Thermoresponsiveness of Copolymers Bearing Cholic Acid PendantsInduced by Complexation with β‑CyclodextrinYong-Guang Jia and X. X. Zhu*

Departement de Chimie, Universite de Montreal, C.P. 6128, Succursale Centre-ville, Montreal, Quebec H3C 3J7, Canada

*S Supporting Information

ABSTRACT: Copolymers of N-alkylacrylamides and meth-acrylate bearing cholic acid pendant groups were synthesizedvia radical polymerization. The cholic acid pendant groups ofsuch copolymers can form complexes with β-cyclodextrin, andthe effect of complexation on their thermoresponsive proper-ties was studied. The phase transition temperatures (transitionfrom hydrophilic to hydrophobic state) of the copolymersgradually increase with the addition of β-cyclodextrin, due tothe complexation of the cholic acid guest with the β-cyclodextrin host. The increase of the phase transitiontemperature may be reversed by the addition of a competingguest molecule, potassium 1-adamantylcarboxylate. The host−guest complexation provides a straightforward way to vary thethermoresponsive properties of such copolymers.

■ INTRODUCTION

Thermoresponsive water-soluble polymers undergo a phasetransition in water from a soluble to an insoluble state when thetemperature rises above a certain point [lower critical solutiontemperature (LCST) or cloud point (CP), in general].1,2

Among the various families of thermoresponsive polymers, N-alkylacrylamide-based polymers, especially poly(N-isopropyla-crylamide) (PiPA), are among the most widely studied.Attempts have been made to use these polymers in fieldsrelated to drug delivery, gene carriers, tissue engineering,sensors, catalysis, and chromatography separation in the pastdecades.3−7 Adjustment and control of the LCST of thesematerials are essential for their applications. For this purpose,copolymerization of iPA with other stimuli-responsive mono-mers and various random, graft, and block copolymers has beencarried out to tune the thermoresponsive properties.8

Bile acids are a group of physiologically important steroids invivo and play a crucial role in lipid digestion, transportation, andabsorption.9 Bile acids are also ideal building blocks in thepreparation of polymeric biomaterials, due to their biocompat-ibility and possibility of functionalization.10,11 In our previouswork, we incorporated bile acids into polymers and developed aseries of thermo- and pH-responsive materials consisting of bileacids moieties.12−16 Meanwhile, bile acids have a remarkableproperty of forming complexes with β-cyclodextrin (β-CD)since the size and shape of bile acid fit well the cavity of β-CD.17−22 Cyclodextrins (CDs) are a series of natural cyclicoligosaccharides composed of six, seven, or eight D-(+)-glucoseunits linked by R-1,4-linkages (correspondingly named as α-, β-,or γ-CD). Cabrer et al. studied the complex geometry anddifferent binding modes of β-CD upon complexation with bileacids derivatives.18,19 It has been demonstrated that the

formation of inclusion complexes between CDs and guestmolecules is cooperatively governed by hydrogen-bonding andthe other weaker interactions.17

The thermoresponsive properties of some polyacrylamideswith side groups23−29 or end groups30−32 may be tuned byadding CDs as supramolecular hosts. Ritter and co-workersinvestigated the LCST of thermoreversible polymers withadamantyl side groups being controlled through noncovalentinteractions with β-CD additives in water.23,24 The solubility ofa photoresponsive polymer with azobenzene pendant groups inthe presence of α-CD showed tunable properties in water, dueto the effect of molecular recognition of α-CD with theazobenzene moiety in the polymer.26,33 Such studies are highlyinteresting, while the materials may be limited in potentialapplications as biomaterials. Bile acid-containing polymers mayrespond to the need for biomaterials from the design point ofview. It is thus interesting to understand how the complexationof bile acids moieties with β-CD affects the thermoresponsive-ness of bile acid-containing polymers. Herein, the thermores-ponsive properties of polyacrylamides copolymers bearingcholic acid pendent groups are adjusted through the formationof supramolecular complexes of cholic acid guest with β-CDhost. We also wanted to study the reversal of such a change bythe addition of competing guest molecules.

■ RESULTS AND DISCUSSION

Characteristics of Copolymers. Radical polymerization ofiPA with cholic acid-based methacrylate monomer (CA) yields

Received: June 5, 2014Revised: September 4, 2014Published: September 9, 2014

Article

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a copolymer P(iPA-CA) bearing cholic acid pendant groups,where the cholic acid moiety is linked through a short spacer onposition 24, resulting in a flexible cholic acid moiety to interactwith the host molecule. However, the phase transitiontemperature of P(iPA-CA) is below room temperature, evenwhen the molar fraction of CA in copolymer is as low as ca. 2%,making its use difficult. It is well-known that acrylamides withdifferent alkyl-substituted groups lead to different phasetransition temperatures.34,35 Therefore, a more hydrophilicmonomer, N,N′-dimethylacrylamide (DMA), was copolymer-ized with iPA and CA, as shown in Scheme 1 to tune the phasetransition temperature of the polymer toward a high temper-ature range. A small increment of ca. 3 °C was shown in thiswork, but may be raised further by incorporating largeramounts of DMA in the copolymer.15,16 For comparisonpurposes, PiPA and P(iPA-DMA), both polymers withoutcholic acid moieties, were also prepared by radical polymer-ization. All these copolymers show similar molecular weightsand dispersity indices (Table 1). The conversions of the

comonomers are monitored and higher than 90%. The 1HNMR spectrum of the resultant P(iPA-DMA-CA) in CDCl3 isshown in Figure 1A. The characteristic proton peaks of cholicacid moieties are observed clearly. For example, the peaks at0.70 and 0.90 ppm are assigned to methyl protons of cholic acidat positions 18 and 19, respectively.Thermoresponsive Properties. The aqueous solution of

P(iPA-DMA-CA) shows a phase transition (Figure 2A) with aCP at 22.0 °C upon heating. The phase transition of thiscopolymer is also reversible upon cooling, but with a certainhysteresis (Figure S3A, dashes, Supporting Information). The

hysteresis can be ascribed to the additional interchain hydrogenbonding formed in the collapsed state at higher temperatures.36

Figure 2A also shows that the CP of P(iPA-DMA-CA) shifts toa higher temperature upon the addition of β-CD and graduallyincreases with increasing molar ratio of β-CD to CA. Forexample, the CP increases from 22.0 to 23.9 °C at a [β-CD]/[CA] molar ratio of 0.5 and further increases to 31.3 °C whenthe [β-CD]/[CA] molar ratio reaches 10. This result isconsistent with a previous report for a PiPA copolymerizedwith 4.4 mol % dodecyl (C12) side groups, for which the CP inthe presence of HP-β-CD increased from 14.2 to 19, 21, and to22.2 °C for host/C12 concentration ratios of 1/3, 1/1, and 3/1,respectively.37 Due to the hydrophilic nature of β-CD on theexterior, the complexation between the cholic acid moiety andβ-CD hinders the formation of hydrophobic microdomains byself-association, resulting in a gradual increase of the CP. Whenthe concentration of the polymer decreases from 2.0 to 1.0 andto 0.5 g/L, the CP of the P(iPA-DMA-CA) increases quicklyfrom 22.0 to 26.8 and to 33.3 °C and the magnitudes of the CP

Scheme 1. Radical Copolymerization of Cholic Acid-Based Methacrylate Monomer (CA) with iPA and DMA in DMF

Table 1. Characteristics of the Polymers

polymersmonomerratio yielda Mn,SEC

b Mw/Mnb

CP(°C)c

P(iPA-CA) 50:1 93 37.6 × 103 1.65 19.2P(iPA-DMA-CA) 75:25:2 91 43.6 × 103 1.79 22.0PiPA 94 43.2 × 103 1.71 34.0P(iPA-DMA) 3:1 93 47.2 × 103 1.72 40.8

aYield calculated from the insoluble portion in ethyl ether. Theconversion of the comonomers was determined by 1H NMR.bDetermined by SEC. cDetermined by UV−vis spectrophotometry.

Figure 1. 1H NMR spectra of (A) P(iPA-DMA-CA) in CDCl3, (B)P(iPA-DMA-CA) in D2O, and (C) P(iPA-DMA-CA) mixed with β-CD in D2O ([β-CD]/[CA] = 2:1), at 25 °C and with a polymerconcentration of 10 g/L and a concentration of CA units of 1.65mmol/L.

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at [β-CD]/[CA] = 10 decreases from 9.3 to 4.9 and to 2.0 °C,respectively (Figure S4, Supporting Information).The 1H NMR spectrum further confirms the complexation of

β-CD with the polymers containing cholic acid moieties. Nosignal of the methyl groups of the cholic acid moieties isobservable in D2O (Figure 1B), indicating the low mobility ofthe polymer due to the formation of aggregates with ahydrophobic cholic acid core surrounded by a hydrophilicpolyacrylamides shell. However, the characteristic methyl peaksof cholic acid moieties appeared after adding β-CD (Figure

1C), which indicates that the cholic acid moieties enter thecavities of β-CD and the polymer chains become morehydrophilic and flexible.It was reported that the CP of Py-PiPA (end-functionalized

with pyrene) in the presence of β-CD also was effectively raisedbut reached a constant value above [β-CD]/[Py-PiPA] of 2/1.31 Py-PiPA seems to be easily saturated by β-CD, probablydue to the easy access of β-CD to the guest pyrene located onthe polymer chain ends. The continuous increase of CP in ourstudy may be caused by two reasons: (1) The cholic acidmoieties are randomly distributed on the polymer chains andaccess to them is thus restricted, limiting the formation ofcomplex in comparison to free cholic acid as guest. Usually,complex stability constant (Ks) is reduced by 1 order ofmagnitude when the guest group is bound to a polymerbackbone.38 (2) The molar ratio of β-CD to guest may be notexactly 1:1, since the cholic acid guest was reported to formcomplexes with β-CD dimers.39 Consequently, the cholic acidguest needs a larger amount of β-CD to saturate. Apparently,adding more β-CD could shift the equilibrium in the directionof complexation, leading to a gradual increase of CP. As shownin the inset of Figure 2A, the increase of CP gradually levels offat higher molar ratios of β-CD to CA. Further addition of β-CDis limited by its solubility in water. In the case of P(iPA-CA), abroad phase transition with a lower CP is observed. The CP ofP(iPA-CA) shifts to a higher temperature upon the addition ofβ-CD (Figure S3B, Supporting Information), showing a similartransition as P(iPA-DMA-CA).To confirm the effect of complexation, control experiments

were carried out with P(iPA-DMA) and PiPA both withoutcholic acid pendent groups under the same conditions asdescribed above. No detectable changes of CP were observedwhen the β-CD was added (Figure S6, SupportingInformation). This agrees well with reports that the physicalmixing of β-CD with PiPA causes no significant changes of theCP.23,40

After the addition of 10 mol equiv of β-CD to CA, the CP ofP(iPA-DMA-CA) increased 9.3 °C. To achieve the reversibleadjustments of the CP, we added a competing guest, potassium1-adamantylcarboxylate (K-Ada), to the aqueous solution andobserved a gradual decrease of CP with increasing molar ratioof K-Ada to CA, as shown in Figure 2B. This decrease is mainlydue to the much higher complex stability constant of K-Ada41

with β-CD (Ks = 3.98 × 104 M−1) than that of cholic acid withβ-CD (Ks = 4.07 × 103 M−1).17 When the molar ratio of K-Adato CA reaches 10, the CP of P(iPA-DMA-CA) regains a similarvalue as in the case of pure polymer without β-CD, indicatingthat almost all of the CAs are replaced by K-Ada. Meanwhile,the phase transition curve becomes sharper than that in thepresence of β-CD. These sharper transitions may result fromthe complexes of K-Ada with β-CD, which may furtheraggregate with the polymer, forming even larger aggregates. Toverify this interpretation, the complexes of K-Ada with β-CDwere removed through dialysis. The phase transition curvebecomes broader and closely resembles that of the purepolymer after the removal of the complexes of K-Ada with β-CD (Figure 2C).A limitation of such an approach for adjusting the CP of the

cholic acid-containing polymer should be noted. There may besome potential disturbance or competition in the presence ofsolutes that may have comparable or even higher bindingconstants with β-CD (such as in the case of Ada-basedmolecules). Therefore, the tuning of the CP of this kind of

Figure 2. Variation of the transmittance of the aqueous solutions ofP(iPA-DMA-CA) (2.0 g/L, [CA units] = 0.33 mmol/L) as a functionof temperature observed at a wavelength of 400 nm and a heating rateof 0.5 °C/min: (A) in the presence of different molar ratios of β-CD toCA, (B) at [β-CD]/[CA] = 10 and in the presence of differentamounts of potassium 1-adamantylcarboxylate (K-Ada), and (C) inthe absence of any additives and at molar ratio [β-CD K-Adacomplex]/[CA units] = 10 before and after dialysis.

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polymer remains valid when the binding constants of solutes toβ-CD are lower than that of CA to β-CD (ca. 4 × 103 M−1).17

Light-Scattering Studies. Figure 3A shows the hydro-dynamic diameter (Dh) of the aggregates formed by P(iPA-DMA-CA) as a function of temperature. From 10 to 16 °C(below the phase transition temperature), no change in size (16nm) is observed and the size distribution of these aggregates isrelatively narrow (PDI ca. 0.18). At 17 °C and above, largeaggregates appear and gradually grow even larger in size (up to

ca. 600 nm at 40 °C). The effect of β-CD on the aggregationbehavior of P(iPA-DMA-CA) was also investigated. Figure 3Aalso shows the Dh of the aggregates formed by P(iPA-DMA-CA) at [β-CD]/[CA] ratios of 1, 3, and 10 as a function oftemperature. Generally, a phase transition is also observed afterthe introduction of β-CD, and the CP gradually increases withincreasing molar ratio of β-CD to CA, consistent with thechange measured by turbidity, as shown in the inset of Figure2A. Below the CP, the size of the aggregates remainsunchanged and only a unimodal peak with a PDI of ca. 0.18is obtained for each sample after adding β-CD. However, thetemperature-dependent aggregation process is greatly sup-pressed with further addition of β-CD, indicating that theaggregates partly dissociated due to the complexation of β-CDwith CA. For example, the Dh of the aggregates dramaticallydecreases from 324 to 207 and then to 16 nm (rectangular areain Figure 3A) when 1 and 10 mol equiv of β-CD to CA areadded at 20 °C, respectively. When the temperature is raisedbeyond the CP, the Dh of the aggregates at each temperaturegenerally decreases with increasing β-CD content. Above theCP, stable globules may form, since the agglomeration of theglobules may be hindered by the cyclodextrin complexes.38 Incontrast, the Dh of the aggregates formed by P(iPA-DMA) andPiPA without cholic acid pendent groups as a function oftemperature both remain unchanged after adding β-CD (FigureS7, Supporting Information).The effect of competing guest (K-Ada) was also studied by

DLS. The CP of P(iPA-DMA-CA) at [β-CD]/[CA] = 10gradually decreases with the addition of K-Ada. Meanwhile, ahigher molar ratio of K-Ada to CA leads to a sharper increase insize around the phase transition temperature. This result agreeswell with that of a K-Ada-dependent phase transitiontemperature, as shown in Figure 2B, where the sharper phasetransition curves are observed. Below the phase transitiontemperature, only a unimodal peak with a PDI of ca. 0.19 isdetected for each sample, and the molar ratio of K-Ada to CAcauses no significant changes to the size of aggregates.Increasing the molar ratio of K-Ada to CA leads to greaterdependence of the aggregation on temperature due to anincreased hydrophobicity of the polymer chains. For example,the Dh of aggregates dramatically increases from 16 to 260 nm(rectangular area in Figure 3B), when [K-Ada]/[CA] increasesfrom 7 to 10 at 20 °C. It indicates that the formation of thelarger aggregates becomes easier, since the complexation of K-Ada with β-CD leads to restoration of the free polymer chains.Above CP, the Dh of the aggregates at the same temperaturegenerally increases with higher molar ratio of K-Ada to CA. Forexample, the Dh of the aggregates formed by P(iPA-DMA-CA)at [β-CD]/[CA] = 10 is 250 nm at 30 °C, whereas the size ofthe aggregates was too large to be reasonably detected by lightscattering after 10 mol equiv of K-Ada to CA were added at thesame temperature.This rapid increase in Dh around the phase transition

temperature is consistent with the results shown in Figures 2Band 2C, where the phase transition is sharper than that of thepure polymer, possibly a result from the complexation of K-Adawith β-CD. The variation of the Dh of the aggregates as afunction of temperature (Figure 3C) shows a similar increasingtrend as that of the pure polymer upon the removal of thecomplexes of K-Ada with β-CD. Small deviations can beobserved for the size of the aggregates of the pure polymer andthe regenerated polymer after dialysis (to remove thecomplexes of K-Ada and β-CD), especially in the range

Figure 3. Size distribution of the aggregates of P(iPA-DMA-CA) inwater (2.0 g/L, [CA units] = 0.33 mmol/L) as a function oftemperature (A) in the presence of different molar equivalents of β-CD to CA, (B) at [β-CD]/[CA] = 10 and in the presence of differentamounts of K-Ada, and (C) in the absence of any additives (solidsquares with dashes) and at molar ratio [β-CD K-Ada complex]/[CAunits] = 10 after dialysis (open squares with solid line). Therectangular areas highlight the size variation of the samples at 20 °C.

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between 20 and 30 °C, possibly due to a change in themolecular weight distribution of the polymer sample afterdialysis.

■ CONCLUSIONS

The CP of the cholic acid-containing polyacrylamides can beraised with the gradual addition of β-CD, which complexes withthe CA pendant groups of the copolymers. The formation ofhost−guest complexes can tune the phase transition temper-ature of the bile acid-containing copolymers. To reverse thistrend, a competing guest molecule, K-Ada, can be added toreplace the cholic acid moieties as the guest and to restore thethermosensitivity of the polymers in the absence of the addedhost. Therefore, the thermoresponsive properties of such apolymer can be reversibly tuned by easily varying the ratios ofguest and host molecules. Such a tuning of the CP may beinteresting and useful in the design of thermoresponsivematerials based on biological molecules such as bile acids and inthe preparation of smart supramolecules or hydrogels.

■ EXPERIMENTAL SECTIONAll reagents were purchased from Aldrich and used without furtherpurification unless otherwise stated. 2,2′-Azoisobutyronitrile (AIBN)was recrystallized twice from methanol. N-Isopropylacrylamide (iPA)(97%, Aldrich) was recrystallized twice from hexane/toluene (10/1, v/v) and stored at −20 °C. N,N′-Dimethylacrylamide (DMA) wasdistilled before use. Cholic acid-based methacrylate monomer (CA)was prepared as reported previously.42

Synthesis of Polymers. Copolymerization was conducted inN,N′-dimethylformamide (DMF) at 70 °C with a [comonomers]/[AIBN] of 200:1. iPA (1.50 g, 13.274 mmol), DMA (438 mg, 4.424mmol), CA (204 mg, 0.354 mmol), AIBN (21 mg, 0.128 mmol), and 5mL DMF were added to a 25 mL round-bottom flask. The mixturewas purged with N2 for 20 min prior to its immersion in a preheatedoil bath. The copolymerization was allowed to proceed for 18 h beforebeing quenched by immersion into ice−water. DMF was removedunder reduced pressure and 5 mL of THF was added to dissolve thepolymer. The precipitate was collected after pouring the reactionmixture into ethyl ether. The polymer was dried in vacuo to yield 1.95g of P(iPA-DMA-CA) (91.0%).Polymer Characterization. Size exclusion chromatography

(SEC) was performed on a Breeze system from Waters equippedwith a 717 plus autosampler, a 1525 Binary HPLC pump, and a 2410refractive index detector using two consecutive Waters columns(Phenomenex, 5 μm, 300 × 7.8 mm; Styragel HR4, 5 μm, 300 × 7.8mm). The eluent DMF containing 0.05 M LiBr was filtered through0.20 μm Nylon Millipore filters. The flow rate was 1 mL/min.Poly(methyl methacrylate) standards (2500−296 000 g/mol) wereused for calibration. 1H and 13C NMR spectra in CDCl3 or D2O wererecorded on a Bruker AV400 spectrometer operating at 400 MHz for1H and 100 MHz for 13C. The cloud points (CPs) of the samples inaqueous solutions were determined on a Cary 5000 UV−vis−NIRspectrophotometer (Agilent) equipped with a Cary temperaturecontroller. Polymer aqueous solutions were normally heated at arate of 0.5 °C/min and the CP was taken as the middle point of thetransmittance change observed at 400 nm. Dynamic light scattering(DLS) measurements were performed on a Malvern Zetasizer NanoZSinstrument (Malvern CGS-2 apparatus) equipped with a He−Ne laserwith a wavelength of 633 nm, and the scattering angle was fixed at173°. Intensity-average hydrodynamic diameters of the dispersionswere obtained by DLS through the use of a non-negative least-squares(NNLS) algorithm. Disposable cuvettes were used and thesuspensions were filtered through 0.2 μm Millipore filters to removedust at 10 °C. The measurements were taken at every 2 °C after 2 minof equilibration time. All the CP measurements and DLS experimentswere conducted in fresh Milli-Q water without pH control.

■ ASSOCIATED CONTENT

*S Supporting InformationH and 13C 1NMR spectra of cholic acid-based methacrylatemonomer (CA) and (co)polymers; variation of the trans-mittance of the aqueous solutions of P(iPA-DMA-CA), P(iPA-CA), P(iPA-DMA), and PiPA as a function of temperature; 2D1H NOESY NMR spectrum of a mixture of P(iPA-DMA-CA)and β-CD; and Dh of aqueous solution of P(iPA-DMA) andPiPA in the presence of β-CD as a function of temperature.This material is available free of charge via the Internet athttp://pubs.acs.org.

■ AUTHOR INFORMATION

Corresponding Author*E-mail: julian.zhu@umontreal.ca.

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

Financial support from NSERC of Canada and FQRNT ofQuebec is gratefully acknowledged. The authors are membersof CSACS funded by FQRNT and GRSTB funded by FRSQ.The authors thank Mr. Sylvain Essiembre and Mr. PierreMenard-Tremblay for their technical support.

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