Thermoresponsiveness of Copolymers Bearing Cholic Acid Pendants

Article pubs.acs.org/Langmuir

Thermoresponsiveness of Copolymers Bearing Cholic Acid Pendants Induced by Complexation with β‑Cyclodextrin Yong-Guang Jia and X. X. Zhu* Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Quebec H3C 3J7, Canada S Supporting Information *

ABSTRACT: Copolymers of N-alkylacrylamides and methacrylate bearing cholic acid pendant groups were synthesized via radical polymerization. The cholic acid pendant groups of such copolymers can form complexes with β-cyclodextrin, and the effect of complexation on their thermoresponsive properties was studied. The phase transition temperatures (transition from hydrophilic to hydrophobic state) of the copolymers gradually increase with the addition of β-cyclodextrin, due to the complexation of the cholic acid guest with the βcyclodextrin host. The increase of the phase transition temperature may be reversed by the addition of a competing guest molecule, potassium 1-adamantylcarboxylate. The host−guest complexation provides a straightforward way to vary the thermoresponsive properties of such copolymers.

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INTRODUCTION Thermoresponsive water-soluble polymers undergo a phase transition in water from a soluble to an insoluble state when the temperature rises above a certain point [lower critical solution temperature (LCST) or cloud point (CP), in general].1,2 Among the various families of thermoresponsive polymers, Nalkylacrylamide-based polymers, especially poly(N-isopropylacrylamide) (PiPA), are among the most widely studied. Attempts have been made to use these polymers in fields related to drug delivery, gene carriers, tissue engineering, sensors, catalysis, and chromatography separation in the past decades.3−7 Adjustment and control of the LCST of these materials are essential for their applications. For this purpose, copolymerization of iPA with other stimuli-responsive monomers and various random, graft, and block copolymers has been carried out to tune the thermoresponsive properties.8 Bile acids are a group of physiologically important steroids in vivo and play a crucial role in lipid digestion, transportation, and absorption.9 Bile acids are also ideal building blocks in the preparation of polymeric biomaterials, due to their biocompatibility and possibility of functionalization.10,11 In our previous work, we incorporated bile acids into polymers and developed a series of thermo- and pH-responsive materials consisting of bile acids moieties.12−16 Meanwhile, bile acids have a remarkable property of forming complexes with β-cyclodextrin (β-CD) since the size and shape of bile acid fit well the cavity of βCD.17−22 Cyclodextrins (CDs) are a series of natural cyclic oligosaccharides composed of six, seven, or eight D-(+)-glucose units linked by R-1,4-linkages (correspondingly named as α-, β-, or γ-CD). Cabrer et al. studied the complex geometry and different binding modes of β-CD upon complexation with bile acids derivatives.18,19 It has been demonstrated that the © 2014 American Chemical Society

formation of inclusion complexes between CDs and guest molecules is cooperatively governed by hydrogen-bonding and the other weaker interactions.17 The thermoresponsive properties of some polyacrylamides with side groups23−29 or end groups30−32 may be tuned by adding CDs as supramolecular hosts. Ritter and co-workers investigated the LCST of thermoreversible polymers with adamantyl side groups being controlled through noncovalent interactions with β-CD additives in water.23,24 The solubility of a photoresponsive polymer with azobenzene pendant groups in the presence of α-CD showed tunable properties in water, due to the effect of molecular recognition of α-CD with the azobenzene moiety in the polymer.26,33 Such studies are highly interesting, while the materials may be limited in potential applications as biomaterials. Bile acid-containing polymers may respond to the need for biomaterials from the design point of view. It is thus interesting to understand how the complexation of bile acids moieties with β-CD affects the thermoresponsiveness of bile acid-containing polymers. Herein, the thermoresponsive properties of polyacrylamides copolymers bearing cholic acid pendent groups are adjusted through the formation of supramolecular complexes of cholic acid guest with β-CD host. We also wanted to study the reversal of such a change by the addition of competing guest molecules.

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RESULTS AND DISCUSSION Characteristics of Copolymers. Radical polymerization of iPA with cholic acid-based methacrylate monomer (CA) yields

Received: June 5, 2014 Revised: September 4, 2014 Published: September 9, 2014 11770

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

a copolymer P(iPA-CA) bearing cholic acid pendant groups, where the cholic acid moiety is linked through a short spacer on position 24, resulting in a flexible cholic acid moiety to interact with the host molecule. However, the phase transition temperature of P(iPA-CA) is below room temperature, even when the molar fraction of CA in copolymer is as low as ca. 2%, making its use difficult. It is well-known that acrylamides with different alkyl-substituted groups lead to different phase transition temperatures.34,35 Therefore, a more hydrophilic monomer, N,N′-dimethylacrylamide (DMA), was copolymerized with iPA and CA, as shown in Scheme 1 to tune the phase transition temperature of the polymer toward a high temperature range. A small increment of ca. 3 °C was shown in this work, but may be raised further by incorporating larger amounts of DMA in the copolymer.15,16 For comparison purposes, PiPA and P(iPA-DMA), both polymers without cholic acid moieties, were also prepared by radical polymerization. All these copolymers show similar molecular weights and dispersity indices (Table 1). The conversions of the

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 βCD in D2O ([β-CD]/[CA] = 2:1), at 25 °C and with a polymer concentration of 10 g/L and a concentration of CA units of 1.65 mmol/L.

Table 1. Characteristics of the Polymers polymers P(iPA-CA) P(iPA-DMA-CA) PiPA P(iPA-DMA)

monomer ratio 50:1 75:25:2 3:1

yielda 93 91 94 93

Mn,SECb

Mw/Mnb

CP (°C)c

× × × ×

1.65 1.79 1.71 1.72

19.2 22.0 34.0 40.8

37.6 43.6 43.2 47.2

103 103 103 103

hysteresis can be ascribed to the additional interchain hydrogen bonding formed in the collapsed state at higher temperatures.36 Figure 2A also shows that the CP of P(iPA-DMA-CA) shifts to a higher temperature upon the addition of β-CD and gradually increases with increasing molar ratio of β-CD to CA. For example, 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 when the [β-CD]/[CA] molar ratio reaches 10. This result is consistent with a previous report for a PiPA copolymerized with 4.4 mol % dodecyl (C12) side groups, for which the CP in the presence of HP-β-CD increased from 14.2 to 19, 21, and to 22.2 °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 the exterior, the complexation between the cholic acid moiety and β-CD hinders the formation of hydrophobic microdomains by self-association, resulting in a gradual increase of the CP. When the concentration of the polymer decreases from 2.0 to 1.0 and to 0.5 g/L, the CP of the P(iPA-DMA-CA) increases quickly from 22.0 to 26.8 and to 33.3 °C and the magnitudes of the CP

a

Yield calculated from the insoluble portion in ethyl ether. The conversion of the comonomers was determined by 1H NMR. b Determined by SEC. cDetermined by UV−vis spectrophotometry.

comonomers are monitored and higher than 90%. The 1H NMR spectrum of the resultant P(iPA-DMA-CA) in CDCl3 is shown in Figure 1A. The characteristic proton peaks of cholic acid moieties are observed clearly. For example, the peaks at 0.70 and 0.90 ppm are assigned to methyl protons of cholic acid at positions 18 and 19, respectively. Thermoresponsive Properties. The aqueous solution of P(iPA-DMA-CA) shows a phase transition (Figure 2A) with a CP at 22.0 °C upon heating. The phase transition of this copolymer is also reversible upon cooling, but with a certain hysteresis (Figure S3A, dashes, Supporting Information). The 11771

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1C), which indicates that the cholic acid moieties enter the cavities of β-CD and the polymer chains become more hydrophilic and flexible. It was reported that the CP of Py-PiPA (end-functionalized with pyrene) in the presence of β-CD also was effectively raised but reached a constant value above [β-CD]/[Py-PiPA] of 2/ 1.31 Py-PiPA seems to be easily saturated by β-CD, probably due to the easy access of β-CD to the guest pyrene located on the polymer chain ends. The continuous increase of CP in our study may be caused by two reasons: (1) The cholic acid moieties are randomly distributed on the polymer chains and access to them is thus restricted, limiting the formation of complex in comparison to free cholic acid as guest. Usually, complex stability constant (Ks) is reduced by 1 order of magnitude when the guest group is bound to a polymer backbone.38 (2) The molar ratio of β-CD to guest may be not exactly 1:1, since the cholic acid guest was reported to form complexes with β-CD dimers.39 Consequently, the cholic acid guest needs a larger amount of β-CD to saturate. Apparently, adding more β-CD could shift the equilibrium in the direction of complexation, leading to a gradual increase of CP. As shown in the inset of Figure 2A, the increase of CP gradually levels off at higher molar ratios of β-CD to CA. Further addition of β-CD is limited by its solubility in water. In the case of P(iPA-CA), a broad phase transition with a lower CP is observed. The CP of P(iPA-CA) shifts to a higher temperature upon the addition of β-CD (Figure S3B, Supporting Information), showing a similar transition as P(iPA-DMA-CA). To confirm the effect of complexation, control experiments were carried out with P(iPA-DMA) and PiPA both without cholic acid pendent groups under the same conditions as described above. No detectable changes of CP were observed when the β-CD was added (Figure S6, Supporting Information). This agrees well with reports that the physical mixing of β-CD with PiPA causes no significant changes of the CP.23,40 After the addition of 10 mol equiv of β-CD to CA, the CP of P(iPA-DMA-CA) increased 9.3 °C. To achieve the reversible adjustments of the CP, we added a competing guest, potassium 1-adamantylcarboxylate (K-Ada), to the aqueous solution and observed a gradual decrease of CP with increasing molar ratio of K-Ada to CA, as shown in Figure 2B. This decrease is mainly due to the much higher complex stability constant of K-Ada41 with β-CD (Ks = 3.98 × 104 M−1) than that of cholic acid with β-CD (Ks = 4.07 × 103 M−1).17 When the molar ratio of K-Ada to CA reaches 10, the CP of P(iPA-DMA-CA) regains a similar value as in the case of pure polymer without β-CD, indicating that almost all of the CAs are replaced by K-Ada. Meanwhile, the phase transition curve becomes sharper than that in the presence of β-CD. These sharper transitions may result from the complexes of K-Ada with β-CD, which may further aggregate with the polymer, forming even larger aggregates. To verify this interpretation, the complexes of K-Ada with β-CD were removed through dialysis. The phase transition curve becomes broader and closely resembles that of the pure polymer after the removal of the complexes of K-Ada with βCD (Figure 2C). A limitation of such an approach for adjusting the CP of the cholic acid-containing polymer should be noted. There may be some potential disturbance or competition in the presence of solutes that may have comparable or even higher binding constants with β-CD (such as in the case of Ada-based molecules). Therefore, the tuning of the CP of this kind of

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

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. No signal of the methyl groups of the cholic acid moieties is observable in D2O (Figure 1B), indicating the low mobility of the polymer due to the formation of aggregates with a hydrophobic cholic acid core surrounded by a hydrophilic polyacrylamides shell. However, the characteristic methyl peaks of cholic acid moieties appeared after adding β-CD (Figure 11772

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ca. 600 nm at 40 °C). The effect of β-CD on the aggregation behavior of P(iPA-DMA-CA) was also investigated. Figure 3A also shows the Dh of the aggregates formed by P(iPA-DMACA) at [β-CD]/[CA] ratios of 1, 3, and 10 as a function of temperature. Generally, a phase transition is also observed after the introduction of β-CD, and the CP gradually increases with increasing molar ratio of β-CD to CA, consistent with the change measured by turbidity, as shown in the inset of Figure 2A. Below the CP, the size of the aggregates remains unchanged and only a unimodal peak with a PDI of ca. 0.18 is obtained for each sample after adding β-CD. However, the temperature-dependent aggregation process is greatly suppressed with further addition of β-CD, indicating that the aggregates partly dissociated due to the complexation of β-CD with CA. For example, the Dh of the aggregates dramatically decreases from 324 to 207 and then to 16 nm (rectangular area in Figure 3A) when 1 and 10 mol equiv of β-CD to CA are added at 20 °C, respectively. When the temperature is raised beyond the CP, the Dh of the aggregates at each temperature generally decreases with increasing β-CD content. Above the CP, stable globules may form, since the agglomeration of the globules may be hindered by the cyclodextrin complexes.38 In contrast, the Dh of the aggregates formed by P(iPA-DMA) and PiPA without cholic acid pendent groups as a function of temperature both remain unchanged after adding β-CD (Figure S7, 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] = 10 gradually decreases with the addition of K-Ada. Meanwhile, a higher molar ratio of K-Ada to CA leads to a sharper increase in size around the phase transition temperature. This result agrees well with that of a K-Ada-dependent phase transition temperature, as shown in Figure 2B, where the sharper phase transition curves are observed. Below the phase transition temperature, only a unimodal peak with a PDI of ca. 0.19 is detected for each sample, and the molar ratio of K-Ada to CA causes no significant changes to the size of aggregates. Increasing the molar ratio of K-Ada to CA leads to greater dependence of the aggregation on temperature due to an increased 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] increases from 7 to 10 at 20 °C. It indicates that the formation of the larger aggregates becomes easier, since the complexation of KAda with β-CD leads to restoration of the free polymer chains. Above CP, the Dh of the aggregates at the same temperature generally increases with higher molar ratio of K-Ada to CA. For example, 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 of the aggregates was too large to be reasonably detected by light scattering after 10 mol equiv of K-Ada to CA were added at the same temperature. This rapid increase in Dh around the phase transition temperature is consistent with the results shown in Figures 2B and 2C, where the phase transition is sharper than that of the pure polymer, possibly a result from the complexation of K-Ada with β-CD. The variation of the Dh of the aggregates as a function of temperature (Figure 3C) shows a similar increasing trend as that of the pure polymer upon the removal of the complexes of K-Ada with β-CD. Small deviations can be observed for the size of the aggregates of the pure polymer and the regenerated polymer after dialysis (to remove the complexes of K-Ada and β-CD), especially in the range

polymer remains valid when the binding constants of solutes to β-CD are lower than that of CA to β-CD (ca. 4 × 103 M−1).17 Light-Scattering Studies. Figure 3A shows the hydrodynamic diameter (Dh) of the aggregates formed by P(iPADMA-CA) as a function of temperature. From 10 to 16 °C (below the phase transition temperature), no change in size (16 nm) is observed and the size distribution of these aggregates is relatively narrow (PDI ca. 0.18). At 17 °C and above, large aggregates appear and gradually grow even larger in size (up to

Figure 3. Size distribution of the aggregates of P(iPA-DMA-CA) in water (2.0 g/L, [CA units] = 0.33 mmol/L) as a function of temperature (A) in the presence of different molar equivalents of βCD to CA, (B) at [β-CD]/[CA] = 10 and in the presence of different amounts of K-Ada, and (C) in the absence of any additives (solid squares with dashes) and at molar ratio [β-CD K-Ada complex]/[CA units] = 10 after dialysis (open squares with solid line). The rectangular areas highlight the size variation of the samples at 20 °C. 11773

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

ASSOCIATED CONTENT

S Supporting Information *

H and 13C 1NMR spectra of cholic acid-based methacrylate monomer (CA) and (co)polymers; variation of the transmittance of the aqueous solutions of P(iPA-DMA-CA), P(iPACA), P(iPA-DMA), and PiPA as a function of temperature; 2D 1 H NOESY NMR spectrum of a mixture of P(iPA-DMA-CA) and β-CD; and Dh of aqueous solution of P(iPA-DMA) and PiPA in the presence of β-CD as a function of temperature. This material is available free of charge via the Internet at http://pubs.acs.org.

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CONCLUSIONS The CP of the cholic acid-containing polyacrylamides can be raised with the gradual addition of β-CD, which complexes with the CA pendant groups of the copolymers. The formation of host−guest complexes can tune the phase transition temperature of the bile acid-containing copolymers. To reverse this trend, a competing guest molecule, K-Ada, can be added to replace the cholic acid moieties as the guest and to restore the thermosensitivity of the polymers in the absence of the added host. Therefore, the thermoresponsive properties of such a polymer can be reversibly tuned by easily varying the ratios of guest and host molecules. Such a tuning of the CP may be interesting and useful in the design of thermoresponsive materials based on biological molecules such as bile acids and in the preparation of smart supramolecules or hydrogels.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from NSERC of Canada and FQRNT of Quebec is gratefully acknowledged. The authors are members of CSACS funded by FQRNT and GRSTB funded by FRSQ. The authors thank Mr. Sylvain Essiembre and Mr. Pierre Ménard-Tremblay for their technical support.

EXPERIMENTAL SECTION

All reagents were purchased from Aldrich and used without further purification 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) was distilled before use. Cholic acid-based methacrylate monomer (CA) was prepared as reported previously.42 Synthesis of Polymers. Copolymerization was conducted in N,N′-dimethylformamide (DMF) at 70 °C with a [comonomers]/ [AIBN] of 200:1. iPA (1.50 g, 13.274 mmol), DMA (438 mg, 4.424 mmol), CA (204 mg, 0.354 mmol), AIBN (21 mg, 0.128 mmol), and 5 mL DMF were added to a 25 mL round-bottom flask. The mixture was purged with N2 for 20 min prior to its immersion in a preheated oil bath. The copolymerization was allowed to proceed for 18 h before being quenched by immersion into ice−water. DMF was removed under reduced pressure and 5 mL of THF was added to dissolve the polymer. The precipitate was collected after pouring the reaction mixture into ethyl ether. The polymer was dried in vacuo to yield 1.95 g of P(iPA-DMA-CA) (91.0%). Polymer Characterization. Size exclusion chromatography (SEC) was performed on a Breeze system from Waters equipped with a 717 plus autosampler, a 1525 Binary HPLC pump, and a 2410 refractive index detector using two consecutive Waters columns (Phenomenex, 5 μm, 300 × 7.8 mm; Styragel HR4, 5 μm, 300 × 7.8 mm). The eluent DMF containing 0.05 M LiBr was filtered through 0.20 μm Nylon Millipore filters. The flow rate was 1 mL/min. Poly(methyl methacrylate) standards (2500−296 000 g/mol) were used for calibration. 1H and 13C NMR spectra in CDCl3 or D2O were recorded on a Bruker AV400 spectrometer operating at 400 MHz for 1 H and 100 MHz for 13C. The cloud points (CPs) of the samples in aqueous solutions were determined on a Cary 5000 UV−vis−NIR spectrophotometer (Agilent) equipped with a Cary temperature controller. Polymer aqueous solutions were normally heated at a rate of 0.5 °C/min and the CP was taken as the middle point of the transmittance change observed at 400 nm. Dynamic light scattering (DLS) measurements were performed on a Malvern Zetasizer NanoZS instrument (Malvern CGS-2 apparatus) equipped with a He−Ne laser with a wavelength of 633 nm, and the scattering angle was fixed at 173°. Intensity-average hydrodynamic diameters of the dispersions were obtained by DLS through the use of a non-negative least-squares (NNLS) algorithm. Disposable cuvettes were used and the suspensions were filtered through 0.2 μm Millipore filters to remove dust at 10 °C. The measurements were taken at every 2 °C after 2 min of equilibration time. All the CP measurements and DLS experiments were conducted in fresh Milli-Q water without pH control.

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dx.doi.org/10.1021/la5030873 | Langmuir 2014, 30, 11770−11775