环糊精-聚合水凝胶主客体复合物.pdf

Tailoring Polymeric Hydrogels throughCyclodextrin HostGuest ComplexationaXuhong Guo,*Jie Wang,Li Li,Duc-Truc Pham,Philip Clements,StephenF.Lincoln,*Bruce L.May,Qingchuan Chen,Li Zheng,Robert K.PrudhommeIntroductionThe basic tenet that interactions at the molecular levelcontrol characteristics at the macroscopic level is increas-inglybeingexploitedinthedesignofnewmaterials.Thisismuchinevidenceinthedesignofbiocompatiblepolymerichydrogels by macromolecular assembly,which havepotential applications in biodegradable drug-deliverysystems and chemical sensors.1Recently,Wenz,Ritterand Harada employed hostguest complexation betweencyclodextrins and a range of guests to create macromole-cular networks.2The optimal size match between b-cyclodextrin(b-CD)and adamantyl(AD)substituents3onsubstituted polymers results in hostguest complexationthat forms effective polymer cross-links,2aas do similarinteractions between b-CD and n-polyalkyl substituents inpolymer systems.4In this study,we have used this knowledge to tailorsubstituted poly(acrylate)s(PAAs)to control hydrogelformation with the aim of preparing biomaterials fortissue engineering and controlled drug delivery.A series ofb-CD and AD 3%randomly substituted PAAs(Scheme 1)inwhich short amide tethers,a)PAAbCD and d)PAAAD;intermediate length diacylamino-1,6-hexyl(hn)tethers,b)PAAbCDhnande)PAAADhn;and,longerdiacylamino-1,12-dodecyl(ddn)tethers,c)PAAbCDddn andf)PAAADddn,areused in a study of nine possible substituted PAA networks,exemplified by g).It is shown that competition betweencomplexation by b-CD substituents of either AD substi-tuent and the variable length polyalkane tethers attachingCommunicationX.Guo,J.Wang,L.Li,Q.Chen,L.ZhengState Key Laboratory of Chemical Engineering,East ChinaUniversity of Science and Technology,Shanghai 200237,PR ChinaFax:86 21 6425 3491.;E-mail:D.-T.Pham,P.Clements,S.F.Lincoln,B.L.MaySchool of Chemistry and Physics,University of Adelaide,Adelaide,SA 5005,AustraliaE-mail:stephen.lincolnadelaide.edu.auR.K.PrudhommeDepartment of Chemical Engineering,Princeton University,Princeton,NJ 08544,USAa:Supporting information for this article is available at the bottomof the articles abstract page,which can be accessed from thejournals homepage at http:/www.mrc-journal.de,or from theauthor.A close correllation between molecular-level interactions and macroscopic characteristics ofpolymer networks exists.The characteristics of the polymeric hydrogels assembled fromb-cyclodextrin(b-CD)and adamantyl(AD)substituted poly(acrylate)s can be tailored throughselective hostguest complexation between b-CD andAD substituents and their tethers.Dominantly,stericeffects and competitive intra-and intermolecularhostguestcomplexationarefoundtocontrolpoly(acrylate)isomeric inter-strand linkage in polymernetwork formation.This understanding of the factorsinvolved in polymeric hydrogel formation points theway towards the construction of increasingly sophis-ticated biocompatible materials.300Macromol.Rapid Commun.2010,31,300304?2010 WILEY-VCH Verlag GmbH&Co.KGaA,WeinheimDOI:10.1002/marc.200900560either substituent to the PAA backbones together withsteric interactions with the PAA backbones control theconstruction of the hydrogels.The1Dand2D1HNOESYNMRspectraofthesubstitutedPAAs,af),in D2O are unexceptional except for those ofb)PAAbCDhn and c)PAAbCDddn.These show weak andstrong cross-peaks,respectively,arising from interactionsbetween the b-CD substituent H3,5,6annular protons andthose of the hn and ddn tethers consistent with theirintramolecular host-guest complexation by the b-CDsubstituents.The 2D1H NOESY NMR spectrum of equimolar PAAbCD/PAAADddn in D2O(Figure 1)shows strong cross-peaksarising from both the AD substituent H24protons andthose of the ddn tether with the b-CD substituent H3,5,6annularprotons.Thisindicatescompetitiveintermolecularcomplexation between the AD substituent and its ddntether in the bCD annulus of PAAbCD(Scheme 2)andresults in isomeric cross-links in the hydrogel g)inScheme 1.The relative intensities of the cross-peaks in the2D1H NOESY NMR spectra of twenty D2O solutions ofeither native bCD or bCD substituents attached to PAAequimolar with either adamantane-1-carboxylate,ADCO?2,or AD substituents attached to PAA appear in Table 1(allspectra are shown in the Supporting Information.)NativebCDcomplexestheADsubstituentsofADCO?2andPAAADandalsothetethersofPAAADhnandPAAADddn,asshownby the corresponding cross-peaks.Complexation of ADCO?2by PAAbCD produces a strong cross-peak for AD andadditional cross-peaks for the tethers of PAAbCDhn andPAAbCDddn,arising from weak and strong intramolecularcomplexation in the latter two systems,respectively.Theabsence of cross-peaks arising from the PAAbCD/PAAADsystem indicates that the tethers are too short to allowcomplexation between the substituents because of sterichindrance between the PAA backbones.However,com-plexation by PAAbCDof theAD substituents andtethers ofPAAADhn and PAAADddn occurs as shown by cross-peaksconsistent with the intermolecular tether complexationTailoring Polymeric Hydrogels through Cyclodextrin Host.Scheme 1.af)The substituted PAAs.g)Hydrogel formationbetween a)PAAbCD and f)PAAADddn showing the AD substi-tuent and ddn tether of PAAADddn isomerically complexedby bCD substituents of PAAbCD.Figure 1.2D1H NOESY NMR 600MHz spectra of a D2O solution0.5wt.?%in PAAbCD and PAAADddn with equimolar bCD andAD substituentsat pD7.The rectangles A andB enclosethe cross-peaksarisingfrominteractionof the ADsubstituentH24andddnprotons with the bCD annular H3,5,6protons.Macromol.Rapid Commun.2010,31,300304?2010 WILEY-VCH Verlag GmbH&Co.KGaA,Weinheimwww.mrc-journal.de301showninScheme1and2.(ThePAAbCD/PAAADddnsystemforms oneof thestrongest hydrogel networks,as discussedbelow).The importance of the tether length is further shown bythe PAAbCDddn/PAAAD system,where only strong cross-peaks for intramolecular complexation of the respectivetethers are observed,consistent with steric hindrancebetween the PAAAD backbone and the bCD substituentspreventingADsubstituentcomplexation.Thesefactorsarefinely balanced,as indicated by the absence of any cross-peaks for the PAAbCDhn/PAAAD system.Lengthening theAD tether in the PAAbCDhn/PAAADhn and PAAbCDddn/PAAADhnsystemsallowsbothADandtethercomplexationand PAA cross-linking.However,lengthening the bCDX.Guo et al.Scheme 2.The dominant species in equimolar solutions of either PAAbCD,PAAbCDhn,or PAAbCDddn and either PAAAD,PAAADhn orPAAADddn.Table 1.RelativeADandtethercross-peak intensitiesin2D1HNOESYNMRspectraarisingfromhost-guest complexation.TheADcrosspeakappears first and the tether cross-peak appears second in brackets.Hosta)Guesta)ADCO?2PAAADPAAADhnPAAADddnbCDStrong(None)Strong(None)Strong(Weak)Strong(Strong)PAAbCDStrong(None)None(None)Strong(Weak)Medium(Strong)PAAbCDhnStrong(Weak)None(None)Strong(Weak)Medium(Strong)PAAbCDddnStrong(Strong)None(Strong)None(Strong)None(Strong)a)The cross peaks are between either native bCD or the bCD PAA substituent hosts and either ADCO?2or the PAA AD substituent guestsin D2O at pD 7.The solutions are equimolar in host and guest.They are 0.5wt.-%in total PAA when present.302Macromol.Rapid Commun.2010,31,300304?2010 WILEY-VCH Verlag GmbH&Co.KGaA,WeinheimDOI:10.1002/marc.200900560tether in the PAAbCDddn/PAAADhn and PAAbCDddn/PAAADddnsystemscausescompetitionbetweeninter-andintramolecular tether complexation,as indicated by thecorresponding tether cross-peaks,the absence of AD cross-peaks,andacorrespondingdecreaseinPAAcross-linkingasshown by the viscosity data discussed below.The zero shear viscosities of mixtures of either nativebCD,PAAbCD,PAAbCDhn,or PAAbCDddn and eitherPAAAD,PAAADhn,or PAAADddn equimolar in eithernative bCD or bCD substituents and AD substituents(Figure 2)show that the macroscopic characteristics ofmixtures of the substituted PAA systems closely reflecttheir molecular characteristics,as deduced from the 2D1H NOESY NMR studies(Table 1).Thus,the zero shearviscosities of the PAAbCD/PAAAD and PAAbCDhn/PAAADsystems are two orders of magnitude lower than those ofthePAAbCD/PAAADhnandPAAbCDhn/PAAADhnsystems(Figure 2).Hence,the AD substituent of PAAAD forms onlyweak intermolecular host-guest complexes with the bCDsubstituents of PAAbCD largely because of the sterichindrance caused by the PAA backbone of the latterpolymer,while the extra flexibility of the hn tether ofPAAbCDhn reduces the effect of steric hindrance.Thegreatest zero sheer viscosities characterize the PAAbCD/PAAADddn and PAAbCDhn/PAAADddn systems(Figure 2).This is due to both PAAbCD and PAAbCDddn formingisomericintermolecularhostguestcomplexeswiththeADsubstituents and the ddn tethers of PAAADddn.The zero shear viscosities of the PAAbCDddn/PAAADhnand PAAbCDddn/PAAADddn systems are about one orderof magnitude lower than those of the PAAbCDhn/PAAADhn and PAAbCDhn/PAAADhn systems(Figure 2),consistent with the preferential intramolecular complexa-tion of the ddn tether of PAAbCDddn in the bCD annulus.This decreases the intermolecular complexation of thePAAADhn and PAAADddn AD substituents and tethers inthe bCD annuli of PAAbCDddn such that there is asubstantialdecreaseinPAAcross-linking.Nevertheless,theviscositiesofthesesystemsarestillmuchgreaterthanthatof PAAbCDddn alone.The viscosity of PAAbCDddn is greater than that ofPAAbCD probably because the hydrophobic ddn tethersaggregate.However,there is little difference between theviscosities of PAAbCDddn and that of the PAAbCDddn/PAAAD system because a combination of the sterichindrance from the PAA backbone of PAAAD in thecomplexation of the AD substituent by the bCD sub-stituent and the intramolecular complexation of the ddntether in PAAbCDddn prevents significant cross-linking.Overall,it has been shown that the characteristics of thehydrogels assembled from bCD and AD substituted PAAsmaybetailoredthroughselectivehostguestcomplexationbetween bCD and AD substituents and their tethers.Thestrength of these interactions is governed by the balancebetween intra-and intermolecular complexation of thesubstituent tethers and steric effects.As the tether lengthshortens steric interactions with the PAA backboneincreasingly inhibit intermolecular complexation.Thisunderstanding of the factors involved in polymerichydrogel formation points the way towards the construc-tionofincreasingly sophisticatedbiocompatiblematerials.Experimental PartThenewamidoadamantyl,1-(6-aminohexyl)amidoadamantyland1-(12-aminododecyl)amidoadamantyl 3%randomly substitutedpoly(acrylic acids)were prepared from poly(acrylic acid)and therespective amines in the presence of dicyclohexylcarbodiimide in1-methylpyrrolidin-2-oneat608Candwereisolatedasthesodiumsalts.4aThe sodium salts of the new 1-(6-aminohexyl)amido-b-cyclodextrin and 1-(12-aminododecyl)amido-b-cyclodextrin sub-stituted poly(acrylic acids)and their previously reported amido-b-cyclodextrin analog were similarly prepared.Yield:7080%.Thedegree of substitution was determined to be 3.0%by1H NMRspectroscopy,as described in the literature.4a2D NOESY NMRspectra were recorded on a Varian Inova 600spectrometer at298.2Kusingastandardpulsesequencewithamixingtimeof0.3s.Rheological measurements were carried out with a Physica MCR501(Anton Parr GmbH)stress-controlled rheometer with 25mmcone and plate geometry.Temperature was controlled to within?0.18C by a Peltier plate.Full experimental details appear in theSupporting Information.Acknowledgements:We gratefully acknowledge the AustralianResearchCouncil,NSFCgrants20774028and20774030,111ProjectGrant B08021,Shanghai Shuguang Plan Project 06SG35,ShanghaiPujiang Talent Project 07PJ14022 and 08PJ14036,and the ChinaScholarship Council for support of this work.Received:August 7,2009;Revised:September 9,2009;Publishedonline:November 24,2009;DOI:10.1002/marc.200900560Tailoring Polymeric Hydrogels through Cyclodextrin Host.Figure 2.Zero sheer viscosities of a)PAAAD,PAAADhn andPAAADddn and their binary mixtures with b)native bCD,c)PAAbCD,d)PAAbCDhn and e)PAAbCDddn in 0.10mol?dm?3aqueous NaCl at pH 7 and 298.2K with total polymer concen-trations of 2wt.-%.Macromol.Rapid Commun.2010,31,300304?2010 WILEY-VCH Verlag GmbH&Co.KGaA,Weinheimwww.mrc-journal.de303Keywords:cyclodextrin;host-guest complexation;hydrogels;polyelectrolytes1 1a S.Kiyonaka,K.Sugiyasu,S.Shinkai,I.Hamachi,J.Am.Chem.Soc.2002,124,10954.1bP.Mukhopadhyay,Y.Iwashita,M.Shirakawa,S.Kawano,N.Fujita,S.Shinkai,Angew.Chem.Int.Ed.2006,45,1592.1c W.G.Wei,J.B.Beck,A.M.Jamieson,S.J.Rowan,J.Am.Chem.Soc.2006,128,11663.2 2a M.Weickenmeier,G.Wenz,Macromol.Rapid 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