DOI: 10.1021/la1048166 1143Langmuir 2011, 27(3), 1143–1151 Published on Web 01/10/2011

pubs.acs.org/Langmuir

© 2011 American Chemical Society

Thermogelling of Double Hydrophilic Multiblock and Triblock Copolymers

of N,N-Dimethylacrylamide and N-Isopropylacrylamide:

Chain Architectural and Hofmeister Effects

Zhishen Ge,† Yueming Zhou,† Zhen Tong,‡ and Shiyong Liu*,†

†CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, HefeiNational Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China,

Hefei, Anhui 230026, China, and ‡Research Institute of Materials Science, South China University ofTechnology, Guangzhou, Guangdong 510640, China

Received May 18, 2010. Revised Manuscript Received December 18, 2010

A series of thermoresponsive double hydrophilic (AB)n multiblock and ABA triblock copolymers of N,N-dimethylacrylamide (DMA) and N-isopropylacrylamide (NIPAM) with varying sequence lengths were synthesizedvia successive reversible addition-fragmentation chain transfer (RAFT) polymerizations by employing polytrithio-carbonate as the chain transfer agent. Previously, we reported that multiblock copolymers in dilute aqueous solutionscan form either unimolecular or multimolecular micelles at elevated temperatures depending on the relative chainlengths of PDMA and PNIPAM sequences (Zhou et al. Langmuir 2007, 23, 13076-13084). In this follow-up work, wefurther explored and compared the chain architectural (multiblock vs triblock) and Hofmeister effects (addition ofvarious sodium salts) on the gelation behavior of multiblock and ABA triblock copolymers at high concentrations andattempted to establish a correlation between the aggregation behavior and gelation properties of multiblock copolymersat low and high polymer concentrations, respectively. It was found that only m-PDMAp-PNIPAMq multiblockcopolymers with PDMA and PNIPAM sequence lengths located within a specific range can form physical gels atelevated temperatures. Rheologymeasurements revealed thatmultiblock copolymers possess considerably lower criticalgelation temperatures (CGT) and higher gel storage modulus, G0

gel, as compared to those of PNIPAM-b-PDMA-b-PNIPAM triblock copolymers possessing comparable sequence lengths. The addition of inorganic sodium salts caneffectively facilitate thermogelling for multiblock and triblock copolymers, resulting in decreasing CGTs and criticalgelation concentrations (CGCs) in the order of Hofmeister series with increasing hydration capabilities. The uniquethermogelling behavior of aqueous multiblock copolymer solutions in the absence and presence of inorganic salts, ascompared to that of ABA triblock copolymers, augurs well for their potential applications in various fields such asbiomaterials and biomedicines.

Introduction

During the past decades, ever-increasing attention has beenpaid to the field of double hydrophilic block copolymers (DHBCs),which exhibit intriguing and versatile stimuli-responsive self-assembling properties in dilute aqueous solutions.1-7 At highconcentrations, aqueous solutions of certain DHBCs can revers-ibly switch between free-flowing liquid and free-standing gelstates under appropriate external stimuli such as pH, temperature,

light, bioactive molecules, or a combination of them.8-18 Amongthem, DHBC-based thermoresponsive hydrogels exhibiting sol-gel or gel-sol transitions are one of the most intriguing types asthey can be applied as injectable biomaterials for the long-termcontrolled release of drugs and bioactive agents.19-29 The uni-form mixing of releasable agents with the polymer matrix can befacilely conducted in the sol state, whereas in situ gelation canoccur at around body temperatures immediately after injection.

Previous examples toward applications in this field typicallyemployed amphiphilic or double hydrophilic ABA triblock

*To whom correspondence should be addressed. E-mail: sliu@ustc.edu.cn.(1) Colfen, H. Macromol. Rapid Commun. 2001, 22, 219–252.(2) Ge, Z. S.; Liu, S. Y. Macromol. Rapid Commun. 2009, 30, 1523–1532.(3) Nakashima, K.; Bahadur, P. Adv. Colloid Interface Sci. 2006, 123, 75–96.(4) McCormick, C. L.; Sumerlin, B. S.; Lokitz, B. S.; Stempka, J. E. SoftMatter

2008, 4, 1760–1773.(5) Riess, G. Prog. Polym. Sci. 2003, 28, 1107–1170.(6) Gohy, J. F. Adv. Polym. Sci. 2005, 190, 65–136.(7) Hu, J. M.; Liu, S. Y. Macromolecules 2010, 43, 8315–8330.(8) Soppimath, K. S.; Aminabhavi, T. M.; Dave, A. M.; Kumbar, S. G.;

Rudzinski, W. E. Drug Dev. Ind. Pharm. 2002, 28, 957–974.(9) Kopecek, J. Biomaterials 2007, 28, 5185–5192.(10) Gil, E. S.; Hudson, S. M. Prog. Polym. Sci. 2004, 29, 1173–1222.(11) Miyata, T.; Uragami, T.; Nakamae, K. Adv. Drug Delivery Rev. 2002, 54,

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A. W.; Lewis, A. L. Biomacromolecules 2005, 6, 994–999.(27) Li, C. M.; Madsen, J.; Armes, S. P.; Lewis, A. L. Angew. Chem., Int. Ed.

2006, 45, 3510–3513.(28) Kirkland, S. E.; Hensarling, R. M.; McConaughy, S. D.; Guo, Y.; Jarrett,

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copolymers as the gellable materials, though AB diblock copoly-mers can also work under certain circumstances.30-33 Originalworks concerning block copolymer-based thermosensitive andbiodegradable hydrogels were reported by Kim et al.,33 in whichconcentrated aqueous solution of amphiphilic triblock and di-block copolymers consisting of poly(ethylene oxide) (PEO) andpoly(L-lactic acid) (PLLA) sequences can exhibit thermo-inducedgel-sol transition. Later on, a variety of amphiphilic blockcopolymer-based physical gels possessing thermoresponsive sol-gel or sol-gel-sol transition properties have also been devel-oped.34-42 Intriguingly, Ding et al.41 investigated the gelationbehavior of ABA triblocks consisting of poly(lactic acid-co-glycolic acid) (PLGA) and PEO sequences and found that thehydrophobicity/hydrophilicity of terminal moiety can exert dra-matic effects on the thermosensitive sol-gel transition behavior.In general, physical hydrogels fabricated from amphiphilic blockcopolymers follows the micelle-network gelation mechanism.

In the context ofDHBC-basedphysical hydrogels, thermogellingpoly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethyleneoxide), PEO-b-PPO-b-PEO, triblock copolymers have been ex-tensively investigated, taking advantage of the lower criticalsolution temperature (LCST) phase behavior of the PPO middleblock.43Armes and co-workers26 reported the synthesis and thermo-responsive sol-gel transition of ABA triblock copolymers com-prising of poly(N-isopropylacrylamide) (PNIPAM) and poly(2-methacryloyloxyethylphosphorylcholine) (PMPC) blocks, whichare unimolecularly soluble at 20 �Cbut form free-standing physicalgels at 37 �C due to thermo-induced hydrophobicity of PNIPAMouter blocks at elevated temperatures. It should be noted thatPNIPAMhomopolymers possess an LCST of∼32 �C in aqueoussolution, and the presence of hydrophilic PMPCmiddle block canconsiderably elevate the phase transition temperatures of triblockcopolymers. The same research group also reported the fabrica-tion of degradable hydrogels from PNIPAM-b-PMPC-b-PNIPAM triblock copolymer with a disulfide moiety located at thecenter of PMPCmiddle block.27 Thus, reversible sol-gel and gel-sol transitions can be induced by temperature variations and bythe addition of glutathione, respectively. Another notable exampleconcerning the thermo-induced sol-gel transition ofABA triblockcopolymers consisting of PNIPAM outer blocks and water-soluble poly(N,N- dimethylacrylamide) (PDMA) middle blockwas reported byMcCormick and his co-workers.28 Recently, theyfurther employed small-angle X-ray scattering and low-shearrheometry to probe the gelation behavior of PNIPAM-PDMA-PNIPAM triblock copolymers in aqueous solution.29 They found

that triblock copolymers below a critical molecular weight (MW)can pack into body-centered-cubic arrays. Moreover, the storagemoduli of physical gels formed at elevated temperatures areinversely related to the MW of ABA triblocks, as revealed byrheological measurements.

It should be noted that the above examples of physicalhydrogels constructed from amphiphilic or double hydrophilicABA triblock copolymers typically possess quite high criticalgelation concentrations (CGCs, g16 wt % for PLLA-b-PEO-b-PLLA,44g15wt%for PLGA-b-PEO-b-PLGA,41 PEO-b-PPO-b-PEO,43 PNIPAM-b-PMPC-b-PNIPAM,26 and g7.5 wt % forPNIPAM-b-PDMA-b-PNIPAM28). As compared to triblockcopolymer-based thermoresponsive physical hydrogels, previousworks reported by Cohn et al.,45 Jeong et al.,46,47 and Li et al.48,49

suggested that amphiphilic multiblock copolymers of the (AB)ntype can form hydrogels possessing enhancedmechanical proper-ties, superior long-term stability, and considerably lower CGCs.It is worthy of noting that these multiblock copolymers weretypically synthesized via the coupling of linear precursors. Thus,their MWs, MW distributions, and block numbers (averagenumber of repeating AB sequences per multiblock chain) are lesscontrollable, and it is quite difficult to elucidate the correlationbetween structural parameters and gelation properties.

On the other hand, the presence of inorganic salts can also exertconsiderable effects on the thermogelling properties of amphi-philic and double hydrophilic block copolymers.28,43,50 Thisaspect is particularly relevant to the biomedical applications ofhydrogels considering the presence of various types of salts underphysiological conditions. McCormick et al.28 reported that thermo-induced gels of PNIPAM-b-PDMA-b-PNIPAM triblocksunder simulated physiological conditions possess lower criticalgelation temperatures (CGTs) and slightly higher gel storagemodulus, G0

gel, as compared to those under salt-free conditions.

Song et al.50 reported that the addition of inorganic salts canconsiderably affect the thermogelling properties of graft copoly-mers comprising of poly(organophosphazene) backbones cova-lently modified with PEO side chains and amino acid esterfunctionalities. Most importantly, the presence of salts results indecreasing CGTs in the order of Hofmeister series, which wasproposed in 1888 by Hofmeister to sequence the ability of salts toprecipitate certain proteins froman aqueous solution.51However,such conclusions cannot be generalized until more thermogellingamphiphilic and double hydrophilic copolymers with varyingchain topologies are being scoped, especially for cases such as thegelation of responsive double hydrophilic triblock andmultiblockcopolymers.

Previously, we reported the controlled synthesis of doublehydrophilic (AB)nmultiblock copolymers comprising hydrophilicPDMAand thermoresponsive PNIPAMsequences,m-PDMAp-PNIPAMq, via consecutive reversible addition-fragmentationchain transfer (RAFT) polymerizations and investigated theirthermo-induced aggregation behavior in dilute aqueous solutions.52

(30) Kim, S. Y.; Kim, H. J.; Lee, K. E.; Han, S. S.; Sohn, Y. S.; Jeong, B.Macromolecules 2007, 40, 5519–5525.(31) Choi, Y. Y.; Joo, M. K.; Sohn, Y. S.; Jeong, B. Soft Matter 2008, 4, 2383–

2387.(32) Hyun, H.; Kim, Y. H.; Song, I. B.; Lee, J.W.; Kim,M. S.; Khang, G.; Park,

K.; Lee, H. B. Biomacromolecules 2007, 8, 1093–1100.(33) Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Nature 1997, 388, 860–862.(34) Gong, C. Y.; Shi, S. A.; Dong, P.W.; Kan, B.; Gou,M. L.;Wang, X. H.; Li,

X. Y.; Luo, F.; Zhao, X.; Wei, Y. Q.; Qian, Z. Y. Int. J. Pharm. 2009, 365, 89–99.(35) Jeong, B.; Lee, K. M.; Gutowska, A.; An, Y. H. H. Biomacromolecules

2002, 3, 865–868.(36) Kim,M. S.; Hyun,H.; Seo,K. S.; Cho, Y.H.; Lee, J.W.; Lee, C.R.; Khang,

G.; Lee, H. B. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 5413–5423.(37) Nagahama, K.; Ouchi, T.; Ohya, Y. Adv. Funct. Mater. 2008, 18, 1220–

1231.(38) Suh, J. M.; Bae, S. J.; Jeong, B. Adv. Mater. 2005, 17, 118–120.(39) Yu, L.; Ding, J. D. Chem. Soc. Rev. 2008, 37, 1473–1481.(40) Ruel-Gariepy, E.; Leroux, J. C. Eur. J. Pharm. Biopharm. 2004, 58, 409–

426.(41) Yu, L.; Zhang, H. A.; Ding, J. D. Angew. Chem., Int. Ed. 2006, 45, 2232–

2235.(42) Joo, M. K.; Park, M. H.; Choi, B. G.; Jeong, B. J. Mater. Chem. 2009, 19,

5891–5905.(43) Malmsten, M.; Lindman, B. Macromolecules 1992, 25, 5440–5445.

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(45) Jiang, J.; Malal, R.; Li, C. H.; Lin, M. Y.; Colby, R. H.; Gersappe, D.;Rafailovich,M.H.; Sokolov, J. C.; Cohn, D.Macromolecules 2008, 41, 3646–3652.

(46) Sun, K. H.; Sohn, Y. S.; Jeong, B. Biomacromolecules 2006, 7, 2871–2877.(47) Lee, J.; Bae, Y. H.; Sohn, Y. S.; Jeong, B. Biomacromolecules 2006, 7, 1729–

1734.(48) Loh, X. J.; Tan, Y. X.; Li, Z. Y.; Teo, L. S.; Goh, S. H.; Li, J. Biomaterials

2008, 29, 2164–2172.(49) Loh, X. J.; Goh, S. H.; Li, J. Biomacromolecules 2007, 8, 585–593.(50) Cho, Y.W.; An, S. W.; Song, S. C.Macromol. Chem. Phys. 2006, 207, 412–

418.(51) Hofmeister, F. Arch. Exp. Pathol. Pharmakol. 1888, 24, 247–260.(52) Zhou, Y. M.; Jiang, K. Q.; Song, Q. L.; Liu, S. Y. Langmuir 2007, 23,

13076–13084.

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It was found that thermoresponsive double hydrophilic multiblockcopolymers can form unimolecular or multimolecular micelles atelevated temperatures depending on the relative chain lengths ofPDMA and PNIPAM sequences, which is quite different fromthose ofPNIPAM-b-PDMA-b-PNIPAMtriblockswith comparableblock lengths; however, in the previous work only twomultiblockcopolymer samples with varying chain sequences, m-PDMA42-PNIPAM37 and m-PDMA105-PNIPAM106, were involved. Re-cently, we also reported that the aqueous solution of multiblockblock copolymers consisting of protonated poly(4-vinylpyridine)and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)sequences at a polymer concentration as low as 6.0 wt % canexhibit novel thermo-induced sequential gel-sol-gel transitionbehavior in the presence of a divalent organic salt, sodium 2,6-naphthalenedisulfonate.53 In this case, thermoregulation of therelative dominance of two types of supramolecular interactions,namely hydrophobic and electrostatic interactions, at low andelevated temperatures contributes to the thermo-induced sequen-tial gel-sol-gel transition. It is worth noting that for doublehydrophilic m-PDMAp-PNIPAMq multiblock copolymers theirthermo-induced gelation properties at high concentrations haveremained to be explored; moreover, it should be intriguing tofurther investigate and compare the chain architectural effects(multiblock vs triblock) and salt effects on the gelation behaviorof double hydrophilic multiblock and ABA triblock copolymers.

On the basis of the previous results,52 our research target of thiswork is threefold: (1) to understand the gelation properties ofthermoresponsive double hydrophilic multiblock copolymers withvarying sequence lengths at high concentrations and to comparewith conventional double hydrophilic ABA triblock copolymers;(2) most importantly, we attempted to explore the correlationbetween gelation behavior of multiblock copolymers at highconcentrations and their aggregation properties in dilute aqueoussolutions; (3) to explore the salt effects on gelation properties ofthermoresponsivemultiblock copolymers.Herein, we synthesizeda series of m-PDMAp-PNIPAMq multiblock copolymers withvarying PDMA and PNIPAM sequence lengths, investigatedtheir thermo-induced gelation properties in concentrated aqueoussolutions, and attempted to correlate the gelationbehavior at highconcentrations with their aggregation behavior at low concen-trations. The chain architectural (multiblock vs triblock) and

Hofmeister effects (addition of various sodium salts) on thegelationbehavior ofmultiblock and triblock copolymerswith com-parable composition and sequence lengths were also reported.

Experimental Section

Materials. N-Isopropylacrylamide (NIPAM, 97%, TokyoKaseiKagyoCo.)waspurified by recrystallization fromamixtureof benzene and n-hexane (1/3, v/v). N,N-Dimethylacrylamide(DMA, 98%, TCI) was vacuum-distilled from CaH2 and storedat -20 �C prior to use. 2,2-Azoisobutyronitrile (AIBN) wasrecrystallized fromethanol.N-Bromosuccinimide (NBS), dibenzoylperoxide (BPO), carbon tetrachloride, carbondisulfide (CS2), andall other reagents were purchased from Sinopharm ChemicalReagent Co., Ltd., and used as received.

Sample Synthesis. Synthetic schemes employed for the pre-paration of polytrithiocarbonate (1) andm-PDMAp-PNIPAMq

multiblock copolymers with varying PDMA and PNIPAM se-quence lengths are shown in Scheme 1, and detailed procedureswere reported previously.52 The corresponding triblock copoly-mers, PNIPAMq/2-b-PDMAp-b-PNIPAMq/2, with comparablesequence lengths to those of multiblocks were prepared by treat-ingmultiblock copolymerswith an excess ofAIBNat 80 �C in 1,4-dioxane (Scheme 1).

The actual degrees of polymerization (DPs) of PDMA andPNIPAM sequences were determined by 1H NMR analysis,whereas the block numbers, i.e., average number of PDMAp-PNIPAMq repeating sequences (n) per multiblock chain, wereobtained by comparing the GPCmolecular weights ofmultiblockcopolymers to those of the cleaved products. Tables 1 and 2summarize structural parameters of m-PDMAp precursors andm-PDMAp-PNIPAMq multiblock copolymers synthesized inthis work.

Sequence Length-Dependent Sol-Gel Transitions of

Multiblock Copolymers. The sol-gel transitions of a series ofm-PDMAp-PNIPAMq multiblock copolymers in aqueous solu-tion at a concentration of 10.0 wt % were determined via the testtube inverting method. Each sample was dissolved in deionizedwater at 10.0 wt % in a 4 mL vial. After equilibration at 20 �Covernight, the vials containing aqueous solutions were immersedin a water bath equilibrated at 60 �C for 20 min. The sol-geltransition was determined by an observation criterion afterinverting the vial. If a homogeneous semisolid formed and noflowwas observed in 30 s, the sample was considered to be able toform physical hydrogels.

RheologyMeasurement. Rheology measurements were con-ducted using an AR-G2 Rheometer (TA Instruments) with a40mmparallel plate geometry and gap of∼250 μm.An insulated

Scheme 1. Schematic Illustration for the Synthesis of Multiblock Copolymers, m-PDMAp-PNIPAMq, by Successive RAFT Polymerizations

Using Polytrithiocarbonate (1) as the Chain Transfer Agent and Triblock Copolymers, PNIPAMq/2-b-PDMAp-b-PNIPAMq/2, by Treating the

Multiblock Copolymers with an Excess of AIBN at 80 �C in 1,4-Dioxane

(53) Hu, J. M.; Ge, Z. S.; Zhou, Y. M.; Zhang, Y. F.; Liu, S. Y.Macromolecules2010, 43, 5184–5187.

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ring was placed around the geometry to prevent water evapora-tion. The shear strainγ dependence of the complexmodulusG* at1.0 rad/s was measured at first to determine the linear viscoelas-ticity region. Subsequentmeasurementswere then conductedwithshear strain γ and angular frequency ω being set at 1.0% and 1.0rad/s, respectively. The measuring temperatures range from 1 to65 �C with a heating rate of 1 �C/min.

Laser Light Scattering (LLS). A commercial spectrometer(ALV/DLS/SLS-5022F) equipped with a multitau digital timecorrelator (ALV5000) and a cylindrical 22 mW UNIPHASEHe-Ne laser (λ0 = 632 nm) as the light source was employedfor dynamic LLSmeasurements. Scattered light was collected at afixed angle of 90� for duration of ∼5 min. Distribution averagesand particle size distributions were computed using cumulantsanalysis andCONTINroutines.All datawere averagedover threemeasurements.

Results and Discussion

Chain Architectural Effects on Thermogelling Properties

of Multiblock and Triblock Copolymers. Bearing hydrophilicPDMAand thermoresponsive PNIPAMsequences,m-PDMAp-PNIPAMqmultiblock copolymers are expected to exhibit thermo-induced aggregation and gelation behavior in aqueous solution.Previously, the aggregation properties m-PDMA42-PNIPAM37

and m-PDMA105-PNIPAM106 multiblock copolymers in diluteaqueous solutions were investigated.52 It was found that chain

lengths of PDMA and PNIPAM sequences can exert dramaticeffects on their aggregation behavior.m-PDMA105-PNIPAM106

behaves as protein-like polymers and exhibit intramolecular chaincollapse upon heating, forming unimolecular flowerlike micellesabove the thermal phase transition temperature. On the otherhand, m-PDMA42-PNIPAM37 multiblock copolymer exhibitschain collapse and intermolecular aggregation, forming asso-ciated multimolecular micelles at elevated temperatures.

In this work, a series of m-PDMAp-PNIPAMq multiblockcopolymers with varying chain lengths of PDMA and PNIPAMsequences were synthesized, and their structural parameters aresummarized in Table 2. We then systematically investigated thegelation properties of multiblock copolymers at high concentra-tions. Figure 1 shows typical photographs recorded for aqueoussolutions ofm-PDMA42-PNIPAM37,m-PDMA105-PNIPAM106,and m-PDMA105-PNIPAM244 (10.0 wt %) at 60 �C. Unexpect-edly, we found that onlym-PDMA105-PNIPAM106 solutions canform free-standing gels at elevated temperature, whereas the othertwo multiblocks in concentrated solutions exhibit macroscopicphase separation upon heating.Moreover, the same phenomenonoccurs even at a polymer concentration of 20.0 wt %.

The sequence length-dependent gelation properties of multi-block copolymers were then determined via the test tube invertingmethod, and the results are shown in Figure 2. It was found thatonly multiblock copolymers possessing appropriate PDMA and

Table 2. Summary ofm-PDMAp-PNIPAMqMultiblockCopolymers Prepared via theRAFTPolymerization ofNIPAMMonomer byEmploying

m-PDMAp as the MacroRAFT Agent

m-PDMAp-PNIPAMqd cleaved producte

samplesa,bmacroRAFTagent used

NIPAM(g)

conversion(%)c

Mn

(�104) Mw/Mn

Mn

(�104) Mw/Mn

DP of PNIPAMsequence (p)f

blocknumber (n)g

m-PDMA42-PNIPAM25 m-PDMA42 0.32 85 5.21 1.57 1.03 1.05 25 5.1m-PDMA42-PNIPAM37 m-PDMA42 0.50 79 4.62 1.55 1.15 1.06 37 4.0m-PDMA42-PNIPAM71 m-PDMA42 0.90 83 5.33 1.53 1.40 1.06 71 3.8m-PDMA42-PNIPAM129 m-PDMA42 1.60 85 6.92 1.50 2.15 1.09 129 3.2m-PDMA65-PNIPAM35 m-PDMA65 0.30 82 6.44 1.52 1.34 1.06 35 4.8m-PDMA65-PNIPAM48 m-PDMA65 0.38 87 6.17 1.55 1.57 1.05 48 3.9m-PDMA65-PNIPAM60 m-PDMA65 0.50 84 6.08 1.58 1.69 1.08 60 3.6m-PDMA75-PNIPAM49 m-PDMA75 0.38 83 6.29 1.53 1.53 1.06 49 4.1m-PDMA75-PNIPAM70 m-PDMA75 0.50 85 7.42 1.50 1.95 1.07 70 3.8m-PDMA75-PNIPAM138 m-PDMA75 0.90 90 8.64 1.55 2.68 1.06 138 3.2m-PDMA75-PNIPAM245 m-PDMA75 1.60 91 10.86 1.59 4.30 1.10 245 2.5m-PDMA105-PNIPAM106 m-PDMA105 0.50 89 9.53 1.49 2.67 1.05 106 3.6m-PDMA105-PNIPAM194 m-PDMA105 0.90 93 10.12 1.51 3.46 1.06 194 2.9m-PDMA105-PNIPAM244 m-PDMA105 1.60 70 10.06 1.55 4.35 1.06 244 2.3

aThe polymerization was conducted in 1,4-dioxane at 80 �C for∼1 h, 0.4 g ofm-PDMApmacroRAFT agent was used, and the molar ratios of AIBNto trithiocarbonate moieties were fixed at 1:10. bThe multiblock copolymer was denoted m-PDMAp-PNIPAMq, where p and q represent the DP ofPDMA and PNIPAM sequences, respectively. cMonomer conversions determined by gravimetry. dNumber-average molecular weights (Mn) andmolecular weight distributions (Mw/Mn) of m-PDMAp-PNIPAMq multiblock copolymers determined by GPC using DMF as eluents. eNumber-average molecular weights (Mn) and molecular weight distributions (Mw/Mn) of the cleaved products after treatingm-PDMAp-PNIPAMq multiblockcopolymers with an excess of AIBN at 80 �C in 1,4-dioxane. fDetermined by 1H NMR in CDCl3.

gRatios of the molecular weights (Mn, GPC) ofm-PDMAp-PNIPAMq multiblock copolymers to those of the cleaved products.

Table 1. Summary of m-PDMAp Precursors Prepared via RAFT Polymerization of DMA Using Polytrithiocarbonate (1) as the Chain Transfer

Agent

m-PDMApd cleaved producte

samplesa [1]b (10-2 M) conversion (%)c Mn (�104) Mw/Mn Mn (�104) Mw/Mn DP of PDMA squence (p)f bock number (n)g

m-PDMA42 16.7 68.5 6.39 1.43 0.89 1.09 42 7.2m-PDMA65 10.0 65.0 7.81 1.42 1.07 1.10 65 7.3m-PDMA75 8.0 64.8 8.59 1.40 1.34 1.05 75 6.4m-PDMA105 6.7 70.0 10.62 1.41 1.85 1.05 105 5.7

aThe polymerization was conducted under bulk conditions: 3 mL of , 80 �C,∼45min; the concentration of polytrithiocarbonate (1) was varied, whilethe molar ratios of trithiocarbonate moieties to AIBN were fixed at 20:1. bThe concentration of trithiocarbonate moieties. cMonomer conversionsdetermined by gravimetry. dNumber-averagemolecular weights (Mn) andmolecular weight distributions (Mw/Mn) ofm-PDMAp precursors determinedby GPC using DMF as eluent. eNumber-average molecular weights (Mn) and molecular weight distributions (Mw/Mn) of the cleaved products aftertreating m-PDMAp precursors with an excess of AIBN at 80 �C in 1,4-dioxane. fDetermined by 1H NMR in D2O. gRatios of the molecular weights(Mn,GPC) of m-PDMAp precursors to those of the cleaved products.

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PNIPAM sequence lengths can form free-standing gels. Thoughm-PDMA42-PNIPAM37 and m-PDMA105-PNIPAM106 pos-sess similar block numbers (∼4), they exhibit drastically differentaggregation and gelation behavior. At low concentration (0.5 g/L),the former can form multimolecular aggregates upon heatingabove the phase transition temperature. With the increase ofpolymer concentrations, macroscopic phase separation occurswith the formation of polymer-rich dense phase at the bottom.Onthe other hand, thermo-induced formation of unimolecularmicellesand homogeneous hydrogels were observed for m-PDMA105-PNIPAM106 at low (0.5 g/L) andhigh concentrations (10.0wt%),respectively.

The aggregation properties of all multiblock copolymers listedin Table 2 in dilute aqueous solutions (0.5 g/L) were then checkedby temperature-dependent optical transmittance and dynamicLLS measurements, and the results are integrated into Figure 2,together with their gelation behavior at 10.0 wt%. It is intriguingto find that only multiblock copolymers exhibiting unimolecularcollapse at low concentrations can form free-standing hydrogelsat high concentrations upon heating. The apparent correlationbetween aggregation and gelation properties of multiblock copo-lymers is tentatively interpreted as follows. At low concentrations(0.5 g/L) and elevated temperatures, unimolecular micelles ofm-PDMA105-PNIPAM106 possess well-defined nanostructures(∼5-7 nm) with the PNIPAM sequences collapsing into the core,which are stabilized bywell-solvated PDMAsequences existing inthe loop conformation. Upon increasing polymer concentrations,soluble PDMAsequences tend to bridge neighboringmicelles and

lead to the formation of interconnected micelle networks, i.e., gelformation. On the other hand, multimolecular aggregates ofm-PDMA42-PNIPAM37 formed at low concentrations possessa dimension of ∼300 nm. Thus, to some extent soluble PDMAsequences tend to be buried inside the aggregates, and this provesto be a disadvantage for the formation of larger networks as thebridging of neighboring micelles by PDMA sequences is gettingless effective; thus, macroscopic phase separation will occur atelevated temperature and polymer concentrations.Moreover, theshort PDMA sequence length within m-PDMA42-PNIPAM37

should be difficult to effectively act as the bridging links betweenprecursor micelles, as compared to that of m-PDMA105-PNIPAM106 multiblock copolymer which possesses much largerPDMA sequence lengths. Previously,McCormick et al.28 reportedthe thermogelling behavior of PNIPAM-b-PDMA-b-PNIPAMtriblocks with fixed PNIPAM (DP = 455) and varying PDMAblock lengths (DP = 210 and 277). They found that bothtriblocks can form reversible physical gels at elevated tempera-tures in aqueous solution (>7.5wt%). Triblock copolymers withlonger PDMA inner blocks tend to form hydrogels with largerstorage modulus at the gelation temperature, as compared tothose possessing shorter PDMA inner blocks. This implies thateven for ABA triblock copolymers the sequence length of thesoluble middle block can exhibit considerable effects on theirgelation properties and short middle blocks do not favor theeffective gelation process.

We can conclude from Figure 2 that multiblock copolymerspossessing long enough PDMA sequences (for effective bridgingbetween neighboringmicelles) and appropriate PNIPAMsequences(for the formation of stable unimolecular precursor micelles) canform stable free-standing hydrogels at elevated temperatures,whereas those with relatively short PDMA sequences (comparedto the PNIPAM sequence lengths) cannot form physical hydro-gels upon heating. We propose that for thermoresponsive multi-blocks the relative sequence length of the soluble block playcrucial roles, and this will directly affect their capability ofbridging precursor micelles, which is a prerequisite for thermo-induced gelation. To the best of our knowledge, the correlationbetween aggregation and gelation properties for multiblockcopolymers at low and high concentrations, respectively, hasnot been previously reported. Further theoretical considerationstoward the understanding of this aspect are necessary.Thermogelling Properties of Multiblock versus Triblock

Copolymers. We then compared the gelation properties ofm-PDMAp-PNIPAMqmultiblock copolymerswith varying sequence

Figure 1. Photographs recorded for 10.0 wt % aqueous solutions of (a) m-PDMA42-PNIPAM37, (b) m-PDMA105-PNIPAM106, and(c) m-PDMA105-PNIPAM244 multiblock copolymers at 60 �C.

Figure 2. Micellization and gelation behavior at low (0.5 g/L) andhigh (10.0wt%) concentrations, respectively, obtainedat 60 �C foraqueous solutions of m-PDMAp-PNIPAMq multiblock copoly-merswith varying degrees of polymerization (DPs) for PDMAandPNIPAM sequences.

1148 DOI: 10.1021/la1048166 Langmuir 2011, 27(3), 1143–1151

Article Ge et al.

lengths to the corresponding PNIPAMq/2-b-PDMAp-b-PNIPAMq/2

triblock copolymers prepared via the cleavage of multiblocks(Scheme 1, Table 2). The presence of cleavable trithiocarbonatemoieties within m-PDMAp-PNIPAMq multiblock copolymershas indeed facilitated the synthesis of PNIPAMq/2-b-PDMAp-b-PNIPAMq/2 triblock copolymers with exactly comparable se-quence lengths to those of multiblock copolymers. It has beenpreviously reported by Cohn et al.,45 Jeong et al.,46,47 and Liet al.48,49 that amphiphilic multiblock copolymers of the (AB)ntype are better polymeric gelators in terms ofmechanical propertiesand CGCs, as compared to ABA triblock copolymers. However,systematic investigations and the comparison of gelation proper-ties of multiblock and triblock copolymers possessing controlledMW, narrow polydispersity, and well-defined sequence lengthshave not been reported yet.

In rheologymeasurements, the shear strainγ dependence of thecomplexmodulusG*wasmeasured at first at 1.0 rad/s to determinethe linear viscoelasticity region (Figure 3). Takingm-PDMA105-PNIPAM106 (10.0 wt %, 60 �C) as an example, we can see that inthe γ range of 0.1-40% the storage modulus G0 is always domi-nant over the loss modulus G0 0, clearly indicating a gel state.Moreover, both of these two values remain constant in theγ rangeinvestigated. In subsequent rheology measurements, the shearstrain γwas fixed at 1%, which is located in the linear region. It isinteresting to note that thoughm-PDMA105-PNIPAM244 multi-block cannot form free-standing hydrogels uponheating (Figures 1and 2), the corresponding triblock copolymer, PNIPAM122-b-PDMA105-b-PNIPAM122, clearly exhibits thermo-induced gela-tion. This indicates that gelation properties of multiblock copo-lymers strongly rely on their relative sequence length ratios andthe absolute sequence lengths (Figure 2). Moreover, this alsorevealed the chain architectural effects, i.e., (AB)n-type multi-block vs ABA-type triblock copolymers, on the gelation proper-ties of thermoresponsive block copolymers. In subsequent sections,we focus on comparing the gelation properties of thermo-gellablemultiblock copolymers and the corresponding ABA triblockcopolymers with comparable sequence lengths.

Figure 4 depicts the temperature dependence of storage mod-ulus G0 and loss modulus G0 0 obtained for aqueous solution ofm-PDMA105-PNIPAM106 and PNIPAM53-b-PDMA105-b-PNI-PAM53 at varying polymer concentrations (wt %). At lowtemperatures, both loss modulus and storage modulus are small,and the former is larger than the latter, indicating a free-flowingsol state. Upon increasing temperatures, both the loss modulusand storage modulus increase abruptly and then reach plateauvalues. Apparently, the storage modulus G0 exhibits larger

temperature-dependent increases compared to that of the lossmodulus G0 0. The crossover of the two curves of each sample wasidentified as the critical gelation temperature (CGT), and thevalue of storage modulus at the end of the test (G0

gel) was used tocharacterize the mechanical properties of the formed physicalhydrogel at elevated temperatures. Compared to the criticalmicellization temperatures (CMT) of multiblock copolymersobtained at low concentrations as reported previously,52 theobtained CGT values were relatively higher. This is reasonableconsidering that CMT only indicates the start point of chaincollapse and aggregation, which were typically measured at lowpolymer concentrations.

CGT and G0gel of the multiblock and triblock copolymers at

varying polymer concentrations are summarized in Figure 5. Itcan be seen that for both m-PDMA105-PNIPAM106 multiblockand PNIPAM53-b-PDMA105-b-PNIPAM53 triblock copolymersCGT decreases and G0

gel increases with increasing polymerconcentrations. Moreover, the CGT value of multiblock copoly-mer was quite lower than that of triblock copolymers at the sameconcentrations, whereasG0

gel of the former wasmuch higher thanthat of the latter. This observation is in good agreement withprevious reports concerning the gelation properties of amphiphi-lic multiblock copolymers by several research groups.45,47,48

Compared to ABA triblock copolymers, the chain architectureof multiblock copolymers endows them with more junctionspoints (collapsed PNIPAM sequences) and bridging links (well-solvated PDMA sequences), which favors the formation of gelnetworks with larger G0

gel and lower CGTs.

Figure 3. Shear strain γ dependence of storage modulus G0 (solidsymbol) and lossmodulusG0 0 (open symbol) obtained for 10.0wt%aqueous solution of m-PDMA105-PNIPAM106 at 60 �C andangular frequency ω = 1.0 rad/s.

Figure 4. Temperaturedependenceof storagemodulusG0 and lossmodulus G0 0 obtained for aqueous solutions of m-PDMA105-PNIPAM106multiblockandPNIPAM53-b-PDMA105-b-PNIPAM53

triblock copolymers at varying polymer concentrations (wt %).The shear strainγ and angular frequencyωwere 1.0%and1.0 rad/s,respectively.

Figure 5. Polymer concentrationdependence of (a) critical gelationtemperatures (CGT) and (b) storagemodulus,G0

gel, of gels formedat elevated temperatures obtained form-PDMA105-PNIPAM106

multiblock and PNIPAM53-b-PDMA105-b-PNIPAM53 triblockcopolymers in aqueous solution.

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Ge et al. Article

Hofmeister Effects onThermogellingProperties ofMulti-

block and Triblock Copolymers. Though the thermogellingbehavior of amphiphilic and double hydrophilic block copoly-mers is mainly determined by their intrinsic parameters such aschemical structure, chain topology, and molecular weights, cer-tain external factors such as solution pH and the presence of saltscan also take effect.28,43,50 The latter is especially importantconsidering that practical applications of physical hydrogels areoften associated with complex environmental conditions. Thus, itis quite necessary to investigate salt effects on the gelation ofthermoresponsive block copolymers. Early in 1888, Hofmeister51

found the ability of salts to precipitate certain proteins fromaqueous solutions follows a recurring trend now termed as theHofmeister series: CO3

2- > SO42- > S2O3

2- > H2PO42- >

F->Cl->Br-≈NO3->I->ClO4

->SCN-. Though thisphenomenon was discovered more than one century ago and hasbeen tested and verified in diverse fields, its nature still remainsunexplained by the present physical chemistry theories. Recently,Cremer et al.54 investigated the effects ofHofmeister anions on thethermal phase transition of elastin-like polypeptides, and Swannet al.55 reported thatHofmeister anions can exhibit a considerableeffect on the swelling of self-assembled pH-responsive hydrogelsfabricated from amphiphilic triblock copolymers containingpolyelectrolyte middle blocks.

In the context of salt effects onneutral responsivewater-solublepolymers, Zhang et al.56,57 and Freitag et al.58 investigated theHofmeister effects on phase transition behavior of thermorespon-sive PNIPAM inaqueous solutions. They found that the ability todecrease LCST of PNIPAM also obey the order of Hofmeisterseries. Later on, Song et al.50 investigated the salt effects on thethermogelling behavior of amphiphilic graft copolymers. It wasfound that the Hofmeister effect is also applicable; i.e., most ofinorganic salts decrease CGT and improve the mechanicalstrength of the gels formed at elevated temperatures, and theability follows the order of Hofmeister series.

We then checked the salt effects on the thermogelling propertiesof double hydrophilic multiblock and triblock copolymers.Two representative salts which are almost on the opposite sideof Hofmeister series, NaCO3 and NaI, were chosen at first to

introduce into the aqueous solutions ofm-PDMA105-PNIPAM106

and PNIPAM53-b-PDMA105-b-PNIPAM53. Figures 6 and 7 showtemperature dependence of G0 and G0 0 obtained for 10.0 wt %aqueous solutions ofm-PDMA105-PNIPAM106 and PNIPAM53-b-PDMA105-b-PNIPAM53 in the presence of varying concentra-tions of Na2CO3. It can be seen that in both cases CGT decreasesand G0

gel increases considerably with increasing Na2CO3 concen-trations. For example, the CGT of PNIPAM53-b-PDMA105-b-PNIPAM53 decreases from 61.2 to 29.7 �C and G0

gel increasesfrom 31 to 478 Pa as Na2CO3 concentration increases from 0 to0.3 M.

For comparison, rheological results of the aqueous solutionsof m-PDMA105-PNIPAM106 multiblock and PNIPAM53-b-PDMA105-b-PNIPAM53 triblock copolymers in the presence ofvarying concentrations of NaI are shown in Figures 7 and 8.Apparently, the effects of NaI on the gelation properties are quitedifferent from those exerted by Na2CO3. With increasing NaIconcentrations, CGTs of both multiblock and triblock copoly-mers remain almost unchanged, and G0

gel only exhibits a moder-ate increase. The decrease of CGTs with Na2CO3 concentrationsreflects its “salting out” nature for PNIPAM sequences. In thework by Zhang et al.,57 they also found that inorganic salts in theleft side of Hofmeister series such as Na2CO3 can dramaticallydecrease the thermal phase transition temperatures of PNIPAMin aqueous solutions, whereas those on the right side such as NaIonly exhibit negligible effects. At the same measurement tempe-rature, the dramatic decrease of CGT due to the presence ofincreasing concentrations of effective inorganic salts such as

Figure 6. Temperaturedependenceof storagemodulusG0 and lossmodulus G0 0 obtained for 10.0 wt % aqueous solutions of m-PDMA105-PNIPAM106 multiblock and PNIPAM53-b-PDMA105-b-PNIPAM53 triblock copolymers in the presence of varyingconcentrations of Na2CO3. The shear strain γ was 1.0%, andthe angular frequency ω was 1.0 rad/s.

Figure 7. (a) NaI and (b) Na2CO3 concentration dependences ofthe CGT and gel storage modulus, G0

gel, at elevated temperaturesobtained for aqueous solutions of m-PDMA105-PNIPAM106

multiblock and PNIPAM53-b-PDMA105-b-PNIPAM53 triblockcopolymers, respectively.

Figure 8. Temperature dependence of storage modulus G0 andloss modulus G0 0 obtained for 10.0 wt % aqueous solutions ofm-PDMA105-PNIPAM106 multiblock and PNIPAM53-b-PDMA105-b-PNIPAM53 triblock copolymers in the presence of varyingconcentrations of NaI. The shear strain γ was 1.0%, and theangular frequency ω was 1.0 rad/s.

(54) Cho, Y.; Zhang, Y. J.; Christensen, T.; Sagle, L. B.; Chilkoti, A.; Cremer,P. S. J. Phys. Chem. B 2008, 112, 13765–13771.(55) Swann, J. M. G.; Bras, W.; Topham, P. D.; Howse, J. R.; Ryan, A. J.

Langmuir 2010, 26, 10191–10197.(56) Zhang, Y.; Furyk, S.; Sagle, L. B.; Cho, Y.; Bergbreiter, D. E.; Cremer, P. S.

J. Phys. Chem. C 2007, 111, 8916–8924.(57) Zhang, Y. J.; Furyk, S.; Bergbreiter, D. E.; Cremer, P. S. J. Am. Chem. Soc.

2005, 127, 14505–14510.(58) Freitag, R.; Garret-Flaudy, F. Langmuir 2002, 18, 3434–3440.

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Article Ge et al.

Na2CO3 will lead to denser and tighter association of PNIPAMsegments, and these strengthened junction points within hydrogelnetworks then lead to much higher G0

gel (Figure 7b).From the above-presented rheological results, it seems that the

Hofmeister effects work on both multiblock and triblock copo-lymers regardless of the differences in chain topology. We furtherchecked the salt effects on CGCs of multiblock and triblock co-polymers in aqueous solutions. The CGC values ofm-PDMA105-PNIPAM106 multiblock and PNIPAM53-b-PDMA105-b-PNI-PAM53 triblock copolymers in the presence of different kinds ofinorganic sodium salts at varying concentrationswere determinedby the test tube inverting method (Figure 9). As can be seen, theCGCof triblock copolymer in purewater is 8.5 wt%,whereas themultiblock copolymer possesses a much lower CGC value of4.75wt%.When inorganic salts were added, the CGC of triblockcopolymer decreased dramatically, especially for salts on the leftside ofHofmeister series. For example, the CGC value of triblockdecreased from 8.5 to 4.0 wt % as Na2CO3 concentrationsincreased from 0 to 0.4 M, whereas the presence of 0.4 M NaIonly leads to the decrease of CGC to ∼8.0 wt %. On the otherhand, for the multiblock copolymer, the CGC value only exhibitsa quite small decrease from 4.75 to 4.0 wt % in the same Na2CO3

concentration range (0-0.4 M).In the Hofmeister series, the ions on the left side are strongly

hydrated (kosmotropes), whereas those on the right side aremoreweakly hydrated (chaotropes). Intuitionally, strongly hydratedanions are capable of competingwith amidemoieties of PNIPAMtomore favorably bindwith watermolecules; thus, theweakeningof hydrogen bonding interactions between amide and watermolecules will lead to the decrease of CGTs. Recent reports byZhang and Cremer et al.56,57 have revealed that the underlyingmechanism of Hofmeister effects on the solubility of neutralresponsive polymers such as PNIPAM is actually quite complex.Three basic types of interactions, namely, surface tension effect,direct anion binding, and the polarization of water moleculeshydrating the amide moieties of PNIPAM, might be involved.Chaotropic anions such as I- can depress the LCST via thecombined mechanism of surface tension effects and “salting-in”effect, whereas kosmotropes such as CO3

2- take effect throughthe weakening of hydrogen bonding between pendent amidegroups and the bound hydration water molecules via the polar-ization effect. Figure 10 plots the variation of CGCs for triblockand multiblock copolymers in aqueous solutions in the presenceof varying types of inorganic salts (0.4 M). For both triblock andmultiblock copolymers, CGCs decrease in the order of Hofmeis-ter series with increasing hydration capabilities, though for themultiblock copolymer, the decrease of CGCs is quite modest

compared to those of the triblock copolymer. The latter might beascribed to the fact that for multiblock copolymers with appro-priate relative sequence lengths hydrophilic and hydrophobicchain segments within the micelle network formed at elevatedtemperatures can pack in a much ordered (denser) fashion evenunder salt-free conditions, as compared to those forABA triblockcopolymers. Thus, under salt-free conditions, they already pos-sess quite low CGCs, and the presence of inorganic salts such asNa2CO3 can only exhibit modest effects on their CGCs. Thisseems to be reasonable considering that under dilute conditionsm-PDMA105-PNIPAM106 multiblock can assemble into well-defined unimolecular micelles, whereas PNIPAM53-b-PDMA105-b-PNIPAM53 triblock copolymer self-assembles into multimole-cular micelles. This argument is further verified by the fact thatunder salt-free conditions and at the samepolymer concentrations(10.0 wt%) G0

gel ofm-PDMA105-PNIPAM106 multiblock copoly-mer is appreciably higher than that of PNIPAM53-b-PDMA105-b-PNIPAM53 triblock copolymer.

Conclusion

Starting from a series of double hydrophilic (AB)n multiblock(m-PDMAp-PNIPAMq) and ABA triblock copolymers(PNIPAMq/2-b-PDMAp-b-PNIPAMq/2), we systematically inves-tigated the chain architectural (multiblock vs triblock) andHofmeister effects (addition of various sodium salts) on theirthermogelling properties. It was found that only m-PDMAp-PNIPAMq multiblock copolymers with PDMA and PNIPAMsequence lengths located within a specific range can formphysicalgels at elevated temperatures. There exists an internal correlationbetween the aggregation properties of multiblock copolymers at

Figure 9. Critical gelation concentrations (CGC, wt %) of (a)PNIPAM53-b-PDMA105-b-PNIPAM53 triblock and (b) m-PDMA105-PNIPAM106 multiblock copolymers in aqueous solu-tion in the presence of varying amounts of sodiumsalts (0-0.4M).

Figure 10. Variation of CGCs (wt %) of (a) PNIPAM53-b-PDMA105-b-PNIPAM53 triblock and (b) m-PDMA105-PNI-PAM106 multiblock copolymers in aqueous solution in the pre-sence of different types of sodium salts (0.4 M).

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low concentrations and their gelation behavior at high concentra-tions. Rheology measurements revealed that multiblock copoly-mers possess considerably lower critical gelation temperatures(CGT) and higher gel storage modulus, G0

gel, as compared tothose of PNIPAM-b-PDMA-b-PNIPAM triblock copolymerspossessing comparable sequence lengths. The addition of inor-ganic sodium salts can effectively facilitate thermogelling formultiblock and triblock copolymers, resulting in decreasingCGTs in the order of Hofmeister series with increasing hydrationcapabilities. The unique thermogelling behavior of multiblock

copolymers compared to that ofABA triblock copolymers augurswell for their potential applications in various fields such asbiomaterials and biomedicines.

Acknowledgment. The financial support from National Nat-ural Scientific Foundation of China (NNSFC) Projects (20534020,20874092, 51033005, and 91027026), Fundamental ResearchFunds for the Central Universities, and Specialized ResearchFund for theDoctoral ProgramofHigher Education (SRFDP) isgratefully acknowledged.