiedbyhydrolysisofthedegradablecomponent,resultinginpolymersthatcanbetailoredtosuitspecificapplications.

SynthesisofArm-DegradableCCSPolymer.Theasym-metricdifunctionalinitiator,2-hydroxyethyl2′-methyl-2′-bro-mopropionate,wasselectedastheinitiatorforthesynthesisofarm-degradableCCSpolymersinceithaspreviouslybeenshowntobeanefficientinitiatorforboththeATRPofvinylmonomersandtheROPoflactone-basedmonomers.16Usingthisinitiator,linearbromoisobutyrylpolycaprolactone(PCL-Br)(Mn)2700g/mol,Mw/Mn)1.12)wassynthesizedviaROPof󰀁-caprolactone(CL)withstannous2-ethylhexanoate(Sn(Oct)2)ascatalystat130°C.

ATRPchainextensionofthePCL-Brmacroinitiatorwithmethylmethacrylate(MMA)monomerwasperformedtotestforlivingness.Asshownbythegelpermeationchromatography(GPC)tracesinFigure1,amonomodalpeakofPCL-b-PMMAblockcopolymerwithlowmolecularweightdistributionwasobtained(Mn)6900g/mol,Mw/Mn)1.09).ThisconfirmsthehighinitiationefficiencyofPCL-Brmacroinitiatorsincethereisnoresidual“deadpolymer”observedintheGPCtrace,suggestingthatallthePCL-BrchainsinitiatedATRPchainextension.Thehighinitiationefficiency,narrowpolydispersity,andlivingnatureofthePCL-Brchainsmakeitanideal

Macromolecules,Vol.39,No.26,2006Figure1.Gelpermeationchromatographytracesofatomtransferradicalpolymerization(ATRP)chainextensionofpolycaprolactonemacroinitiator)[CuBr]/1.3)(PCL-Br)[PMDETA]/1.3bymethyl)[MMA]/40methacrylateat(MMA)100°Cin([PCL-Br]38.0mLofanisole)followedbyhydrolysisofthePCL-b-PMMAblockcopolymer.

Figure2.1HNMR(400MHz)of(a)polycaprolactonemacroinitiator(PCL-Br),(b)polycaprolactone-b-poly(methylmethacrylate)blockcopolymer(PCL-b-PMMA),and(c)PMMAfromthehydrolysisofPCL-b-PMMAblockcopolymer(CDCl3).

macroinitiatorforthesynthesisofCCSpolymerviathe“armfirst”approach.

ThedegradabilityofthePCLsegmentwastestedbyhydrolyzingthePCL-b-PMMAblockcopolymerunderacidicconditions(12MHCl/H2O/THF)1/3/40volumetricratio).Thehydrolysisreactionwasstoppedafter24hbytheadditionofmethanoltoprecipitateanyunhydrolyzedpolymer.1HNMRanalysisoftheunhydrolyzedpolymer(Figure2)showedittobepurePMMA,asexpected,withnoresidualpeaksduetothealiphaticprotonsofthePCLchain.ThemolecularweightoftheunhydrolyzedPMMAasdeterminedbyGPC(Figure1)was3900g/mol,whichcorrespondstothetheoreticalmolecularweightofthePMMAsegmentofthePCL-b-PMMAblockcopolymer(4200g/mol).Thecombined1HNMRandGPCresultsofthePCL-b-PMMAblockcopolymerhydrolysisconfirmthatthePCLsegmentofapolymercanbecompletelydegradedundertheacidicconditionsdescribedwithoutaffectingnondegradablepolymersegmentssuchasPMMA.

ThePCL-Brmacroinitiatorwasusedtosynthesizearm-degradableCCSpolymerbycross-linkingtheATRPactive

DegradableCoreCross-LinkedStarPolymers9021

Scheme2.SynthesisofArm-DegradableCCSPolymerand

SubsequentHydrolysis

chainendswithdivinylbenzene(DVB)orethyleneglycoldimethacrylate(EGDMA)(Scheme2).BothDVBandEGDMAwerechosentoactasthecross-linkingagentsincebothhavebeenwidelyusedinthe“armfirst”approachtosynthesizingnondegradableCCSpolymers.4-7Thechoiceofcross-linkerisalsoimportantasthecoreoftheCCSpolymerneedstobestableunderthehydrolysisconditionsusedtodegradethePCLarms.ThiswasshowntobetrueforbothDVB-andEGDMA-basedCCSpolymerswhichwerecapableofproducingstablecoredomainsuponhydrolysisasdescribedinlaterresults.

BecauseofthefactthatCCSpolymershaveamorecompactstructurethancorrespondinglinearpolymersofthesamemolecularweight,GPCmeasurementsusingamass-sensitivedetector(e.g.,RIdetector)calibratedbasedonlinearpolymerstandardswillgiveanapparentmolecularweightsmallerthanthetruemolecularweight.AmoreadvancedandaccuratetechniquetomeasurethemolecularweightofCCSpolymersuseslightscatteringtechniques.Forthisreasonamultianglelaserlightscattering(MALLS)detectorwasusedinconjunctionwithGPCtodeterminetheabsolutemolecularweightoftheCCSpolymersreportedinthiswork.

Aseriesofarm-degradableCCSpolymersweresynthesizedundervariousreactionconditionsusingPCL-Brmacroinitiator(Mn)2700g/mol,Mw/Mn)1.12)withDVBorEGDMAcross-linker(Table1,experiments1-6,andTable2,experi-ments8-12,respectively).Theeffectsofthemolarratioofcross-linkertolinearPCL-BrandthereactionconcentrationwerefoundtohaveasignificantimpactontheextentofCCSformation.WhenDVBwasusedasthecross-linker,thehighestconversionofarmsintoCCSpolymeroccurredatacross-linkertomacroinitiatormolarratioof15:1andamacroinitiatorconcentrationof40mM(Table1,experiment4).Varyingtheamountofcross-linkerandthereactionconcentrationresultedindecreasedarmconversionorgelationofthereactionsolution(Figure3a).Forthearm-degradableCCSpolymerformedusingEGDMAtheoptimalreactionconditionswerefoundtooccuratacross-linkertomacroinitiatormolarratioof25:1withanarmconcentrationof5mM(Table2,experiment10)withdeviationfromtheseconditionsalsoresultingindecreasedarmconversionorgelation(Figure3b).

TheoptimalreactionconditionfortheDVB-basedarm-degradableCCSpolymerwasfoundtooccuratamuchhigherconcentration(40mM)comparedtothatoftheEGDMA-basedarm-degradableCCSpolymer(5mM).ConversionofarmsintoCCSpolymerwasalsomuchlesswhenDVBwasusedasthecross-linkingagentasopposedtoEGDMA(42%comparedto78%).ThissuggeststhatDVBisalessreactivecross-linkerthanEGDMAunderthesereactionconditions.Thechoiceofcatalystsystem,solvent,reactiontemperature,andthemolecularweightofthemacroinitiatoralsoplayanimportantroleintheextentofCCSconversion.Byusingsmallermolecularweight

9022WiltshireandQiaoMacromolecules,Vol.39,No.26,2006

Table1.SynthesisofArm-DegradableCoreCross-LinkedStar(CCS)PolymerUsingPolycaprolactoneMacroinitiator(PCL-Br)and

Divinylbenzene(DVB)Cross-Linkerexptno.a

1234567

a

MnPCL-Br(g/mol)b

2700270027002700270027002300

PDIPCL-Brb1.121.121.121.121.121.121.05

[PCL-Br](mM)7.5203040704040

[DVB]/[PCL-Br]

15151515152015

PCLconv(%)c0192942gelgel57

Mn(g/mol)b270019060021250023440085200

PDIb1.121.251.561.451.16

fd15.022.632.115.1

Allpolymerizationswerecarriedoutat100°Cinanisole[PCL-Br])[CuBr]/1.3)[PMDETA]/1.3.bNumber-averagemolecularweight(Mn)andpolydispersity(PDI)measuredbygelpermeationchromatographyequippedwithmultianglelaserlightscattering(GPC-MALLS).cPercentageofincorporatedlinearPCLprecursorintoCCSpolymer.dNumberofarmsinCCSpolymer,determinedfromeq1.

Table2.SynthesisofArm-DegradableCoreCross-LinkedStar(CCS)PolymerUsingPolycaprolactoneMacroinitiator(PCL-Br)andEthylene

GlycolDimethacrylate(EGDMA)Cross-Linkerexptno.a

10111213

a

MnPCL-Br(g/mol)b

270027002700270027002300

PDIPCL-Brb1.121.121.121.121.121.05

[PCL-Br](mM)55510155

[EGDMA]/[PCL-Br]

152025252525

PCLconv(%)c597178gelgel85

Mn(g/mol)b2878002200382900367100

PDIb1.481.451.361.19

fd38.035.742.955.1

Allpolymerizationswerecarriedoutat100°Cinanisole[PCL-Br])[CuBr]/1.3)[PMDETA]/1.3.bNumber-averagemolecularweight(Mn)andpolydispersity(PDI)measuredbygelpermeationchromatographyequippedwithmultianglelaserlightscattering(GPC-MALLS).cPercentageofincorporatedlinearPCLprecursorintoCCSpolymer.dNumberofarmsinCCSpolymer,determinedfromeq1.

f)

WFarmsMw,CCS

Mw,arms

(1)

wheretheCCSmolecularweight(Mw,CCS)andthemolecularweightofthelineararms(Mw,arms)weredeterminedbyGPC-MALLS.Theweightfractionofarms(WFarms)canbedeter-minedaccordingtoeq2wheretheconversionofcross-linker(󰀃C)wasdeterminedbygaschromatography(GC)analysisandtheconversionofarms(󰀃A)determinedbyGPCanalysis.

WFarms)

m(arms)󰀃A

m(cross-linker)󰀃C+m(arms)󰀃A

(2)

Figure3.Gelpermeationchromatographytracesofpolycaprolactone(PCL)arm-degradablecorecross-linkedstar(CCS)polymerformationfor(a)divinylbenzene(DVB)cross-linkerwithvariablereactionconcentration(Table1,experiments2-4)and(b)ethyleneglycoldimethacrylate(EGDMA)cross-linkerwithvariablecross-linkeramount(Table2,experiments8-10).

PCL-Brmacroinitiator(Mn)2300g/mol,Mw/Mn)1.05)toformCCSpolymeratthepreviouslydeterminedoptimalconditions(Table1,experiment7,andTable2,experiment13),itwasfoundthatthearmconversioncouldbeincreasedfrom42%to57%fortheDVB-basedCCSpolymerandfrom78%to85%fortheEGDMA-basedCCSpolymer.Theseresultsareinaccordancewithfindingsfromourearlierwork5,17andthatofMatyjaszewskietal.,18whoshowedthatemployingshorterarmlengthsledtohigherCCSpolymeryields.

ThenumberoflinearpolymericarmsincorporatedintotheCCSpolymer(f)wascalculatedusingthefollowingequation:

TheDVBandEGDMAarm-degradableCCSpolymerswiththehighestconversion(Table1,experiment7,andTable2,experiment13)werehydrolyzedunderacidicconditionstodegradethepolycaprolactonearmsandliberatethecross-linkedcore.GPCtraceswereobtainedforthehydrolyzedproducts(Figure4a,b)whichrevealedthenumber-averagemolecularweight(Mn)oftheDVBcorestobe30600g/mol(Mw/Mn)1.84)whiletheEGDMAcoreshadaMnof232300g/mol(Mw/Mn)1.47)(Table3,samples1and2).ThetheoreticalmolecularweightofthecorescanbecalculatedbymultiplyingthemolecularweightoftheCCSpolymerandtheweightfractionofcross-linker(1-WFarms).FortheCCSpolymersanalyzedheretheDVBandEGDMAcoresweredeterminedtohavetheoreticalmolecularweightsof43700and215700g/mol,respectively,closelymatchingtheexperimentallydeter-minedvaluesof30600and232300g/mol.ExperimentalobservationsindicatethattheshoulderpeakinthehydrolyzedproductofFigure4a(28mLelutionvolume)correspondstothehydrolyzedproductofmacroinitiatorwhichhasundergonechainextensionbuthasnotbeenincorporatedintoCCSpolymer.SimilarresultsarealsoobservedforthehydrolyzedproductinFigure4b(29mLelutionvolume)withthepeakbeingsignificantlyreducedduetothesmalleramountofunconvertedmacroinitiatorbeforehydrolysis.

Macromolecules,Vol.39,No.26,2006Figure4.Gelpermeationchromatographytracesofarm-degradablecorecross-linkedstar(CCS)polymersynthesizedwith(a)divinylben-zene(DVB)(Table3sample1)and(b)ethyleneglycoldimethacrylate(EGDMA)cross-linker(Table3sample2)beforeandafterhydrolysisandcorrespondingdynamiclightscatteringmeasurements[(c))DVB,(d))EGDMA].

Dynamiclightscatteringmeasurementsofthehydrolysisreactionsolutionwererecordedbeforeandafterhydrolysis(Figure4c,d)inordertocomparethediameteroftheCCSpolymertothatoftheliberatedcore.TheaveragediameterbasedonscatteringintensityfortheDVBandEGDMACCSpolymerswasfoundtobe27and52nm,respectively,whichcorrespondswithpreviousfindingsforothernondegradableCCSpolymers.6bAfterhydrolysisthediameteroftheremainingpolymerwasfoundtohavebeenreducedtoyieldDVBandEGDMAcoreswithaveragediametersof11and37nm,respectively.ThereductioninsizeforboththeDVBandEGDMACCSpolymerswasfoundtobeverysimilar(16and15nm,respectively),owingtothesamePCL-Brmacroinitiator(Mn)2300g/mol)beingusedinbothinstances.However,themagnitudeofthissizereductionisnotsolelyduetothelengthoftheremovedarmsinceshrinkageoftheexposedcorewillalsooccur.Thisshrinkageoccursduetothehighlycross-linkedcoreparticlesbecominglesssolubleuponremovalofthearms.

SynthesisofPartiallyArm-DegradableCCSPolymer.Thesynthesisofpartiallyarm-degradableCCSpolymerinvolvestheintroductionofasecondtypeofarmtocreatemiktoarmCCSpolymerwithamixtureofdegradableandnondegradablearms.Traditionally,miktoarmCCSisgeneratedbythe“in-out”method8,19-21wherethe“armfirst”approachisusedtocreateCCSpolymerfrompolyAmacroinitiatorandadivinylcross-linker.Asecondmonomer(B)isthenusedtogrowarmsoutfromtheinitiatingsitesinthecoretogeneratemiktoarmCCSpolymerwithpolyAandpolyBarms.Onedrawbackofthe“in-out”methodistheunknownefficiencyofthechainextensionreactionwiththesecondmonomersincenotalloftheinitiationsitesinthecorewillbeaccessibleduetothehighcross-linkingdensityinthecoreandthesterichindrancecreatedbythearms.Alternatively,miktoarmCCScanbesynthesizedusingthe“armfirst”approachbysimplycross-linkingtwodifferentpolymericmacroinitiators(polyAandpolyB)simultaneously.However,thisrequiresthetwomacroinitiatorstohavesimilarreactivitysothattheresultantmiktoarmCCScontainsbothpolyAandpolyBarms.

DegradableCoreCross-LinkedStarPolymers9023

Themethodofcross-linkingtwomacroinitiatorssimulta-neously,asopposedtothe“in-out”method,wasemployedforthisworkusingPCL-Br(Mn)2300g/mol,Mw/Mn)1.05)asthedegradablearmcomponentandtosylchlorideinitiatedpoly(methylmethacrylate)(PMMA-Cl)(Mn)7500g/mol,Mnondegradablearmcomponent.EGDMAwasw/Mn)1.08)astheusedtocross-linkthePCL-BrandPMMA-ClmacroinitiatorsunderATRPconditionstosynthesizemiktoarmCCSpolymer(Scheme3)withanumber-averagemolecularweightof559600g/molandapolydispersity(Mw/Mn)of1.24(Figure5).TheextentofCCSformationwaslimited(28%conversionofarmsintoCCSpolymer)andassuchwasfractionatedtoremoveanyunconvertedarmsandyieldpuremiktoarmCCSpolymer.SincethemolecularweightsofthePCLandPMMAarmsweredifferent,itisexpectedthattheirreactivitywillalsobedifferent,resultinginmiktoarmCCSpolymerwithahigherratioofonetypeofarmcomparedtotheother.1HNMRwasusedtodeterminetherelativeamountofPCLandPMMAarmsincorporatedintothemiktoarmCCSpolymer(Figure6)bycomparingthepeakareaofa(CH2COOfromPCLunit)toh(OCH3fromPMMAunit).ThemolarratioofPCLtoPMMAwasdeterminedtobe2.6:1,showingthatthesmallerPCLarmsweremorereadilyincorporatedintothemiktoarmCCSpolymer.Fromthisdataitwaspossibletocalculatetheaveragenumberofarms(f)incorporatedintotheCCSpolymerasbeing53.1(14.8PMMAand38.3PCLarms).

ThemiktoarmCCSpolymerreportedherecanbeclassifiedaspartiallyarm-degradableCCSpolymersinceonetypeofarm,thePCLcomponent,canbeselectivelydegradedtoproduceCCSpolymerwithareducednumberofarms.Byhydrolyzingthepartiallyarm-degradableCCSpolymer,wecancreateCCSpolymerwhichwouldpotentiallyhaveverydifferentphysicalpropertiestothatofstandardCCSpolymersincethenumberofarmswouldbemuchlesscomparedtoCCSpolymerofasimilararmmolecularweight.

GPCtracesshowareductioninmolecularweightafterhydrolysisofthemiktoarmCCSpolymer(Figure5)suchthattheresultantCCSpolymerhadaMnof460800g/molandapolydispersityof1.36(Table3,sample3).1HNMRanalysisofthehydrolyzedpolymerconfirmedthatallofthePCLarmshadbeenremovedtoyieldpurePMMAarmCCSpolymer.SincethenumberandmolecularweightofthedegradablePCLarmsinthemiktoarmCCSpolymerareknown,thetheoreticalmolecularweightoftheCCSpolymerafterhydrolysiscanbecalculated.ForthemiktoarmCCSpolymerreportedherethetheoreticalMnafterhydrolysiswascalculatedtobe472500g/mol,whichisinaccordancewiththatmeasuredbyGPC-MALLS(460800g/mol).

SynthesisofCore-DegradableCCSPolymer.Tosynthesizecore-degradableCCSpolymer,ahydrolyzablemonomermustbeemployedasthecross-linkingagent.Forthisworkthebislactone4,4′-bioxepanyl-7,7′-dione(BOD),synthesizedac-cordingtoliterature,22waschosenasthedegradablecross-linkerduetoitsstructuralsimilarityto󰀁-caprolactone,withBODconsistingoftwocaprolactoneringsbridgedatthe4-position(Scheme1).Bycross-linkinglineararmswithBODunderROPconditions,theresultantCCSpolymerwillpossessapolyester-basedcorewhichcanbedegradedviahydrolysisoftheincorporatedesterlinkages.

Sincethecross-linkingstepisperformedunderROPcondi-tions,themacroinitiatorarmsneedtobehydroxylend-functionalizedsotheycaninitiatethepolymerizationoftheBODcross-linker.ForthisreasontheduelATRP/ROPinitiator,2-hydroxyethyl2′-methyl-2′-bromopropionate,wasusedto

9024WiltshireandQiaoMacromolecules,Vol.39,No.26,2006

Table3.SelectivelyDegradableCoreCross-LinkedStar(CCS)Polymers

CCS

hydrolyzedCCS

fg15.155.153.113.3.034.4

Mn(g/mol)f3060023230046080010700

PDIf1.841.471.361.09

Mn,theory(g/mol)4370021570047250010700

armconv(%)d

578528558541

Xconv(%)e709380878683

Mn(g/mol)f85200367100559600214800362000335800

samplea

123456

a

armbPCLPCL

PMMAPCLPStPCLPCL

XcDVBEGDMAEGDMABODBODBCP

PDIf1.161.191.241.181.131.27

ReactionconditionsforCCSpolymersasdefinedintext(sample1)Table1experiment7,sample2)Table2,experiment13).bTypeofarmusedtosynthesizeCCSpolymer;definitions:PCL)poly(󰀁-caprolactone),PMMA)poly(methylmethacrylate),PSt)polystyrene.cTypeofcross-linker(X)usedtosynthesizeCCSpolymer;definitions:DVB)divinylbenzene,EGDMA)ethyleneglycoldimethacrylate,BOD)4,4′-bioxepanyl-7,7′-dione,BCP)2,2-bis(󰀁-caprolactone-4-yl)propane.dPercentageofincorporatedlineararmprecursorintoCCSpolymer.eDeterminedbygaschromatography.fNumber-averagemolecularweight(Mn)andpolydispersity(PDI)measuredbygelpermeationchromatographyequippedwithmultianglelaserlightscattering(GPC-MALLS).gNumberofarmsinCCSpolymer,determinedfromeq1.

Figure5.Gelpermeationchromatographytracesofpolycaprolactone(PCL)poly(methylmethacrylate)(PMMA)miktoarmcorecross-linkedstar(CCS)polymerandsubsequenthydrolysis(Table3,sample3).Scheme3.SynthesisofPartiallyArm-DegradableCCSPolymer

andSubsequentHydrolysis

synthesizehydroxylend-functionalizedpolystyrenemacroini-tiator(PSt-OH)viaATRP(Mn)10700g/mol,Mw/Mn)1.09).BODcross-linkerwaspolymerizedwiththePSt-OHmac-roinitiatorintolueneat110°C([BOD]/[PSt-OH])10,[PSt-OH])0.02M)usingSn(Oct)2catalyst(Scheme4).TheconversionofBODmonomerwasmonitoredbygaschroma-tographymassspectrometrywhichshowedthatafter48h87%oftheBODmonomerhadbeenconsumed.GPCanalysis(Figure

Figure6.1HNMR(400MHz)ofpolycaprolactonepoly(methylmethacrylate)miktoarmcorecross-linkedstar(CCS)polymer(CDCl3)(Table3,sample3).

Scheme4.SynthesisofCore-DegradableCCSPolymerand

SubsequentHydrolysis

7)revealedthat∼55%ofthelinearPSt-OHhadbeenconvertedintoCCSpolymer,whichwassubsequentlyfractionatedtoremoveanyunconvertedarmstoyieldpureCCSpolymerwithaMnof214800g/mol(Mw/Mn)1.18)andanaverageof13.6arms(calculatedfromeq1).

HydrolysisofthistypeofCCSpolymerresultedindegrada-tionofthecoredomainandliberationofthenondegradablePStarms(Table3,sample4),effectivelyconvertinghighmolecularweightCCSpolymerintolowmolecularweightlinearpolymer.GPCanalysis(Figure7)confirmedthiswiththeCCSpolymerbeingcompletelydegradedtoyieldtheoriginallinearPStarms(Mn)10700g/mol,Mw/Mn)1.09).

Macromolecules,Vol.39,No.26,2006Figure7.Gelpermeationchromatographytracesofpolystyrene(PSt)core-degradablecorecross-linkedstar(CCS)polymerandsubsequenthydrolysis(Table3,sample4).

Scheme5.SynthesisofFullyDegradableCCSPolymerand

SubsequentHydrolysis

SynthesisofFullyDegradableCCSPolymer.WerecentlyreportedaprocedureforthesynthesisoffullydegradableCCSpolymerbasedonROPoflactone-basedmonomers.12AsimilarprocedurewasalsoreportedatthesametimebyBielaetal.23TheROPmethodisdifferenttothepreviousmethodsdescribedforsynthesizingarm-degradableorcore-degradableCCSpoly-mersinceonlyoneformofcontrolledpolymerizationisrequiredratherthanacombinationofROPandATRP.ThisallowsforthesynthesisofCCSpolymerviaatwo-stepone-potprocesswherebylivinglinearPCLarmsaresynthesizedunderROPconditions.Oncompletionofthisreactionabislactoneisaddedtothereactionmixturetocross-linkthearmsandformacompletelypolyester-basedCCSpolymer(Scheme5).

Asshownearlier,12arangeofreactionconditionsforthesynthesisoffullydegradableBOD/PCL-basedCCSpolymerhavebeeninvestigated,anditwasfoundthatoptimalCCSformationoccurredwhen1-butanol([BuOH])19.2mM)wasusedtoinitiatethering-openingpolymerizationof󰀁-caprolac-tone([CL])1M)intolueneat110°Cusingstannous2-ethylhexanoate([Sn(Oct)2]/[BuOH])0.5)ascatalyst.Oncethisreactionreachedcompletion(CLconversion>99%,24h,Mn)5300g/mol,Mw/Mn)1.07),theBODcross-linkerwasadded([BOD]/[PCL])10)andallowedtoreactforafurther16huntil86%oftheBODmonomerhadbeenconsumed,andahighconversionofarmsintoCCSpolymer(85%)wasachieved.TheCCSpolymergeneratedwascalculatedtohave

DegradableCoreCross-LinkedStarPolymers9025

Figure8.(a)Cross-linkerconversion(BOD)4,4′-bioxepanyl-7,7′-dione,BCP)2,2-bis(󰀁-caprolactone-4-yl)propane)duringthesynthesisoffullydegradablecorecross-linkedstar(CCS)polymerand(b)gelpermeationchromatographytracesoffullydegradableCCSpolymersandprecursorpolycaprolactone(PCL)arms(Table3,samples5and6).

anumber-averagemolecularweightof362000g/mol(M1.13)withanaverageof43.0arms.

w/M)nHere,wealsoreporttheuseofanalternativedegradablebislactonecross-linker,2,2-bis(󰀁-caprolactone-4-yl)propane(BCP).ThestructureofBCPisverysimilartothatofBOD,exceptthatthebridgingunitbetweenthe󰀁-caprolactoneringsinBCPconsistsofamethylatedquaternarycarbon(Scheme1).TheBCPcross-linkerwaspolymerizedundertheoptimalreactionconditionspreviouslydescribedtosynthesizeBODcross-linkedCCSpolymerwithBODbeingdirectlysubstitutedwithBCP.48hafteradditionoftheBCPcross-linker83%oftheBCPmonomerhadbeenconsumed,buttheconversionofarmsintoCCSwasonly41%.TheresultantCCSpolymergeneratedwascalculatedtohaveanumber-averagemolecularweightof335800g/mol(Mw/Mn)1.27)withanaverageof34.4arms.AcomparisonofthetwofullydegradableCCSpolymers(Figure8)synthesizedunderthesamereactionconditionsshowsthatsimilarmolecularweightCCSpolymer(elutionvolume)22mL)isgeneratedinbothinstances,Mn)362000g/molfortheBOD-basedCCScomparedto335800g/molfortheBCP-basedCCS(Table3,samples5and6).However,thereactiontimetoreachsimilarcross-linkerconversion(83-86%)took3timeslongerfortheBCPreaction(Figure8a)withtheresultantconversionofarmsintoCCSpolymeralsobeingsignificantlyreduced,lessthanhalfthatachievedfortheBOD-basedreaction.TheseresultssuggestthattheBCPcross-linkerislessreactivetowardtheformationofCCSpolymerthanBODcross-linker,possiblyduetothebulkymethylgroupscreatingsterichindrance,whichmakesithardertogeneratethedensecoreregionduringthecross-linkingstep.

GPCtracesofthetwofullydegradableCCSpolymers(Figure8b)revealthatinadditiontothesynthesisofCCSpolymer(elutionvolume)22mL)thegenerationofveryhighmolecular

9026WiltshireandQiaoFigure9.1HNMR(400MHz)of2,2-bis(󰀁-caprolactone-4-yl)propane(BCP)corecross-linkedstar(CCS)polymer(Table3,sample6)taken(a)beforeand(b)after24hofhydrolysis(60°C,CD3COCD3:D2O(13.3:1),0.272MHCl),/)bridgingmethylgroupsfromBCPcross-linker.

weightpolymer(1-2million)hasalsooccurred(elutionvolume∼be17aproductmL).Thisofstarhigh-starmolecularcouplingweightandispolymermoreprevalentisbelievedinthetoBCPcross-linkedreactionduetothelongerreactiontimerequiredforCCSformation,resultinginanincreasedprobabilityofstar-starcouplingoccurring.

Ourpreviouswork12hasshownthatPCL/BOD-basedCCSpolymercanbecompletelydegradedbyhydrolyzingtheesterbondsinthepolymertogeneratesmallchainacids.Thisdegradationreactionwasquantitativelymonitoredbyconductingthehydrolysisexperimentindeuteratedsolvents(THF-d8andD2O)andanalyzingthereactionsolutionovertimewith1HNMRspectroscopy.SimilarexperimentswereconductedforthehydrolysisofBCP/PCL-basedCCSpolymerwithcompari-sonofthe1HNMRspectrabeforeandafterhydrolysis(Figure9),revealingthatthetripletatδ4.02ppmcorrespondingto󰀁-CH2inthepolyesterbackboneisgreatlyreducedafterhydrolysisandiscomplementedbytheappearanceofthetripletatδ3.50ppmcorrespondingto󰀁-CH2ofthehydrolyzedester.Theextentofhydrolysiscanbecalculatedbycomparingtherelativepeakareaof󰀁-CH2beforeandafterhydrolysis,whichrevealedthatfortheBCP/PCL-basedCCSpolymer∼97%oftheesterlinkageshadbeenhydrolyzedbacktotheirmonomericconstituents.

WhenBODisusedtosynthesizefullydegradableCCSpolymer,1HNMRspectroscopyofthestarcannotbeusedtodetecttheBODcorestructureduetothereducedsegmentalmobilityofthecorewhichresultsinbroadeningofthecharacteristicpeaksofthecoresuchthattheydisappearintothebaseline.However,whenBCPisusedasthecross-linker,thetwomethylgroupsinthebridgingunitbetweenthelactoneringsareflexibleenoughandofahighenoughintensitythattheycanbedetectedby1HNMRspectroscopy(Figure9a:*δ0.80ppm),eventhoughsignificantbroadeningisstillobserved.Forthe1HNMRspectraofthehydrolyzedproductthepeakduetothebridgingmethylgroupsbecomesstrongerandsharper

Macromolecules,Vol.39,No.26,2006

(Figure9b:*δ0.76ppm)asitisnolongerboundwithintherigidcorestructurebutinsteadexistsasasmall-chainhydrolysisproductresemblingtwo6-hydroxyhexanoicacidunitsbridgedatthe4-positionbyamethylatedquaternarycarbon(1inScheme5).Theothercharacteristicpeaksof1areobscuredbythepeaksassociatedwiththehydrolysisproductofthelineararms,6-hydroxyhexanoicacid(2inScheme5),duetotheirstructuralsimilarityandthesmalleramountof1relativeto2.Conclusions

ArangeofselectivelydegradableCCSpolymersweresuccessfullysynthesizedbycombiningATRPofnondegradablemonomerswithROPofdegradablelactone-basedmonomers.Utilizingthismethod,degradablePCLarmCCSpolymersweresynthesizedwithbothEGDMAandDVBcores.Variousreactionparameters,especiallythemacroinitiatorconcentrationandthemolarratioofcross-linkertomacroinitiator,werestudiedtodeterminetheoptimalreactionconditionswithEGDMAbeingfoundtoyieldhigherconversionofarmsintoCCSpolymercomparedtoDVB.HydrolysisexperimentsshowedthatthePCLarmscouldbeselectivelydegradedtoyieldEGDMAandDVBcores,forwhichthesizewasdirectlydetermined.

MiktoarmCCSpolymerwassynthesizedinasimilarfashionwithamixtureofdegradablePCLandnondegradablePMMAarms.ThehighermolecularweightPMMAmacroinitiatorshowedlowerreactivitythanthePCLwithlessPMMAarmsbeingincorporatedintotheCCSpolymer.AcidichydrolysisconditionswereusedtoselectivelydegradethePCLarmsandyieldCCSpolymerwithareducednumberofarms.Degradablefunctionalitywasalsoincorporatedintothecoredomainusingadegradablebislactone,BOD,tocross-linknondegradablelinearPSt-OHmacroinitiatorunderROPconditions.HydrolysisofthisCCSpolymerresultedindegradationofthecoreandfullrecoveryoftheoriginallinearPStarms.

Degradablebislactonemonomerwasalsoshowntobeabletocross-linkdegradablePCLarmsviaatwo-stepone-potreactiontoproducefullydegradableCCSpolymer.Theef-fectivenessoftwobislactonecross-linkers,BODandBCP,wasexaminedwithahigherconversionofarmsintoCCSpolymerbeingachievedwhenBODwasusedcomparedtoBCP,possiblyduetotheaddedstericbulkoftheBCPmonomermakingformationofthedensecoreregionunfavorable.Bothbislactone-basedCCSpolymerswereshowntobefullydegradablebeinghydrolyzedbacktomonomericconstituents.

Acknowledgment.WethanktheAustralianResearchCoun-cil(ARCDiscoveryGrantDP0345290)forfinancialsupportofthiswork.

ReferencesandNotes

(1)Thisclassofpolymerisalsoreferredtoasstarmicrogelorstarnanogel

intheliterature;however,theterm“corecross-linkedstar(CCS)polymer”betterrepresentstheirmoleculararchitecture.

(2)Worsfold,D.J.;Zilliox,J.G.;Rempp,P.Can.J.Chem.1969,47,

3379-3385.

(3)Tsitsilianis,C.;Graff,S.;Rempp,P.Eur.Polym.J.1991,27,243-246.

(4)(a)Solomon,D.H.;Abrol,S.;Kambouris,P.A.;Looney,M.G.WO

9831739,1998,TheUniversityofMelbourne,AProcessforPreparingPolymericMicrogels.(b)Abrol,S.;Kambouris,P.A.;Looney,M.G.;Solomon,D.H.Macromol.RapidCommun.1997,18,755-760.(c)Abrol,S.;Caulfield,M.J.;Qiao,G.G.;Solomon,D.H.Polymer2001,42,5987-5991.(d)Bosman,A.W.;Vestberg,R.;Heumann,A.;Frechet,J.M.J.;Hawker,C.J.J.Am.Chem.Soc.2003,125,715-728.

(5)Connal,L.A.;Gurr,P.A.;Qiao,G.G.;Solomon,D.H.J.Mater.

Chem.2005,15,1286-1292.

Macromolecules,Vol.39,No.26,2006

(6)(a)Solomon,D.H.;Qiao,G.G.;Abrol,S.WO9958588,1999,The

UniversityofMelbourne,ProcessforMicrogelPreparation.(b)Gurr,P.A.;Qiao,G.G.;Solomon,D.H.;Harton,S.E.;Spontak,R.J.Macromolecules2003,36,5650-5654.(c)Xia,J.;Zhang,X.;Matyjaszewski,K.Macromolecules1999,32,4482-4484.(d)Zhang,X.;Xia,J.;Matyjaszewski,K.Macromolecules2000,33,2340-2345.(e)Baek,K.Y.;Kamigaito,M.;Sawamoto,M.Macromolecules2001,34,215-221.(f)Baek,K.Y.;Kamigaito,M.;Sawamoto,M.Macromolecules2001,34,7629-7635.(g)Baek,K.Y.;Kamigaito,M.;Sawamoto,M.Macromolecules2002,35,1493-1498.(h)Baek,K.Y.;Kamigaito,M.;Sawamoto,M.J.Polym.Sci.,PartA:Polym.Chem.2002,40,1972-1982.(i)Baek,K.Y.;Kamigaito,M.;Sawamoto,M.J.Polym.Sci.,PartA:Polym.Chem.2002,40,633-1.

(7)(a)Lord,H.T.;Quinn,J.F.;Angus,S.D.;Whittaker,M.R.;Stenzel,

M.H.;Davis,T.P.J.Mater.Chem.2003,13,2819-2824.(b)Moad,G.;Mayadunne,R.T.A.;Rizzardo,E.;Skidmore,M.;Thang,S.H.Macromol.Symp.2003,192,1-12.(c)Zheng,G.;Pan,C.Polymer2005,46,2802-2810.

(8)Hadjichristidis,N.J.Polym.Sci.,PartA:Polym.Chem.1999,37,

857-871.

(9)Peppas,N.;Nagai,T.;Miyajima,M.Pharm.Tech.Jpn.1994,10,

611-617.

(10)Ho,A.K.;Gurr,P.A.;Mills,M.F.;Qiao,G.G.Polymer2005,46,

6727-6735.

(11)Heise,A.;Nguyen,C.;Malek,R.;Hedrick,J.;Frank,C.;Miller,R.

Macromolecules2000,33,2346-2354.

DegradableCoreCross-LinkedStarPolymers9027

(12)Wiltshire,J.T.;Qiao,G.G.Macromolecules2006,39,4282-4285.(13)Pitt,C.G.InBiodegradablePolymersasDrugDeliVerySystems;

Chasin,M.,Langer,R.,Eds.;Dekker:NewYork,1990;p71.

(14)Vert,M.;Li,S.M.;Spenlehauer,G.;Guerin,P.J.Mater.Sci.:Mater.

Med.1992,3,432-446.

(15)Doi,Y.;Kunioka,M.;Nakamura,Y.;Soga,K.Macromolecules1988,

21,2722-2727.

(16)Xu,Y.;Pan,C.;Tao,L.J.Polym.Sci.,PartA:Polym.Chem.2000,

38,436-443.

(17)Gurr,P.A.TheSynthesisandCharacterizationofStar-Microgelsby

AtomTransferRadicalPolymerization.Ph.D.Thesis,TheUniversityofMelbourne,2004.

(18)Gao,H.;Matyjaszewski,K.Macromolecules2006,39,3154-3160.(19)Georgiades,S.N.;Vamvakaki,M.;Patrickios,C.S.Macromolecules

2002,35,4903-4911.

(20)Gao,H.;Tsarevsky,N.V.;Matyjaszewski,K.Macromolecules2005,

38,5995-6004.

(21)Du,J.;Chen,Y.Macromolecules2004,37,3588-3594.

(22)Nijenhuis,A.J.;Grijpma,D.W.;Pennings,A.J.Polymer1996,37,

2783-2791.

(23)Biela,T.;Polanczyk,I.J.Polym.Sci.,PartA:Polym.Chem.2006,

44,4214-4221.

MA0622027