2012--Synthesis and functionalization of nanoengineered materials using click chemistry

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ProgressinPolymerScience

journalhomepage:www.elsevier.com/locate/ppolysci

Synthesisandfunctionalizationofnanoengineeredmaterialsusingclickchemistry

GeorginaK.Such,AngusP.R.Johnston,KangLiang,FrankCaruso∗

DepartmentofChemicalandBiomolecularEngineering,TheUniversityofMelbourne,Parkville,Victoria3010,Australia

article

info

abstract

Articlehistory:

Received14July2011Receivedinrevisedform25November2011

Accepted2December2011

Available online 13 December 2011

Keywords:

ClickchemistryThinfilmsParticles

Thesynthesisofnanoengineeredmaterialswithprecisecontrolovermaterialcompo-sition,architectureandfunctionalityisintegraltoadvancesindiversefields,includingbiomedicine.Overthelast10years,clickchemistryhasemergedasaprominentandver-satileapproachtoengineermaterialswithspecificproperties.Herein,wehighlighttheapplicationofclickchemistryforthesynthesisofnanoengineeredmaterials,rangingfromultrathinfilmstodeliverysystemssuchaspolymersomes,dendrimersandcapsules.Inaddition,wediscusstheuseofclickchemistryforfunctionalizingsuchmaterials,focusingonmodificationsaimedatbiomedicalapplications.

© 2011 Elsevier Ltd. All rights reserved.

Contents1.2.

3.

Introduction........................................................................................................................Fundamentalsofclickchemistry...................................................................................................2.1.Copper-catalyzedalkyne-azidecycloaddition..............................................................................2.2.Cu-freealkyne-azidecycloaddition.........................................................................................2.3.Diels–Aldercycloaddition...................................................................................................2.4.Thiol–enereaction..........................................................................................................Applicationofclickchemistryformaterialssynthesis.............................................................................3.1.Clickfilms...................................................................................................................3.2.Clickparticlesandcapsules.................................................................................................

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Abbreviations:Ab,antibody;ATRP,atomtransferradicalpolymerization;Az,azide;BSA,bovineserumalbumin;Cu,copper;CuAAC,copper-catalyzedalkyne-azidecycloaddition;CB(6),cucurbit[6]uril;CD,cyclodextrin;DA,Diels–Alder[4+2]cycloaddition;DNA,deoxyribosenucleicacid;DOX,doxoru-bicin;EDC,1-ethyl-3-(3-dimethylaminopropyl)carbodiimideenealkene;HYA,hyaluronan;LbL,layer-be-layerassembly;LCST,lowercriticalsolutiontemperature;NAS,N-acroyloxysuccinimide;NCCM,noncovalentlyconnectedmicelle;NHS,N-hydroxysuccinimide;PAA,poly(acrylicacid);PBLG,poly(␥-benzyl-l-glutamate);PCL,poly(␧-caprolactone);PDPA,poly(2-diisopropylaminoethylmethacrylate);PEG,poly(ethyleneglycol);PHEMA,poly(2-hydroxyethylmethacrylate);PGAAlk,alkyne-modifiedpoly(l-glutamicacid);PGA,poly(l-glutamicacid);PMA,poly(methacrylicacid);PMMA,poly(methylmethacrylate);PNIPAM,poly(N-isopropylacrylamide);POEGMA–PDMA–PDEA,poly(oligo(ethyleneglycol)monomethylethermethacrylate)-b–poly(2-dimethylamino)ethylmethacylate-b–poly(2-diethylamino)ethylmethacylate);PPDSM,poly(pyridyldisulfideethylmethacrylate);PS,poly(styrene);PSS,poly(styrenesulfonate);PtBA,poly(tert-butylacrylate);PVPON,poly(N-vinylpyrrolidone);Q␤,capsidofbacteriophage;rDA,retro-Diels–Alder;RGD,arginine–glycine–asparticacid;ROP,ringopeningpolymerization;SAMs,self-assembledmonolayers;SPAAC,strain-promotedcycloadditionofalkynesandazide;SPIO,superparamagneticironoxide.

∗Correspondingauthor.Tel.:+61383443461;fax:+61383444153.E-mailaddress:fcaruso@unimelb.edu.au(F.Caruso).

0079-6700/$–seefrontmatter© 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.progpolymsci.2011.12.002

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4.

5.

3.3.Clickhydrogelscaffolds.....................................................................................................995Applicationofclickchemistryforfunctionalizationofmaterials..................................................................9954.1.Functionalizationoffilms...................................................................................................9954.2.Functionalizationofparticlesandcapsules................................................................................997Conclusion..........................................................................................................................1000Acknowledgments..................................................................................................................1000References..........................................................................................................................1000

1.Introduction

Thedevelopmentoffunctionalnanoengineeredmate-rialsisfundamentalforadvancesindiversefieldssuchasbiomedicine,optics,andgreenenergyproduction.Thesynthesisofsuchmaterialsrequiressynthetictechniquesthataffordprecisecontrolovermaterialproperties.Inthelastdecade,clickchemistryhasemergedasapromis-ingtechniquetoengineerthearchitectureandfunctionofmaterials[1,2].Typicalclickreactionsdisplayseveralimportantcriteria,suchashighefficiencyundermildcon-ditions,minimalbyproducts,andlimitedsidereactions.Themostwell-documentedexampleisthecopper(Cu)(I)catalyzedalkyne-azidecycloadditiontoform1,2,3tri-azoles.However,recentlyanumberofotherreactions,includingCu-freeclickandDiels–Aldercycloaddition,havealsogeneratedsignificantinterest.

Recently,theapplicationoftheseclicktechniqueshasfoundwidespreaduseinthesynthesisofnovelnanos-tructuredpolymers.Thereareanumberofcomprehensivereviewshighlightingthisarea,detailingthecomplexandinnovativepolymerbuildingblocksthatcanbedesigned[3,4];hencethisreviewwillnotdiscussthesestudies.How-ever,thisenhancedversatilityinpolymerdesignhasledtothedevelopmentandfunctionalizationofarangeofnewnanoengineeredfilms,particlesandscaffolds.Inthistrendarticlewehighlighttherecentdevelopmentsforsynthe-sizingmaterialsusingclickreactions,focusingonmaterialswithapplicationinbiomedicine.Wealsodiscusstheappli-cationofclicktechniquestofunctionalizebothnewandexistingnanoengineeredmaterialstooptimizetheirinter-actionsbothinvitroandinvivo.

2.Fundamentalsofclickchemistry

Sharplessandco-workersintroducedtheconceptofaclickreactionin2001[5].Thereactionswereidentifiedbyastringentsetofcriteria,includingsimplereactioncon-ditions,highefficiency,regio-andstereoselectivity,andamenabletoreactionundermildconditions.Clickreactionsachievethesecharacteristicsbyhavingahighthermo-dynamicforce,usuallygreaterthan20kCalmol−1.Suchreactionsproceedrapidlytocompletionandtendtobehighlyselective.Thelattercharacteristicisimportantforapplicationswherethereisadiverserangeoffunctionalitypresent,forexampleinvivo.

In2002,boththeSharplessandMeldallabora-toriesreportedadramaticincreaseinreactionrateforthetraditionalHuisgencycloadditionusingacop-percatalyst[6,7].Thisnewreaction,termedcopper-catalyzedalkyne-azidecycloaddition(CuAAC),hassince

becomethepremierexampleofclickchemistry.Since2004,thisreactionhasbeenappliedtotheconstruc-tionofnumerousnewmaterialsfromblockcopoly-mersthroughtocomplexdendrimerorself-assembledmaterials[8].

2.1.Copper-catalyzedalkyne-azidecycloaddition

TheCuAACreactionoccursbetweenanorganicazideandaterminalalkyneinthepresenceofCu(I)toforma1,4disubstituted1,2,3triazole(Fig.1a).Thisisincontrasttothenoncatalyzedreaction,whichproceedsunderelevatedtemperaturestoformamixtureof1,4-and1,5-triazoleregioisomers[9].TherateoftheCuAACreactionisover107timesfasterthantheconventionalreaction,whichmeansitproceedsefficientlyatroomtemperature.TheCuAACmechanismiscomplexandsomeaspectsarestillunclear,suchastheformofthecopperacetylideintermediate.How-ever,itbasicallyinvolvesthreekeysteps:firstlythereistheinitialformationofa5-triazolylcopperintermediate.Secondly,thisintermediatecoordinatestheorganicazideandthenthenucleophiliccarbononthecopper(I)acetylidereactswiththeelectrophilicterminalnitrogenontheazide.Finally,thismetallocycleundergoesringcontractionandsubsequentdissociationoftheproducttoregeneratethecatalyst[9].

CuAACproceedsinmanyproticandaproticsolvents,includingwater,andisunaffectedbymostinorganicandorganicfunctionalgroups.Duetoitstoleranceforotherfunctionality,anumberofspeciescanbeaddedwithoutaffectingtheCuAACreaction,includinginorganicazidesinlargeexcess.Cu(I)isrequiredtocatalyzetheclickreac-tion;however,itcaneitherbeaddedorproducedinsitu.OnetypicalapproachistouseaCu(I)saltsuchascopperiodide,chlorideoracetate.However,itcanbechalleng-ingtokeeptheCuactivethroughoutthereaction.AmongthecommonoxidationstatesofCu(0,+1and+2),the+1stateistheleastthermodynamicallyfavored.There-fore,cuprousionscanbereadilyoxidizedtoformCu(II)ordisproportionatetoamixtureofCu(II)andCu(0)[10].Whenpresentinsignificantamounts,Cu(II)canfacili-tateGlaser-typealkynecouplingprocesseswhileimpairingtriazoleformation.Thus,whenusingCu(I)directly,itisoftennecessarytoperformthereactionunderoxygen-freeconditions.

AcommonalternativetotheuseofCu(I),whichremovestheneedforoxygen-freeconditions,wasdevel-opedbyHeinandFokin[10].ThisprocessinvolvescombiningCu(II)salts,suchascopper(II)sulfatepen-tahydrateorcopper(II)acetate,withamildreductantsuchassodiumascorbate.Inadditiontoreducingthe

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Fig.1.Selectionofreactionsthatbestmeetthecriteriafora“click”reaction:(a)Cu(I)-catalyzedHuisgen1,3-dipolarcycloadditionofalkynesandazides;(b)strain-promotedcycloadditionofalkynesandazides;(c)Diels–Alderreaction;and(d)thiol–enereaction.

Cu(II)intotheactiveCu(I)forreaction,theascorbatealsoreducesanydioxygenpresent,thuslimitinganyoxidativebyproducts.Otherreducingagentsthathavebeenusedincludehydroquinoneandtris(carboxyethyl)phosphine[11].

TheCuAACreactioncanalsobecatalyzedbyCu(I)pro-videdbyelementalcopper,suchasapieceofcopperwireorturning.Althoughusingcoppermetalgenerallyleadstolongerreactiontimesatambienttemperatures,thisapproachhastheadvantageoflowcoppercontaminationlevels.ToimprovetherateoftheCuAACreactionanumberofligandshavebeenused,includingphosphine-oramine-basedsystems[10].ThisbehaviorisprobablyduetoligandstabilizationoftheactiveCu(I)thusimpedingitsdegrada-tion.

OneinherentlimitationwithCuAACistheneedforCu(I)andtheassociatedpotentialtoxicity.Althoughtheeffi-ciencyandlackofsidereactionsoftheCuAACsystemlendsitselftoinvitroandinvivobiologicalcouplingreactions[11,12],anumberofstudieshaveshownthatcoppercanbetoxictocellsatconcentrationsaslowas10␮M[12].Inmaterialsynthesis,Cu(I)canbeefficientlyremovedfrommostmaterialsaftertheclickreactionhasbeenperformed;however,forinsitureactions,freeCu(I)canposeaproblem.Toaddressthis,Finnandco-workershavedemon-stratedthattris-(hydroxypropyltriazolylmethyl)amine-chelatedCu(I)preventscelltoxicityandhastheaddedbonusofacceleratingtheclickreactionfasterthanfreeCu(I)[12].Itwasdemonstratedthatclickcouplingofazide-functionalizedmannantolivingmammaliancells(JurketandHeLa)resultedinnoevidenceoftoxicityafter48h.

2.2.Cu-freealkyne-azidecycloaddition

AnalternativeapproachtoovercomingpotentialissueswithCu(I)toxicityhasbeentoimprovetherateoftheHuisgenalkyne-azidecycloadditionwithouttheneedforacoppercatalyst.ThemostwelldocumentedapproachwasdevelopedbyBertozziandco-workers,andusesafamilyofstrainedalkynescalledcyclooctynestoallowstrain-promotedcycloadditionofalkynesandazide(SPAAC)[13].Inaseriesofstudiesthisgroupdemonstratedthereactionratecouldbetunedbythesubstituentsonthecyclooctynegroup.ThemechanismofSPAACisbasedonintroducingring-strainintothealkynemolecule,whichisreleasedinthetransitionstateofthereaction(Fig.1b).Asitisanaccel-eratedalkyneandazidecycloaddition,itleadstoamixtureofstereoisomers.Otherrelatedsystemshavealsobeeninvestigatedusingdibenzocyclooctynesoroxanorbornadi-enes[14].

2.3.Diels–Aldercycloaddition

AnotherclickreactionrecognizedbySharplessandco-workersistheDiels–Alder[4+2](DA)cycloadditionbetweenadieneandadienophile[5].Thiscycloaddi-tionreactionisattractiveforarangeofapplicationsas,inadditiontobeinghighyielding,regioandstereo-controlledunderreagentfreeconditions,italsoproducesthermoreversibleproducts(Fig.1c)[15].TheDiels–Alderandtheoppositeretro-Diels–Alder(rDA)reactioncanbecontrolledbytemperaturetoformthecyclizedprod-uctandnoncyclizedstartingmaterials,respectively.Thewidevarietyofdieneanddienophilesallowstuningof

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thethermoreversibility;forexamplefuranandmaleimideproductsundergoreversionatapproximately110◦Cwhileantraceneandmaleimideproductsrequiretemperaturesabove200◦C.Thesereactionscanbealsoperformedatmildertemperatures,ashasbeendemonstratedrecentlyforcouplingofpolymersusingcyclopentadieneandacti-vatedRAFTendgroups[16].ThereversiblenatureoftheDAreactionhasledtothedesignofnewmaterialswith‘self-healing’potential,includingpolymerresinsandgels[17].

2.4.Thiol–enereaction

Thethiol–enereaction,basedonathiolandanalkenegroupusingaradicalsourcetocatalyzethereaction,hasalsoreceivedsignificantattentioninmaterialsresearch(Fig.1d).Whilethiol–enechemistryiscommonlyreferredtoasaclickreaction,itisnotedthatduetothehighreactiv-ityofthethiolgrouptoarangeofdifferentfunctionalities,itfallsshortofclickbehaviorasitisnottrulyorthogonal[18].Therefore,thereactionconditionsmustbechosencare-fullytocontrolthispotentialforsimultaneousreactions.Reactionsbetweenthiolsandalkyneorbromoderiva-tiveshavealsobeenreportedintheliterature;however,thiol–eneisthemostwidelyexploredsystem.Therefore,thisreviewwilllimitdiscussiononthiol-basedsystemstothethiol–enereaction.Ifconditionsarecontrolledsothatsidereactionsdonotinterferewiththesystem,thiol–enereactionshavemanyoftheotherbenefitsofaclicksystemandcanalsooffersomeadditionaladvantages[19].Duetothereactivityofthethiolthesereactionsoftenproceedmorerapidlythanotherclicksystems(highconversioncanbeachievedinaslittleas1–10s)[18].

Schlaadandco-workersfirstintroducedtheradicalmediatedthiol–enereactionasapotentialclickreac-tionin2007,highlightingthesimple,highlyefficientandrobustnatureofthereaction[20].Thermal,redoxandphotochemicalmethodologiescanallbeusedtogener-ateradicalstoinitiatethethiol–enereaction.However,theuseofphotoinitiationisparticularlyattractive,asitallowsbothspatialandtemporalcontrolovertheprogressofthereaction.Aswithradicalinitiatedpolymerization,thethiol–enereactionencompassesthreedistinctprocesses[18]:initiation,thepolymerizationorcouplingprocess,andtermination.Thecombinedpropagationandchaintransferreactionproceedatequivalentratesinanidealthiol–enereaction,wherenopolymerizationofthe–eneoccurs.Thisleadstothehighlyefficientsinglecoupledproductinwhichonethiolreactsacrossone–enetoproduceanadditionproduct.Thestepgrowthnatureofthisprocessmeansthattheproductsarehomogenousanduniform,acharacteristicthatisunusualfortypicalphotochemicalreactions.

3.Applicationofclickchemistryformaterialssynthesis

3.1.Clickfilms

Controloverthedesignofnanostructuredsurfacesisfundamentalforapplicationsinthefieldsofdrugdelivery,sensingandoptics.Oneofthemaingoalsistoengineer

thepropertiesoftheinterfacetocontroltheinteractionswiththelocalenvironment.Forexample,fordrugdeliverythesurfacemustbelow-foulinginvivotoallowefficientdeliveryofthetherapeuticwithminimalsideeffects[21].Surfacepropertiescandependonanumberoffactors,includingtopography,functionality,andspatialposition-ingonthesurface.Thereareanumberoftechniquesusedtomodifysurfaceproperties,includingphysicaladsorption,layer-be-layerassembly(LbL)andself-assembledmono-layers(SAMs).However,thereisstillaneedtoimprovetheversatilityoftheseapproachesandthuscombiningthemwithhighyieldingcouplingtechniquesisofsignificantinterest.

Oneofthesimplesttechniquesforsurfacemodifica-tionisdirectpolymerdeposition.RecentlyCuAACandSPAACwerecombinedwithpolymerdepositiontosyn-thesizecrosslinkedpolymercoatings[22].Thefilmsweresynthesizedbydepositinganazide-modifiedpoly(methylmethacrylate)(PMMA)andanalkynecrosslinkerontoanalkyne-modifiedglassslide.Twotechniqueswereusedtocrosslinkthefilm,eitherastandardalkynecrosslinkeratincreasedtemperature(110◦C)orastrainedalkynecrosslinkerwithreducedtemperature(65◦C).Inbothcasesthecoatingwastransparentandstrongandcouldbereadilyfunctionalized.

SAMshavealsobeenusedforsurfacemodification.SAMsareformedbasedonathiol-facilitatedinteractionwithasurface[23].SAMscanbeassembledonavarietyoftemplates,suchasglassandsilicon,butareofparticularinterestongoldsurfacesduetotheefficiencyofthethiolinteraction.Duetothehighefficiencyandthecompatibil-itywithawiderangeoffunctionalitiesandsolvents,clickchemistryhasattractedinterestforthedesignoffunctionalSAMs.Earlystudiesdemonstratedazidefunctionalalkanescouldbeassembledonagoldsurfaceandmodifiedsuccess-fullywithferroceneforapplicationaselectrodes[24].

AnumberofstudieshavealsobeenconductedusingSAMscapableofDAreactions.Inonesuchsystemanelec-troactivehydroquinoneSAMwassynthesizedandwhenanelectricpotentialwasappliedtothehydroquinoneitwasoxidizedtoformaquinone,whichcouldthenundergoaDAreactionwithacyclopentadiene[25].Laterstudiesusedacelladhesionpeptide,RGD,todemonstratecellmigrationonasurface.Inthatworkapoly(ethyleneglycol)(PEG)-basedhydroquinoneSAMwaspatternedwithfibronectin,andthesurfacewasincubatedwithcells.Initiallythecellsgrewonlyinthefibronectinregions;however,whenapotentialwasappliedtothesurfacethehydroquinonewasoxidized.Therefore,whenthesurfacewassubsequentlymodifiedwithRGD-modifiedcyclopentadieneitunder-wentaDAreaction,allowingthecellstomigrateoverthesurface[26].

Layer-by-layerassemblyisanotherwidelyusedapproachfordesigningthinfilms,asitallowsahighlevelofcontroloverpropertiessuchasfilmthickness,compositionandnanostructure.Thetechniquewasdevel-opedbyDecherandHongin1991,andisbasedonthesequentialdepositionofchargedmaterialsontoaplanartemplate[27].Overthelast20yearsthisapproachhasbeenextendedtoarangeoftemplates,suchasemulsiondropletsorcolloidalparticles.Furthermore,LbLmaterials

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canbeassembledbasedonavarietyofinteractions,includ-inghydrogenbondingandcovalentinteractions[28,29].

AlthoughtheLbLapproachisversatile,thesynthesisofsamechargeorlow-chargefilmsisstillchallengingusingconventionalLbLassembly.In2006,ourgroupcombinedclickchemistryandLbLassemblytoprepareultrathinmultilayerfilms.Theapproachwasbasedonfunc-tionalizingpolymerswithaminorcomponentofeitheralkyneorazidefunctionality,andthenassemblingthesematerialsalternatelyinthepresenceofaCucatalyst.Initialworkshowedthatthisapproachcouldbeusedtoassemblemultilayersofpoly(acrylicacid)(PAA)[30].Laterworkbyourgroupandothersdemonstratedthatthisapproachcouldbeextendedtoarangeofotherpolymers,includingpoly(N-isopropylacrylamide)(PNI-PAM)[31]andpoly(N-hydroxypropylmethacylamide)andpoly(allylaminehydrochloride)[32].Wefurtherdemon-stratedthesynthesisofbiodegradableclickLbL-assembledfilmsusingpoly(l-lysine)orpoly(l-glutamicacid)(PGA)[33]andlow-foulingfilmsusingpoly(ethyleneglycolacry-late)[34].Inthislatterwork,itwasalsodemonstratedthatexcessfunctionalitycouldbeusedtofunctionalizethefilmtotailorsurfaceinteractions.Anumberofothergroupshavedemonstratedthatthisapproachcanbeextendedbeyondlinearpolymers:multilayersofsmallmolecules[35],dendrimers[36]andpolymer/smallmoleculecombi-nations[37]haveallbeenused.Oneinterestingapplicationofthistechniquewasthesynthesisofsuperhydropho-bicsurfaces[38],wherehierarchicalsilicaparticleswereassembledbyreactingalkyne-andazide-modifiedsilicainaseriesofsequentialcycles.Theparticleswerethendepositedonasilicasurfaceandmodifiedwithhydropho-bicfunctionality.Itwasdemonstratedthatthesurfacesweresuperhydrophobicwithacontactanglethatincreasedfrom134◦to152◦withincreasingsilicacouplingcycles.

Therehavealsobeenanumberofstudiessynthesizingclickfilmsusingchemicaldepositiontechniques.Inonesuchsystem,chemicalvapordepositionpolymerizationofsubstituted[2,2]paracyclophaneswasusedtosynthe-sizealkynefunctionalizedpoly-(p-xylylene)films[39].Itwasshownthatthesefilmscouldbepatternedusingazidefunctionalbiotin.Inarelatedapproach,werecentlydemonstratedthesynthesisofclickfunctionalfilmsusingplasmapolymerization[40],athinfilmdepositionpro-cessinwhichaplasmasourceisusedtogeneratea‘glowdischarge’thatactivatesorfragmentsgaseousmonomervapors.Inthatstudy,weutilized1-bromopropanetoyieldbromo-functionalizedplasmafilms,whichcouldberead-ilyconvertedintoazidesurfacesbyreactionwithsodiumazide.

3.2.Clickparticlesandcapsules

Overthelastfiveyearstherehasbeensignificantinter-estinthedesignofnanoengineeredparticles,particularlyforapplicationinbiomedicine[47].Suchadvancedapplica-tionsrequirepreciseandtunablesyntheticstrategiesthatarecompatiblewitharangeofbiologicalspecies.Thus,clickchemistryhasbeenappliedtothesynthesisofarangeofmaterials,includingpolymersomes,micelles,andLbLcapsules(Fig.2).Earlyworkinthisareafocusedon

synthesizingavarietyofnovelpolymers,andthesenewmaterialshavebeenhighlightedinanumberofexcellentreviews[16,18,48].Thisreviewwillfocusontheassem-blyofthesefundamentalbuildingblocksintoparticulatepolymericcarriers,aswellasinorganic-polymerhybrids.Starpolymersareinterestingandversatilepolymericstructures,andarebasedonmultiplepolymericarmsconnectedtoacentralcore.Suchmaterialscanbesyn-thesizedbyeithera“corefirst”oran“armfirst”approach.GaoandMatyjaszewskireportedthesynthesisof4-armpoly(styrene)(PS)starpolymersbyan“armfirst”approach.LinearPSwassynthesizedusingatomtransferradicalpoly-merization(ATRP)andthebromineendgroupwasthenmodifiedtoformanazide[45].Thepolymerswerethencombinedwithafunctionalcorewitheitherone,threeorfouralkynegroupsbyCuAAC.Theyieldsofthe3and4-armstarpolymerwere90%and83%,respectively.Miktoarmstarpolymerscontainmorethanonetypeofpolymericarm.Whittakeretal.reportedthesynthesisofarangeof3-miktoarmstaranddendrimerarchitecturesusingPS,poly(methacrylicacid)(PMA),PAAandpoly(tert-butylacrylate)(PtBA)[49].AtypicalpolymerwassynthesizedbyATRP,andtheendgroupwasthenmodifiedtoanazideandcoupledtoatripropargylamine.Thetworemainingalkynegroupsweresubsequentlycoupledtoadifferentazidemodifiedpolymer,thusforming3-miktoarmstarpoly-mers.DendriticpolymersweresynthesizedbystartingthisprocesswithabifunctionalPS.Inanotherapproach,per-6-(tert-butyldimethylsilyl)-␤-cyclodextrin(CD)wasusedasaninitiatorforthecontrolledring-openingpolymerization(ROP)ofpoly(␧-caprolactone)(PCL)[50].AfterdisilylationfromtheCDcore,theywereconvertedtoazidegroups.TheazidegroupswerethenmodifiedwithPEG.Thesemateri-alswereshowntoself-assembleintoarangeofstructuresinaqueoussolutionbasedonmacromoleculararchitectureandcomposition.

Dendrimersarehyperbranchedmacromoleculessyn-thesizedbyaseriesofiterativeorganicreactions.Thesetree-likemacromoleculesareassembledusingtwomainstrategies,knownasdivergentorconvergentsynthesis[51].Thedivergenttechniqueinvolvesbuildingincreas-inglevelsofbranchingfromapolyfunctionalcorewhiletheconvergentapproachentailsattachmentofpreformeddendrimerwedgestoacentralcore.Whiletherehasbeensignificantprogressinmakingdendrimerssimplyandefficiently,thereisstillaneedforcheaper,moreefficienttechniquestobuildthesestructures,andclickchemistryoffersonesolution.Mullenandco-workerswerethefirsttouseclickchemistryforthedesignofden-drimers.InthisworktheyusedDAtodesignarangeofpoly(phenylene)systems[52].Thesematerialsdemon-stratedinterestingenergyharvestingandlightemittingproperties[53,54].Furan-terminaldendrimerswerealsocombinedwithmaleimidelinkersusingDA.Itwasdemon-stratedthattheseconjugatescouldbedegradedat95◦CthrougharDAreaction[55].Whilethesetemperaturesaretoohighforbiomedicalapplications,itcouldbeenvisagedthattriggeredreleaseofdrug-loadeddendrimerswouldbeofinterestfordeliveryapplications.

TheCuAACreactionhasbeenwidelyusedforthesyn-thesisofdendrimersduetoitsabilitytogivehighyields

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Fig.2.Polymericcarriersystemsinvolvingclickchemistry:(a)polymersomes;(b)polymermicelles;(c)dendrimers;(d)LbLcapsules;(e)starpolymers;and(f)polymernanoparticles.(b)[42]Copyright2009RSCPublishing,reproducedwithpermission;(a)[41]Copyright2009,(c)[43]Copyright2008,(d)[44]Copyright2009,(e)[45]Copyright2006,and(f)[46]Copyright2005,AmericanChemicalSociety,reproducedwithpermission.

andlimitedsideproducts.ThefirststudyofthistypedemonstratedAB2convergentdendrimersynthesisusingarangeofmonomerscontainingbothchloromethylandalkynesmoieties[56].ThechloromethylgroupcouldbereadilyconvertedtoanazidebeforeCuAACreaction,allow-ingstep-by-stepgrowthofdendriticarms.Thesearmswerethencombinedwithacentralmultifunctionalcore[56].InlaterworkadivergentCuAACsyntheticprocesswassuccessfullyappliedtothesynthesisofFrechet-typedendrimers[57].Recently,thiol–enechemistryhasbeenusedtosynthesizepoly(thioether)dendrimers[43].InthisworkanAB2typemonomer1-thioglycerolwasaddedtoamultifunctionalcore.Furthergenerationswerethensynthesizedbyrepetitiveesterificationoftheendgroupswith4-penenoicanhydrideandthenthiol–enecouplingto1-thioglycerol.Thiol–enechemistryisattractiveforthesynthesisofdendrimersbecauseitisextremelyefficient,canbeperformedinbulkanddoesnotrequireadditionalsolvents.However,duetothereactivityofthiolswitharangeofbiofunctionalities,loadingwiththerapeuticcargoneedstobepostthiol–enereaction.Oneofthekeylimita-tionswithusingdendrimersisthetime-intensivesynthesis

ofthesematerials.However,progressinapproacheslikeclickchemistryaresimplifyingtheprocess,allowingmate-rialstobeefficientlysynthesizedathighyields.RecentlyCuAACandthiol–enechemistrywerecombinedtodevelopasynthetictechniquethatallowed6thgenerationden-drimerstobeformedin24h[58].

Clickchemistryhasalsobeenusedforthesynthesisofasymmetricorbow-tiedendrimers.Thefirststudyofthistypedemonstratedtheassemblyof4thgenerationden-drimersusinganhydridechemistrywitheitheranalkyneorazidemoietyatthecore[59].Thisfunctionalitywasthensubsequentlymodifiedtoformabow-tiestructure.

Polymerscanself-assembleintoavarietyofstructures;twoofthemostwell-knownexamplesaremicellesandpolymersomes[60].Micellesaregenerallyspherical,withahydrophobicinteriorandahydrophilicexterior.Incon-trast,polymersomeshaveahollowvesiclestructure,withapolymermembranethathasahydrophobicinteriorandahydrophilicinnerandoutersurface.Whiletherearearangeofpolymerstructuresthatcanbeusedtoassem-blemicellesandpolymersomes,theyaretypicallyformedfromamphiphilicblockcopolymers.Clickchemistryhas

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becomeanattractivealternativeforthesynthesisofsuchblockcopolymers,especiallywhenitisnotpossibletopoly-merizethembythesamepolymerizationtechnique.Anearlystudyusedanazide-functionaldendrimertocrosslinktheshellofanalkyne-modifiedmicelle,thusformingshell-crosslinkednanoparticles[46].Itiswellknownthatself-assemblyofpolymericmaterialscanbetunedbyvary-inganumberoffactorssuchashydrophilicorhydrophobicblocklength.Inarecentstudy,delBarrioetal.synthesizedaseriesoflinearPEG-dendriticcopolymersbasedonlinearPEGandazobenzene-baseddendrimerscombinedusingCuAAC[61].Itwasdemonstratedthatthedendrimergen-erationnumber,thenumberofazobenzenemesogens,andthePEGmolecularweightcouldbeusedtotunethetypeofpolymerstructureobtained.

MorecomplexstructuresweredesignedbyJiangetal.bysynthesizingamicellebasedonaterminalalkynetri-blockcopolymerpoly(oligo(ethyleneglycol)monomethyl

ethermethacrylate)-b–poly(2-dimethylamino)

ethylmethacylate-b–poly(2-diethylamino)ethylmethacylate)(POEGMA–PDMA–PDEA)[62].Thispolymerwasassem-bledintomicellesandthentheinnerPDMAlayerwascrosslinkedusing2-bis(2-iodoethoxy)ethane.Afour-layernanoparticlewasthensynthesizedbycouplinganazidefunctionalPNIPAMtothesurfaceusingclickchemistry.Thesenanoparticleswerebothtemperature-andpH-responsiveduetothePNIPAMandPDEAcomponents,respectively.AnotherinterestingmicellesystemwasreportedbyQuanetal.[63],whichisbasedonaCDdimerlinkingoftwopolymerchains.An␣–␤CDdimerwassynthesized,whichassociatedwithaphenyl-terminalpoly(NIPAM-co-N-acroyloxysuccinimide(NAS))andaadamantaneterminalPCL,respectively.Thisconjugateself-assembledintomicellesofapproximately100nmindiameter.Thesemicelleswereengineeredwithresponsivecharacteristicsbyfunctionalizingthepoly(NIPAM-co-NAS)withPEGchainsthroughacid-responsivebenzoic-iminegroups.ThePEGgroupswereengineeredtopreventcellularuptakeofthemicellesinphysiologicalcondi-tions;however,tumorstypicallyhavealowerpHthanthestandardphysiologicalenvironment,sowhenthemicellesenteratumor,thedecreaseinpHcausesthePEGchainstoberemoved,allowingthecarrierstobeinternalized(Fig.3).Themicelleswerealsofunction-alizedwithanRGDpeptidetoimprovecellbinding;however,theeffectivenessofthiscomponentwasnotfullyinvestigated.ThePEGgroupsalsoincreasethelowercriticalsolutiontemperature(LCST);thereforeinacidicenvironments,themicellesdeconstructedatalowertemperature(35.5◦Cascomparedto38◦C),leadingtothepossibilityforcargotobereleased.Thiol–enechemistryhasalsobeenusedtopreparefunctionalmicelles.Inarecentstudy,Chenetal.synthesizedmicellesfromthermoresponsivepoly(di(ethyleneglycol)methylethermethacrylateandpoly(2-hydroxyethylmethacrylate)(PHEMA)[42].ThesemicellesweremodifiedtohaveactivealkenegroupsbyreactionofthePHEMAmoietieswith4-pentenoicanhydride,andthenformedglycomicellesbyathiol–enereactionwithglycothiose.Thesemicelleswereshowntobethermoresponsiveandactiveforlectinbinding.

PolymersomeshavealsobeensynthesizedusingCuAACforbiomedicalapplicationsandhavetheadvantageofpotentiallyloadingbothhydrophilicandhydrophobicther-apeutics.InonestudyvanDongenetal.incorporatedaminorcomponentofaclick-synthesizedpoly(styrenesulfonate)(PSS)–PEGcopolymerwithastandardpoly-mersomeformingcopolymerpolystyrene40-block–poly[l-isocyanoalanine(2-thiophen-3-yl-ethyl)amide]50[64].ThePSS–PEGcopolymerwasfoundtobeincorporatedintothepolymersomestructureandasitcontainedatermi-nalalkyne,thiswasthenusedtopostmodifythestructure.Polymersomescanalsobedesignedcontainingotherfunc-tionalcomponentssuchascyclodextrins[65]orbiologicalmolecules.Oneapproachinvolvestheconjugationofpro-teinswithsyntheticpolymers[66].Suchmaterialshavethepotentialtocontainbuilt-inbioactivity.Dirksetal.synthesizedthistypeofconjugatebycouplingalkyne-modifiedbovineserumalbumin(BSA)toPSwithaterminalazideusingCuAAC[67].Theconjugateswerefoundtoself-assembleintosphericalaggregatesof30–70nmindiameter.Inadifferentsystem,Schatzetal.[68]syn-thesizedasimpleglycoproteinanaloguebycouplinganalkyne-modifieddextrantoanazidefunctionalpolypep-tide,poly(␥-benzyl-l-glutamate)(PBLG),usingCuAAC.Thiscopolymerwasfoundtoself-assembleintosmallpolymer-somes(45nm)bynanoprecipitation.Inarelatedsystem,thesamegroupsynthesizedablockcopolymerofPBLGandhyaluronan(HYA)usingCuAAC,whichformedextremelyuniformpolymersomestructures[41].Thesematerialswerealsosuccessfullyloadedwithdoxorubicinandthiscargowasstablyretainedwithinthepolymersomesforseveralmonths(10%lossat4◦C).

Surfactantscanalsoself-assembleintomicelles;how-ever,theysufferfromlimitedstability.InarecentapproachbyZhangandZhao,alkyne-modifiedsurfactantswereusedtosynthesizestabilizedsurfactantmicellesusingarangeofazidefunctionalcrosslinkersbyCuAAC[69].Thesematerialswereoftheorderof8–10nminsizeandcouldbepostmodifiedusingexcessalkynegroupsonthesurface.Laterworkdemonstratedthatthesecrosslinkedmicellescouldbeusedtoloadsmallhydrophobiccargoover15h.Thiscargowasreleasedextremelyrapidlywhenthecrosslinksweredegraded(Fig.4)[69].

AnothertechniqueforassemblingpolymercarriersisbasedonLbLassembly.Thistechniquecanbeusedtoconstructthinfilmsonparticletemplateswhicharesub-sequentlyremovedtoformpolymercapsules.TheLbLapproachisattractiveforthesynthesisofpolymericcap-sulesforbiomedicalapplicationsasthepolymericbuildingblockscanbetunedtodesigntailoredcarriers[70].Recently,clickchemistryhasbeenappliedtothesynthesisofLbLcapsulescontainingasinglepolymericcompo-nentbysequentialassemblyofazideandalkyne-modifiedpolymersinthepresenceofacoppercatalyst.ThiswasdemonstratedinitiallybyourgroupusingPAAtoformresponsivehydrogelcapsules[71].Laterworkshowedthatthistechniquecouldalsobeappliedtoavarietyofpoly-mers,includingtemperatureresponsivepolymers[72],polypeptidesandpolysaccharides[73].

Arelatedtechniquedevelopedbyourgroupinvolvedcombininghydrogen-bondedLbLfilmswithCuAAC

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Fig.3.Formationofcore–shellnoncovalentlyconnectedmicelles(NCCM)withswitchabletumorcelltargeting:(a)diblockcopolymerassociatedwithan␣–␤cyclodextrindimer;(b)thisconjugateself-assembledintomicelleswithprotectedtargetligandsatpH7.4;(c)tumor-triggereddeshieldingtoswitchonthetargetingpropertythroughremovalofPEGsegmentsatpH<6.8;(d)endocytosisanddrugreleaseafterdestructionoftheofmicellestructureatT>LCST.(d)Apoptosisoftumorcells.[63]Copyright2010,AmericanChemicalSociety,reproducedwithpermission.

stabilization.Hydrogen-bondedLbLfilmsareofsignifi-cantinterestforthedevelopmentofpolymericcarriersbecausetheycanbedesignedtoberesponsivetoarangeofstimulisuchaspHortemperature,althoughtheyaregenerallyonlystableatlowpHandthusrequirecovalentstabilization.Anumberofstabilizationtechniqueshavebeenused,includingmodificationwiththiolsandformingdisulfidecrosslinksorcrosslinkingthecarboxylicacidsusingdiaminecrosslinkersandcar-bodiimide.CuAACisanattractivealternativeasitishighlyefficient,thusensuringthatonlyasmallamountofthefilmismodifiedtoachievethedesiredcrosslink-ing.Inaninitialstudy,analkyne-modifiedpoly(N-vinylpyrrolidone)(PVPON)wasassembledwithPMAbasedonhydrogen-bonding[44].ThisfilmwasstabilizedbyCuAACusingabifunctionalazidecrosslinker.Thiswasthefirstuseofacrosslinkertostabilizesuchfilms,andimpor-tantly,thisapproachallowedtuningofthedegradation

propertiesofthefilm.Onecrosslinkercontainedadisul-fidemoiety,afunctionalitywhichisofinterestbecauseitisstableinoxidizingconditionssuchasthoseinthebloodstreambutsusceptibletodegradationinreducingenvironmentssuchasthosefoundinthecellularcyto-plasm.Thisfilmwascomparedwithanon-degradablevarianttoinvestigatetriggereddegradation.Ineachcase,whenthesacrificialcorewasremovedandthepHincreased,thehydrogen-bondinginteractionbetweenPMAandPVPONwasdisruptedandthePMAwasremoved,leavingsingle-componentPVPONcapsules.Itwasdemon-stratedthatthesecapsuleswerelow-foulingtoarangeofproteinsandcouldbedegradedinsimulatedcellularcon-ditionswhencontainingadisulfidebond.Inlaterwork,wesynthesizedpoly(ethyleneglycol)methacrylate-basedmultilayersusingasimilarapproachandthesecapsulesdemonstratedenhancedlow-foulingpotentialtohumanserum[74].

Fig.4.Hydrophobicencapsulationinmicellesofanalkynylatedsurfactantinthepresenceofanazide-functionalizedcrosslinkerusingclickchemistry.Thecrosslinkerwasdesignedtocontaincleavablebonds.[69]Copyright2010,AmericanChemicalSociety,reproducedwithpermission.

Fig.5.(a)LbLassemblyofdrug-loadedPGAAlkcapsulesfollowedbystabilizationofthecapsulesbycrosslinkingthemultilayerfilmsviaclickchemistryusingabisazidecrosslinker.Theincorporateddrug(DOX)canbetailoredatspecificpositionswithinthemultilayer.(b)Representativeconfocalmicroscope(CLSM)imagesofLIM1899cellstreatedwithDOX-loadedPGAAlkcapsulesafter24hincubation,showingcolocalizationofDOXandcellnuclei.[75]Copyright2010,AmericanChemicalSociety,reproducedwithpermission.

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Inrelatedwork,thesameapproachwasusedtosyn-thesizePGAcapsulesbyassemblingalkyne-modifiedPGA(PGAalk)withPVPONandthencrosslinkingwithanon-degradablelinker[75].APGAconjugateofawell-knownanti-cancerdrug,doxorubicin(DOX),wasthensynthesized(Fig.5).Itwasshownthatthisconjugatecouldbeincorpo-ratedintoPGAcapsulesinacontrolledlocationanddose.Theconjugateswerefoundtobeactivewithinthecap-sulesbutnotintheconjugateform,indicatingthatthecellinternalizationmechanismwasimportantforconjugatedegradationanddrugrelease.Inlaterwork,thePGAandPVPONcapsuleswerecombinedtoformvariousstratifiedcapsules[76].Itwasdemonstratedthatthedegradationofthesematerialscouldbetunedbythecompositionandarchitectureofthecapsules.Finally,PGAcapsuleswereinvestigatedformultidrugresistancebyloadingwitheitherDOXorpaclitaxelandcomparingthecytoxicityindrugresistantandstandardcells[77].Itwasdemonstratedthatdrugsloadedinthisformcouldpartiallyovercomemul-tidrugresistance.Thiswasattributedtotheinternalizationmechanismbypassingp-glycoproteinonthesurfaceofthecells.PGAcapsuleshavesignificantpotentialfordeliveryapplications,astheyhavetunabledegradationproperties,canbeloadedwitharangeofdrugs,andcanbefunction-alizedusingexcessalkynegroups.

Recently,anewcharge-shiftingcapsulesystemwassynthesizedbasedonpoly(2-diisopropylaminoethylmethacrylate)(PDPA)[78].ThispolymerisofinterestforbiomedicalapplicationsbecauseitissensitivetovariationsinconditionsthatsimulatecellularpH.ThecapsuleswereassembledusingasimilartechniquetoPVPONcapsules(asdescribedearlier)andcrosslinkedwithclick-linkerscontainingdisulfidefunctionality.TheassembledcapsulesdemonstratedvariationsinsizewithpH:atphysiologi-calpH(7.4)theywerecompactbutswelledsignificantlywithadecreaseinpH(6).ItwasdemonstratedthatpH-andredox-potentialcouldbecombinedtoachievetailoredsynergisticreleaseofamodelpeptidecargofromthesecarriers.Thiol–enechemistrycanalsobeusedtostabi-lizeLbLcapsules.PMAcapsuleswereformedbyalternatelydepositingPMA(modifiedwithalkeneandthiolmoieties)andPVPONandthencrosslinkingusingUVlight[79].

Anotherassemblytechniquealsoutilizingthiol–enecouplingwasreportedbyKimetal.[80].Inthatstudy(allyl-oxy)12curcurbit[6]urilwasusedasasynthetichostmoleculewith12allyloxygroupstoreactwithadithiolbythiol–enephotopolymerization.Thistechniqueallowedtheone-potsynthesisofnanocapsuleswithouttheuseofatemplate.

Theuseofpolymerstoformpolymericparticlesiswellstudiedintheliterature.Recently,Davisandco-workersreportedtheuseofpoly(pyridyldisulfideethylmethacry-late)(PPDSM)forthesynthesisofpolymericnanoparticles[81].PEGchainsweregraftedontothePPDSMusingthedisulfidegroupsbyfirstreducingthedisulfidestothiolgroupsandthenreactingwithanacrylatefunctionalPEGbythiol–enechemistry.Itwasdemonstratedthattheseconjugatesformedparticlesof∼100nmwithapolydisper-sityof0.22.Suchcarriersareattractive,astheirsynthesisisstraightforwardandtheycouldbeloadedwithmodelcargoand/ortargetingagentsusingexcessfunctionality

onthepolymerbackbone.AtemplatedassemblyapproachwasreportedbyYapetal.usingpoly(ethyleneglycol)acry-latecopolymers[82].Thesepolymersweremodifiedwithalkynemoietiesandtheninfiltratedintomesoporoussil-icatemplates.Thepolymerswerethencrosslinkedwithabiazidelinkercontainingadisulfide.Thetemplatewasfinallyremoved,leavingapolymerparticle.ItwasalsodemonstratedthattheseparticlescouldbeloadedwithDOXandbothdrugreleaseandparticledegradationcouldbecontrolledbychangingtheredoxpotential.

Poly(ester)nanoparticlesarewidelyreportedintheliteratureandareofinterestastheycandegradeinvivo.Recently,vanderEndeetal.comparedthiol–eneandCuAACreactionsfortheconstructionofpoly(ester)nanoparticles[83].Inthatwork,bothanalkyneandallylpendantpolyesterwassynthesized,andcrosslinkedwithadiazideanddithiol,respectively.Itwasdemonstratedthatparticlesizecouldbetunedbyeitherthecrosslinkingamountorpercentageofpolymermodificationwiththethiol–enereaction,resultinginlargerparticlesingeneral.Recentlytherehasbeenanincreaseintheapplicationoflargerbiologicalmaterials,suchasproteinsorviruses,astherapeuticcarriers.Thistypeofsystemwasdemon-stratedbyFinnandco-workersusingavirus-likeparticleformedfrom180copiesofthecoatproteinbacteriophageQ␤expressedrecombinantlyinEscherichiacoli[84].Theparticlesweremodifiedwithazidegroupsandthenwitharangeofpoly(2-oxazoline)polymers.Itwasreportedthatbyvaryingtheamountoffunctionality,itwaspossibletoeitherpolymer-decoratethevirusorcompletelyencaseitwithinapolymershell;inbothcasesincreasedenzy-maticstabilityofthesystemwasobserved.Inarelatedsystem,Steinmetzetal.conjugatedfunctionalizedC60toacapsidofbacteriophageQ␤,whichisaviralnanoparti-cleapproximately30nminsize[85].Itwasdemonstratedthatconjugateswith45–50C60toeachQ␤particlecouldbesynthesized.

Numerousinorganicmaterialshavealsoshownpromiseforbiomedicalapplications.Recently,CuAACwasusedtoassembleinorganicnanoparticlesintolargeagglomeratedsuperstructures.Suchmaterialscouldhaveapplicationsinmedicalimaging.Core–shellCdSe/ZnSandFe3O4nanopar-ticlesweremodifiedusingpolymerscontainingeitheralkyneorazidegroups[86].Ineachcase,whenalkyneandazidevariantswerecombinedinthepresenceofCu(I),theparticlesaggregatedtoformlargerparticles.Thequantumdots(QDs)formedananoparticleapproximately56nmindiameterwhiletheFe3O4magneticnanoparti-cleswere46nm.Inorganicnanoparticlescanalsobeusedtosynthesizecolloidosomes,whicharehollowcapsuleswherethewalliscomprisedofdenselypackednanopar-ticles.Samantaetal.recentlyusedCuAACtosynthesizecolloidosomesbasedonFe3O4nanoparticles[87].Inthisapproach,alkyne-andazide-modifiednanoparticleswereco-assembledonthesurfaceofanoil-in-wateremulsionandcrosslinkedbyCuAAC.

Janusparticlesareinterestingmaterialswithtwohemi-spherescontainingdifferentproperties.Suchsystemsareofgeneralinterestforapplicationssuchascatalysisandswitchabledevices.Inoneapproach,Zhaoandco-workerssynthesizedJanusparticlesbasedonazide-functionalized

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silicaparticles[88].Inthatwork,onesurfaceofthesilicaparticlewasburiedinaPSparticleandtheexposedsur-facewasmodifiedwithalkynatedbiotinusingCuAAC.ThePSwasthendissolvedandtheexposedsurfacewasmodi-fiedwithalkynatedPEG.ArelatedtechniquewasreportedbyBhaskaretal.fortheformationofbiphasicparticlesandfibers[89].Thisapproachwasbasedonelectrohydro-dynamicco-jettingoftwodifferentpoly(lactic-co-glycolicacid)polymers,includingpoly[lactide-co-propargylglycol-ide]forsubsequentmodificationwithazidemoietiesusingCuAAC.Theseparationofeachhemispherewasobservedbyconfocalmicroscopy.Recently,ourgroupdemonstratedanotherapproachtoJanusparticlesynthesis[90],basedonmodifyingamine-modifiedsilicaparticleswithabrominefunctionalizedplasmapolymer.Thesilicaparticleswerearrangedonasodiumchloridecrystalsothatonlyonehemispherecouldbemodified.SuccessfulmodificationwasdemonstratedbylabelingthedifferenthemisphereswithCuAACandN-hydroxysuccinimide(NHS),respec-tively,andalsobyremovingthetemplate.

3.3.Clickhydrogelscaffolds

Clickchemistryhasalsobeenappliedtothedesignofhydrogelscaffoldsforapplicationssuchastissueengineer-ingandcellculture.Inoneoftheearlystudies,PEG-basedhydrogelsweresynthesizedbycombiningdiacetyleneandtetraazidePEGderivatives.Thesesystemswerecomparedtotraditionalhydrogelsanditwasfoundthatproper-tiessuchasswellingdegreeand“stresstobreak”wereimprovedintheCuAACcaseandcouldbesystematicallyvariedwithmolecularweightofthePEG[91].OneoftheearliestusesoftheSPAACtechniqueformaterialdesignwasdemonstratedonnetworkformation.Inthatstudytetra-nitrobenzyloxylcarbonyltetra-azidoterminalPtBAstarpolymerswerecrosslinkedusingeitheradifunctionalmonofluorinatedordifluorinatedcyclooctyne[92].Inlaterwork,Ansethandco-workersusedSPAACchemistrytosynthesizeahydrogelnetwork[93].Thiswasdesignedbasedonafour-armpoly(ethyleneglycol)tetra-azidewhichwasreactedina1:1ratiowithbis(difluorinatedcyclooctyne)difunctionalizedpolypeptide.Thepeptidealsocontainedavinylgroupforsubsequentthiol–enemod-ificationandametalloproteinasecleavablesequencetoallowdegradation.Thehydrogelwasfoundtosustaincellswithhighviability(>90%after24h).Thematerialwasthenthiol-functionalizedwitharangeofpeptidesusingalight-inducedthiol–enereaction.Itwasshownthatselectivelyexposingthehydrogelsurfaceallowedspatialandtem-poralcontroloverthecoupling(Fig.6).Subsequentworkshowedthatthistechniquecouldbeusedtocreategradientfilmswithoneormorepeptides[94].

4.Applicationofclickchemistryforfunctionalizationofmaterials

4.1.Functionalizationoffilms

Controloversurfacefunctionalityandinteractionwiththelocalenvironmentarekeytotheperfor-manceofmaterialsusedinbiomedicalapplications[21].

1-Ethyl-3-(3-dimethylaminopropyl)

carbodiimide(EDC)/NHSchemistriesandthiol–maleimidecouplinghavebeenwidelyusedinmaterialssciencetomod-ifysurfaces;however,theseapproachesarelimitedbycross-reactivitywithfunctionalgroupscommonlyfoundinbiology(suchasamines,carboxylicacidsandthiols)andtheaqueousstabilityofthereactivecomponents[95].Biotin/avidininteractionsarealsowidelyemployedforbiomoleculefunctionalization,butcanbehamperedbysignificantnon-specificbindingofbiomoleculesandpotentialimmunogeniceffectsforinvivoapplications[95].Therefore,thespecificandquantitativenatureofclickchemistrylendsitselftosurfaceimmobilization.

Proofofprinciplesurfacemodificationusingclickchem-istryhasbeendemonstratedforthiol–ene[96],DA[97]andCuAAC[98]reactionsusingfluorescentorganicdyes.Tomodifymaterialswithclickfunctionalspeciesitisnec-essarytoengineerthematerialstopresentclickgroupsontheirsurface.Thiscanbeachievedbydirectmodificationusingspincoating[99],SAMs[23]orchemicalvapordepo-sition[39]whereclickgroupsaredirectlyattachedtoasurface,aswellasviaindirectmethods,suchassilanecon-densation[100]andplasmapolymerization[40],whereanamino,thiolorhalogengroupisdepositedonthesurfaceandthensubsequentlyreactedtoformclickmoieties.

Surfacesengineeredforbiomedicalapplicationsaretypicallymodifiedfortworeasons:(i)tolowernon-specificinteractionswithabiologicalenvironment,and/or(ii)toengineerspecificinteractions,suchasforsensorsanddrugdeliverydevices.AsPEGisawidelyusedpolymertolowernon-specificinteractionswiththelocalenvironment,awiderangeofmaterialshavebeenmodifiedwithPEG.Inoneapproach,Ostacietal.demonstratedtheuseofchem-icalvapordepositiontomodifyasiliconsubstratewithalkynes,andanazide-modifiedlinearPEG(20000g/mol)wasthengraftedontothesurface[101].Similarly,cot-tonhasalsobeenclick-modifiedwithPEG[102].Leeetal.combinedcontrolledradicalpolymerizationwithCuAAC[103].SAMswithaterminalATRPinitiatorwasfirstsyn-thesized,andthenapoly(oligo(ethyleneglycol)methylethermethacrylate)wasgrownfromthissurface,asthispolymerisalsowellknowntohavelow-foulingcapabili-ties.ThebromineendgroupoftheATRPinitiatorwasthenmodifiedtoanazidemoiety,allowingeasyCuAACfunc-tionalization.Morerecently,usingaclickLbLapproach,Kinnaneetal.showedthatglassslidescouldbemodifiedwithpoly(ethyleneglycol)acrylatetocreatealow-foulingsurfacethatwasresistanttocelladhesion[34].

Modificationofsurfaceswithbiomoleculesforspecificinteractionsrequirescarefulmaterialsdesignduetothedelicatenatureofthemolecules.Thus,differentclickcou-plingchemistriesarebettersuitedtocertainapplications.Forexample,useofUVlightinthiol–enecrosslinkingcandamageDNA,renderingitinactive,andcysteineresiduesinproteinsarecross-reactivewiththiol–eneclickchem-istryandcanalsoundergoMichaeladditiontomaleimidesusedinsomeDAreactions.NosidereactionsoccurwithCuAACcoupling;however,thepresenceofCu(I)canbealimitationduetotoxicityofCu(I)tolivingcells[12].IthasalsobeenobservedthatfreeCu(I)causessignifi-cantaggregationofproteins[104]duetothechelating

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Fig.6.(a)Formationofahydrogelnetworkbetweenbis(difluorinatedcyclooctyne)-difunctionalizedpolypeptidesandazidecrosslinkersusingtheSPAACtechniqueforpromotingcellgrowth.(b)Thishydrogelnetworkcanbefurtherfunctionalizedutilizinglight-inducedthiol–eneclickreactions.[93]Copyright2009,NaturePublishingGroup,reproducedwithpermission.

effectofglutamicacidandlysineresidues,anditcanalsocausedegradationofsomebiomaterialssuchaspolysac-charides[105].Recentreportshaveshownthatsomeoftheselimitationscanbeovercomebytheadditionofachelatingagent,openingupclickchemistryforpotentialuseininvitroandinvivoapplications[104,106].Similarly,strainedalkynes,particularlycyclooctynesdevelopedby

Bertozziandco-workers,canalsoovercomeCu(I)toxic-itybyactivatingthealkyneandremovingtheneedforacatalyst[13].Whiletheclickreactionitselfremainshighlyspecific,thehydrophobicnatureofthecyclooctynecanleadtonon-specificlocalizationofthealkynewithhydrophobicdomainsinproteins,andmayalsoleadtosol-ubilityissues.However,withtheadventofstrainedalkynes

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withhigherwatersolubilitytheselimitationsshouldbeovercome.

Fortissueengineeringandimplantapplications,itiscriticaltopromotetheadhesionofthedesiredcellsontoasurface.Todemonstratecontrolledcelladhesion,sur-facescanbemodifiedwithadhesionpromotingpeptides,suchasRGDwhichbindstointegrinreceptorsthatarepresentonanumberofcells.InonesuchstudyabrushPEGacrylatefilmassembledviatheLbLtechniqueandfunc-tionalizedwithalkynegroupswasusedasamodelsurfaceandshowedminimalcelladhesionover72h[34].However,whenthissurfacewasfunctionalizedwithanazide-functionalizedRGDpeptide,celladhesionandgrowthwaspromoted.UsingamutatedRADpeptideasacompari-son,similaradhesiontotheunmodifiedPEGsurfaceswasobserved.Similarly,Beckerandco-workersusedaSAM-coatedcoverslipwithagradientdensityofalkynegroups,andsubsequentlyclickedanazide-modifiedRGDontothesurface[107].Asexpected,greatercelladhesionoccurredwheretherewasahighdensityofRGD.Chelmowskietal.demonstratedthatpeptidebasedSAMscouldalsobesyn-thesized.Thesedemonstratedsimilarlow-foulingtoPEGsurfaces[108].Itwouldbeexpectedthatthesesurfacescouldbereadilytunedtopromotecelladhesioninspecificregions.

Modificationofsurfacesformicroarraysandsen-sorshasalsobeenachievedbyclickchemistry.Chenetal.immobilizedazide-modifiedDNAontospin-coated␣-alkyne-␻-Br-poly(tBA-b-MMA)surfaces[109].Azide-functionalizedDNAwasattachedtothatsurfacewithadensityof1.1×1013/cm2;however,ifthePtBAwasdepro-tectedtoformahydrophilicPAAsurface,a20%increaseinsurfacedensitywasobserved.ThebasepairingofDNAoligomerscanalsobeusedtocreateself-assembledstruc-turesthatcanbeexploitedtopatternsurfaces.ArelatedstudybySunandco-workersusedalkynemodifiedDNAthathybridizesinsolutiontoformorderedstructuresthatcanbeclickedontoanazide-modifiedsiliconsubstrateinaone-stepprocess[110].

Formoreadvancedmicroarraysandsensingappli-cations,morecontrolledsurfacepatterningisrequired.Surfacepatterningtechniquesusingmicrocontactprinting[111],photolithography[112]andelectron-beamlithogra-phy[113]haverecentlybeendemonstrated.Microcontactprintinghasbeenextensivelyemployedtopatternsur-facesusingtheCuAACreaction.Ithasbeenadaptedtoprintsmallfluorescentmolecules[114],DNA[115],sug-ars[116],andcyclodextrins(Fig.7a)[117].Interestingly,ithasbeendemonstratedinsomesystemsthatprintinganazide-modifiedprobeontoalkyne-modifiedsurfacesdoesnotrequiretheadditionofaCucatalysttopromotethereaction.Thisishypothesizedtobeduetothehighlocal-izedconcentrationofthereactantsdrivingthereactiontocompletion.

Microcontactprintinghasalsobeenemployedtopat-ternelectroactivesubstrateswithswitchablecelladhesionproperties.Mrksichandco-workerspatternedahydro-quinone/hexadecaneSAMontitaniumandgold-coatedglasscoverslips[25,26].Thehexadecaneregionswerefunctionalizedwithfibronectintopromotecelladhesion.Thehydroquinonecomponentcanbeoxidizedbythe

applicationofa500mVpotentialtothesubstratetoformquinone,whichactsasadienophileinDAreac-tionswithmaleimides.Itwasshownthatwhenincubatingcellswiththehydroquinone/fibronectinsurface,thecellsonlyadheredtothefibronectinregions;however,afterapplicationofthevoltageandadditionofamaleimide-modifiedRGDpeptide,thecellswereabletomigrateovertheentiresurface(Fig.7b)[26].Thistechniquecanbeusedtostudytheinhibitionorpromotionofcellmigration.

Photolithographycanbeemployedtopatternclickfunctionalsurfacesusingphotoactivatedsurfaces.Locklinandco-workershavedemonstratedthatcyclopropenoneundergoesrapiddecarbonylationwhenexposedto350nmUVlighttoformacyclooctynewhich,inturn,rapidlyundergoesSPAACreactionwithazides[118].Usingacyclo-propenonefunctionalizedsurface,ashadowmaskwasusedtosequentiallyactivateareasonthefilmtoformapatternedsurface.

4.2.Functionalizationofparticlesandcapsules

Thetranslationofclicksurfacefunctionalizationfromplanarsurfacestoparticleshasbeendemonstratedonanumberofsystemsviareactingorganicdyesontothesur-faceoftheparticles.Thisopensupanarrayofapplications,potentiallyleadingtoimprovedcontrolofdrugrelease,targeteddeliveryofdrugstospecificcellsandbiologicalsensors.

Thegatedreleaseofdrugsfromtherapeuticreservoirsiscriticalforthedeliveryofanumberofdrugs.Oneappli-cationofclickchemistryhasbeentosynthesizegatednanoporestocontrolthereleaseofsmallmoleculesfrommesoporousmaterials(Fig.8)[119].Mesoporoussilicawithaporesizeof∼2nmwasfunctionalizedwithalkynegroupswitha1–3carbonaliphaticchainspacingthealkynefromthesurface.RhodamineBwasloadedintothepores,andfollowingloading,thesurfacewascappedwith2-azidoethylamineinthepresenceofcucurbit[6]uril(CB[6]).CB[6]catalyzesthecycloadditionreactionbetweentheazideandalkyneandalsoformsapseudorotaxaneviaaninteractionwiththebisammoniastalksformedbytheclickreaction.TheRhodamineBremainedencapsulatedwithinthemesoporousmaterialswhenashortchainlinkerwasused;however,whenalongerchainwasused,notice-ableleakagewasobserved.WhenthepHwasraisedabove10,thedipoleinteractionswitchedoffcausingtherotax-anetodisassembleandreleasetherhodamine.WhilethepHresponsedemonstratedhereisnotinthephysiologicalrange,itcanbeenvisagedthatpH-inducedreleaseofdrugsinaphysiologicalrangecouldbeachievedbyengineeringthepKaofthebisammoniumgroup.Inarelatedstudy,arotaxanewithacleavablestopperwasusedasthemolecu-larvalveonmesoporoussilica.Thisstudydemonstratestheuseofenzyme-cleavablestopperremoval;however,themechanismcanbereadilytuned.Goodcontrolovercargoreleaseinthissystemwasdemonstrated[120].Biologicalsystemshavealsobeendesignedbasedondouble-strandedDNA[121].

Smallmetallicnanoparticles,suchasQDsandgoldnanoparticles,havebeenfunctionalizedwithtargeting

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Fig.7.(a)Fluorescencemicroscopyimagesofone-stepfunctionalizationoforthogonalpatternedcoumarin-cyclodextrinsurfacesbyclickchemistry,followedbymicrocontactprintingoffluorescentlylabeledmoleculesonthesurfaces[116].(b)Diels–Aldermediatedfunctionalizationofpeptide(right)onplanarsurface(leftandcenter)thatcanbeelectricallyswitchedtoturnoncellmigration.Immobilizationofthepeptideonthesurfaceledtothemigrationofcells(rightopticalimage)fromthecircularregions(leftopticalimage).(a)[117]Copyright2010,AmericanChemicalSociety,reproducedwithpermission;(b)[26]Copyright2001,Wiley-VCHVerlagGmbH&Co.KGaA,reproducedwithpermission.

moleculesandactiveenzymes,suchaslipase,foruseasbiologicalmarkersorsensors[122].Texierandco-workersusedSPAACtocouplemannosamineto10nmgreenfluorescentQDstoavoidtheuseofCu(I),whichhasbeenshowntoquenchthefluorescenceoftheQDs[123].ThefunctionalizedQDsremainedfluorescentaftertheclickcouplingstepandboundeffectivelytoChineseHamsterOvarycells.Thisapproachisaversatiletech-niqueforfluorescentlabelingthatcouldbeextendedtoavarietyofbiomoleculestoexploitthefluores-cencepropertiesofQDs(narrowemissionwavelengthandgoodphotostability).Thishasparticularimplica-tionsforuseininvitroandinvivoimaging.SPAACcouplinghasalsobeenappliedtoantibodyfunctionaliza-tionofchitosanpolymerparticles[105]andpoly(amide)dendrimer[124].

Fordrugdelivery,clickchemistryhasbeenusedtofunctionalizenanoparticleswithtargetingmoleculessuchasfolate[125],RGDpeptides[125–128],tumortarget-ingpeptides[129],andwholeantibodies[104].SmallmoleculessuchasfolateandRGDpeptidesarereadilycou-pledtonanoparticlesbymodifyingthefolateorpeptidewitheitheranazideoralkynegroup.Forexample,Leeetal.showedthatpolymer-coatedliposomeswithalkynegroupscanbemodifiedwithazidefunctionalfolate[125].Thesecapsulesshowedsignificantbindinganduptakeincellsthatexpressedthefolatereceptor.Similarly,usinganalkyne-modifiedRGDpeptide,Luetal.showedthatRGD-functionalizedpolymerparticlesboundtorabbitcornealepithelialcells[126].Inarelatedstudy,Shokeenetal.modifiedPEG-basedmicelleswithvariousamountsofRGDfunctionality(0–50%)andinvestigatedtheeffectthis

G.K.Suchetal./ProgressinPolymerScience37 (2012) 985–1003

999

Fig.8.Graphicalillustrationsofgatednanopores.RhodamineB(RhB)isloadedintheporesofmesoporoussilicaparticlesandcappedbycucurbit[6]uril-catalyzedclickreaction(aandb).UponraisingthepHvalue,rhodamineisreleasedbyswitchingoffthedipoleinteractionsbetweenCB[6]andthebisammoniumstalks(bandc).[119]Copyright2008,Wiley-VCHVerlagGmbH&Co.KGaA,reproducedwithpermission.

functionalityhadoncellularinteractionsandbiodis-tribution[127].Interestingly,significantchangesinbiodistributionoftheirparticleswereseenwhentheyhad10%RGDormore,implyingthereisabalancerequiredbetweentargetingmoietiesandbiodistribution.

Inanovelapproach,Passarellaetal.functionalizednanospongeswitharadiation-inducedtargetingpeptide(GIRLRG)usingthiol–enechemistry[129].WhentumorcellsareexposedtoradiationtheGRP78receptor(whichisrecognizedbytheGIRLRGpeptidesequence)isexpressedonthesurfaceofthecell,makingitanidealcandi-datefornanoparticletargeting.Invivoanimalstudies

demonstratedthattargetednanospongesloadedwithpaclitaxelsignificantlyinhibitedtumorgrowthcomparedtoradiationtreatmentalone[129].

Superparamagneticironoxide(SPIO)particleshavealsobeenfunctionalizedwiththealkynemodifiedcyclicpep-tidesequenceLyP-1whichbindstop32,amitochondrialproteinwhichisoverexpressedonsomecancercells,aswellasmacrophagesandlymphaticendothelialcells[130].TheseLyP-1functionalizedSPIOsboundspecificallytop32expressingcellsbothinvitroandinmousetumormodels.

Folate,p32andintegrinreceptorsarefoundonmanycells,hencefortargetingtospecificcells,antibodies(Abs)

Fig.9.(a)SchemeshowingantibodyfunctionalizationwiththeNHS-PEG2000-Azlinkerandsubsequentcapsulefunctionalizationviaclickchemistry.(b)FluorescencemicroscopyimagedemonstratinghuA33Ab-functionalizedcapsulesselectivelybindtocomplementaryantigenpresentingcells(blue).[104]Copyright2010,AmericanChemicalSociety,reproducedwithpermission.(Forinterpretationofthereferencestocolorinthisfigurelegend,thereaderisreferredtothewebversionofthearticle.)

1000G.K.Suchetal./ProgressinPolymerScience37 (2012) 985–1003

canofferenhancedspecificity.ForwholeAbfunctionaliza-tion,thepresenceofCu(I)hasbeenfoundtoaggregatetheAbs;however,thepresenceofachelatorfortheCu(I)mini-mizesthisaggregation[104].WehaverecentlyshownthatPVPONcapsulesfunctionalizedwiththehuA33Abspecif-icallybindtocellsthatexpressthehuA33antigen(Fig.9).Invitroexperimentsshowedthatover95%ofhuA33+cellshadcapsulesbound,whereaslessthan5%ofhuA33−cellswereassociatedwiththeAb-functionalizedcapsules.Thesecapsulesshowedspecificbindingtocellsevenwhenthetargetcellwaspresentaslessthan0.1%ofthetotalcellpopulation[104].Inthiscase,theAbwasfunctionalizedwithanazidebyreactingbifunctionalNHS-PEG-AztothelysineresiduespresentontheAb.Thisresultsintheran-domfunctionalizationoftheAb,withanaverageof1azideperAb.Tocontrolthepositionofthefunctionalization,Eliasetal.haveengineeredtheexpressionoftheanti-HER2affi-bodytocontainaC-terminalthioester[131].ThethioesterisreactivetoN-terminalcysteinecontainingpeptidessobyaddinganalkynemodifiedN-terminalcysteinepeptide,theclickfunctionalitycouldbespecificallyattachedtotheC-terminusoftheaffibody.Thisalkyne-modifiedAbwascoupledtoliposomes,dendrimersandSPIOsandshowedspecificbindingtoHER2expressingcells.

5.Conclusion

Inthelast10yearsclickchemistryhasbecomeanimportanttoolformaterialsscience.Thereisnowawell-studiedsetofreactionswhichsatisfymostclickcriteriaandthusthechoiceoftheappropriatereactionforaspecificsetofconditionsisstraightforward.Thismeansanylimitationswithorthogonalityandtoxicity,whilesignificant,canbeefficientlymanaged.Therangeoffunctionalityrequiredisalsodiverseandmeansthatbuildingblockscanbereadilyfunctionalizedwithclickmoieties.Thus,thereissignificantpotentialforcreativecombinationsofexistingmaterialstopushtheboundariesofcurrentcapabilities.Theabilitytofunctionalizeisalsofundamentaltotailoringthesurfacepropertiesofthesematerialswiththeirenvironment.Clickchemistryoffersapowerfultoolboxformaterialscientiststodesignthenextgenerationofmaterialswithtargetedresponsetotheenvironment.Theabilitytosynthesizesuchmaterialsisimportanttomakeimpactinmanyareas.Thisisparticularlytrueinthefieldofbiomedicinewhereknowledgeontheinteractionsbetweensyntheticdeliverysystemsbothinvitroandinvivoisrapidlyexpanding.Thenextfewyearsshouldprovideexcitingopportunitiesinthefieldofclickchemistry,asnewnanoengineeredfilmsandparticulatedeliverysystemsemerge.

Acknowledgments

ThisworkwassupportedbytheAustralianResearchCouncilundertheFederationFellowship(F.C.)andDiscov-eryProjectschemes(F.C.,A.P.R.J.andG.K.S.).

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