Tuning the Thermoresponsivity of Amphiphilic Copolymers via

Letter Cite This: ACS Macro Lett. 2019, 8, 357−362

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Tuning the Thermoresponsivity of Amphiphilic Copolymers via Stereocomplex Crystallization of Hydrophobic Blocks Xiaohua Chang, Hailiang Mao, Guorong Shan, Yongzhong Bao, and Pengju Pan* State Key Laboratory of Chemical Engineering, College of Chemical and Biological Engineering, Zhejiang University 38 Zheda Road, Hangzhou 310027, China

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S Supporting Information *

ABSTRACT: Thermoresponsive polymers that exhibit a cloud point temperature (Tcp) are an important class of stimuliresponsive polymers that have great potential for biomedical applications. Precise tuning of the Tcp is of fundamental importance for designing thermoresponsive polymers. However, tuning the Tcp generally requires sophisticated control over the chemical and assembled structures of thermoresponsive polymers. Here, we report a simple yet effective method to tune the Tcp of thermoresponsive polymers only by mixing and varying the mixing ratios of amphiphilic copolymer pair that contains L- and D-configured hydrophobic blocks in a dilute solution. Stereocomplex (SC) crystallization of the L- and D-configured blocks led to form core−shell micelles with a larger size, a bigger core, and a higher aggregation number, which facilitated the intermicellar aggregation upon heating due to improved intermicellar attractions. SC crystallization of the hydrophobic blocks improved the separation efficacy of the thermoresponsive copolymers for removal of hydrophobic pollutants from water.

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fraction of hydrophobic blocks or decreasing the fraction of hydrophilic blocks can decrease the Tcp. The hydrophobic/ hydrophilic block ratio can also be tuned by other stimuli, such as ions,19 pH, and light.20 Besides, control over of the Tcp can also be achieved by mixing different thermoresponsive polymers21−23 or varying the size of thermoresponsive colloid particles.24 Generally, thermoresponsive (co)polymers undergo hierarchical structural changes during the thermally induced phase transition, which can be induced by structural changes of the (co)polymer assemblies.25,26 Core−shell micelles are the most common assemblies of thermoresponsive amphiphilic (co)polymers. Control over assembled structures of (co)polymers, which depends on the copolymer composition, has also been demonstrated to be effective for tuning the Tcp.25,26 However, almost all of the reported methods for tuning the Tcp require sophisticated syntheses of parent (co)polymers or the precise design of complicated assembled structures. Herein, we report a simple yet effective method for tuning the Tcp of thermoresponsive copolymers in dilute aqueous solution by mixing the enantiomeric copolymer pair bearing the L- and D-configured hydrophobic blocks or varying their mixing ratios. We used random graft copolymers containing

timuli-responsive materials have gained significant attention due to their great potential in biomedical applications and nanotechnology.1−3 Self-assembling systems, such as copolymer micelles, are assemblies with a morphology that usually exhibit an observable response upon a change in the external stimuli.4−6 Temperature is one of the most commonly used stimuli among many. Some thermoresponsive polymers exhibit a change in turbidity at a specific temperature, which is commonly referred to the cloud point temperature (Tcp) or lower critical solution temperature (LCST).7,8 A representative, well-studied thermoresponsive polymer is poly(Nisopropylacrylamide) (PNIPAM), which exhibits a Tcp close to body temperature;9,10 however, its application is impacted by suspected toxicity. Recently, several types of biocompatible, thermoresponsive (co)polymers, such as poly(oligo(ethylene glycol) (meth)acrylate)s [POEG(M)A],11−13 poly(oligo(ethylene glycol) vinyl acetate),14 poly(vinyl ether),15 and poly(2-oxazoline)s,16−18 have been developed for applications in biomedical fields. Because the physical properties and functions of thermoresponsive (co)polymers generally vary abruptly with the Tcp, the Tcp is a critical parameter for their practical application, and the precise tuning of the Tcp is of fundamental importance in designing thermoresponsive (co)polymers. A common way to tune the Tcp of thermoresponsive (co)polymers is by varying hydrophobic/hydrophilic block ratios.12,18 Increasing the © XXXX American Chemical Society

Received: February 20, 2019 Accepted: March 12, 2019

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DOI: 10.1021/acsmacrolett.9b00125 ACS Macro Lett. 2019, 8, 357−362

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Figure 1. (a) Synthesis of EG-L and EG-D copolymers. (b) Schematic illustration of core−shell structure and thermally induced aggregation of EG-L/EG-D enantiomerically mixed micelles.

volume fractions at 25 °C. For simplicity, the mass fraction of EG-D (0−1) in the copolymer mixtures is denoted as mD. The EG-L and EG-D homochiral copolymers and their mixtures formed micelles in aqueous solution. As measured by dynamical light scattering (Figure 2a), the hydrodynamic radii

oligo(ethylene glycol) and chiral poly(L-lactic acid) (PLLA) or poly(D-lactic acid) (PDLA) grafts as the enantiomeric copolymer pair (Figure 1a). PLLA and PDLA were used as the complementary stereoisomer pair that could form stereocomplex (SC) crystallites,27 both of which were biocompatible, biodegradable, and widely used as the hydrophobic blocks of copolymer micelles. As illustrated in Figure 1b, the copolymers containing either L- or D-configured hydrophobic blocks self-assembled into thermoresponsive micelles in aqueous solution. SC crystallization occurred inside the micelle core in the enantiomeric mixture of the L- and Dconfigured copolymers, and this led to a decrease in the Tcp. We further demonstrated that the crystallization-induced decrease of Tcp was caused by the formation of micelles with a larger size, a larger and denser core, which had a stronger intermicellar attraction and aggregated more easily upon heating. Copolymers bearing PLLA and PDLA grafts are denoted as EG-L-MPLA and EG-D-MPLA, where EG denotes oligo(ethylene glycol), L and D represent PLLA and PDLA, respectively, and MPLA denotes the mass fraction of PLLA or PDLA. EG-L and EG-D were synthesized via the atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) methyl ether methacrylate (OEGMA, Mn = 300 g/mol) and the PLLA or PDLA macromonomer with a degree of polymerization of ∼15. Synthesis of PLLA or PDLA macromonomer was elaborated in Supporting Information (Figures S1 and S2, Table S1). Successful syntheses of the enantiomeric copolymers with a controlled molecular weight (Mn ∼ 20 kg/mol), composition (MPLA = 0.3 and 0.5), and narrow dispersity (Đ < 1.3) were confirmed via SEC and NMR (Table S2, Figures S3 and S4). MPLA measured by NMR agreed well with that in feed (Table S2). Through analyzing the composition of copolymers with different monomer conversions, the random distribution of OEGMA and PLA monomer units in the synthesized copolymers (Figure S5, Table S3) was confirmed. To prepare the dilute aqueous solutions, EG-L and EG-D were separately dissolved in tetrahydrofuran; then, the solvent was switched to deionized water. The solutions of EG-L and EG-D with the same concentrations (0.5 wt %) were mixed at different

Figure 2. Micelle structure and thermoresponsive behavior of the EGL-0.3 and EG-D-0.3 copolymers and their mixtures in dilute solution (0.5 wt %): (a) distribution of Rh, (b) WAXD patterns of freeze-dried micelles, (c) temperature-dependent transmittance, and (d) Tcps of the enantiomeric mixtures for different mDs.

(Rh) of the homochiral and enantiomerically mixed copolymers showed a single and narrow peak. The Rh of the EG-L-0.3 and EG-D-0.3 homochiral copolymers was ∼17 nm, which increased to 34 nm for the EG-L/D-0.3 (mD = 0.5) mixture (Figure S7). This was in agreement with the mean size measured by transmission electron microscopy (Figure S8). As shown in Figure 2b, the wide-angle X-ray diffraction (WAXD) pattern of the EG-L and EG-D homochiral micelles did not show any sharp diffraction, indicating that both the core and 358

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Figure 3. SAXS results for the EG-L/D-0.3 enantiomeric mixture in dilute solution (0.5 wt %). (a) SAXS patterns for the enantiomeric mixtures with various mD values collected at 20 °C; (b) changes in Rg and Nagg with mD; (c) changes in Rc and Ls with mD; (d) changes in ρc and SPEG with mD; (e) temperature-dependent SAXS patterns for the enantiomeric mixture with mD = 0.3; and (f) changes in Rc and Ls with temperature for the enantiomeric mixture with mD = 0.3.

structure, the core−shell structures of various micelles in dilute solution were analyzed by synchrotron radiation small-angle Xray scattering (SAXS). Figure 3a shows the representative SAXS profiles of micelle solutions (0.5 wt %) of homochiral copolymers and their mixtures. Analyses of the SAXS data are detailed in the Supporting Information. As shown in Figure 3b, the radius of gyration, Rg, of the micelles increased from 8.6 to 9.6 nm, and the aggregation number (number of copolymer chains per micelle), Nagg, increased from 72 to 153 as mD increased from 0 to 0.5 in the EG-L/EG-D-0.3 mixture. This indicated that SC formation inside the micelle core drove more copolymer chains to associate into one micelle, leading to the formation of larger micelles. To examine the precise micelle structure, the core radius, Rc, and shell thickness, Ls, of the micelles were determined by fitting the SAXS data via a core−shell spherical model (Supporting Information).30 As shown by the solid lines in Figure 3a, good fits were obtained for all the micelles of various EG-L/D mixing ratios. As shown in Figure 3c, Ls remained nearly constant at ∼0.6 nm when all the copolymers contained the same PEG grafts. Ls was comparable to the length of PEG with Mn = 300 g/mol.31,32 Rc increased as mD approached 0.5 or with an enhancement in the SC crystallinity, which was consistent with the Nagg result. Therefore, the crystallizationinduced increase in micelle size originated from the core part. Based on the structural parameters of micelles, we further calculated the chain packing density in the micelle core, ρc, and the average area occupied by each PEG chain on the core− shell interface, SPEG. As shown in Figure 3d, ρc increased from 0.47 to 0.62 g/cm3, and SPEG decreased from 9.0 to 5.9 nm2/ chain as mD varied from 0 to 0.5, demonstrating that SC crystallization drove the more compact packing of the hydrophobic blocks in the micelle core and the denser grafting of PEG on the core−shell interface. The intermolecular Hbond interactions in SCs promoted more compact packing of enantiomeric chains.28 Additionally, the stronger hydrophobic association induced by the higher Nagg also caused more compact chain packing in the micelle core.

shell of the freeze-dried micelles were not crystallized. However, the micelle core was crystallized in the EG-L/D mixed micelles, and the crystallinity could be controlled by the mixing ratio. A diffraction peak was observed for the EG-L/D mixed freeze-dried micelles (Figure 2b) and micelle solution (Figure S9a) at 2θ = 9.6°, which is characteristic of SCs. The diffraction intensity of the SCs increased as mD approached 0.5, indicating an increase in the crystallinity. SC crystallization in the micelle core of the enantiomerically mixed copolymers was also confirmed by the FTIR spectra, in which the carbonyl stretching band of the PLLA/PDLA blocks shifted from 1760 to 1750 cm−1 as mD increased from 0 to 0.5 (Figure S9b).28 The critical micelle concentration (CMC) of the copolymer micelles decreased from 4.4 to 3.1 mg/L, as the mD increased from 0 to 0.5, meaning that the formation of SCs enhanced the stability of the assembled micelles (Figures S10 and S11). The EG-L and EG-D copolymers and their mixtures were thermoresponsive in aqueous solution. As shown in Figure 2c, the solutions were all transparent at low temperature but became turbid upon heating. The temperature corresponding to a transmittance of 90% is designated as the Tcp.29 The Tcps of EG-L-0.3 and EG-D-0.3 copolymers were almost the same (52.6 and 52.9 °C). As shown in Figure 2c,d, the Tcp decreased when the EG-L and EG-D solutions were mixed. Tcp decreased gradually as mD changed from 0 (or 1) to 0.5, even though the fraction of the hydrophobic block, MPLA, remained the same upon mixing. The EG-L/D-0.3 racemic mixture (mD = 0.5) had the lowest Tcp of 47.1 °C. Therefore, Tcp could be tuned only by varying the mixing ratio of theL- and D-configured copolymers, which controlled the degree of crystallization. Similar dependence of Tcp on the mixing ratio was also observed for enantiomeric copolymers with a large MPLA of 0.5 (Figure S12). Except for the turbidity change, no obvious precipitate was observed when the solutions of EG-L, EG-D and their mixtures were heated to above Tcp. Different Tcps for the homochiral and enantiomerically mixed copolymers originated from their different micelle structures. To elucidate the effect of SC formation on micellar 359

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Since SC crystallization led to increases in the Rc, Nagg, and ρc, the enantiomerically mixed micelles aggregated more easily than the homochiral ones upon heating due to the stronger van der Waals attractions between adjacent micelle particles,35,38 which were proportional to the weights of the particles. The positive value of ε (i.e., smaller DHS than Dtot) indicated that the PEG shells overlapped with each other when the micelles aggregated. In the overlapping region, the polymer chains interpenetrated to squeeze out some solvent molecules, producing effective attractions at the micellar surface in addition to the excluded volume repulsion.34 On the other hand, the decrease of SPEG in enantiomerically mixed micelles (Figure 3d) indicated an increase in the crowding of polymer chains in the micelle shell. This crowding would increase the polymer−polymer interactions and thus lower the Tcp.24 Additionally, SC crystallization of the hydrophobic blocks caused a higher interchain entanglement and intermicellar physical cross-linking, which were promoted at high temperature.39−41 Because hydrophobic interiors can encapsulate hydrophobic molecules, the thermally induced aggregation of micelles can be used for the separation of hydrophobic pollutants from water by filtration or centrifugation above Tcp.42,43 As a proof of concept, Nile red was chosen as a model pollutant to be removed from water. By simply heating the micelle solution from 25 to 60 °C, the solution was filtered through a microporous film (0.45 μm) at different temperatures. As shown in the emission spectra (Figure 4a,b), the copolymer

To illustrate the mechanism of crystallization-tuned thermoresponsivity, we detected the structural transition of the copolymer micelles upon heating with synchrotron radiation SAXS. Figure 3e depicts the SAXS profiles of the EG-L/D-0.3 (mD = 0.3) micelles during heating. The SAXS profiles changed little with temperature below Tcp, implying that the dispersed micelles were stable and absent of notable intermicellar associations. However, the SAXS profiles varied upon heating to above Tcp (≥50 °C), where the I(q) ∼ q slope at a low q increased, and a correlation peak was present at q = 0.4 nm−1 at 70 °C. The appearance of correlation peak indicated the occurrence of intermicellar aggregation and the strong interactions between micelles.31 To quantitatively analyze the thermally induced structural changes of the micelles, SAXS profiles collected below Tcp (≤45 °C) were fitted by the spherical core−shell model. Structural factor, S(q), was included in the fitting model when handling the SAXS data measured above Tcp (≥50 °C). A sticky hard sphere (SHS) model, that is, Baxter model,33 which describes the interactions between hard spheres with adhesive surfaces of interpenetrating polymer chains between neighboring micelles, was used as S(q) in this study. SHS model has been widely used to analyze the intermicellar interactions of aggregated micellar systems.32,34,35 As detailed in the Supporting Information, the intermicellar interactions and perturbation in the SHS model were reflected by parameters τ and ε. The reciprocal of τ is the stickiness, which represents the strength of adhesion.33 A smaller τ means stronger intermicellar interactions. The perturbation parameter, ε, is defined as (Dtot − DHS)/Dtot, where Dtot [Dtot = 2(Rc + Ls)] and DHS are the total diameters of the spherical core−shell particles and the diameter of the hard-sphere interaction distance (Figure 1b),36 respectively. A larger ε means greater penetration between the shell layers of neighboring micelles (i.e., smaller intermicellar distance). As shown in Figure 3f, Rc for the EG-L/D-0.3 (mD = 0.3) mixed micelle increased from 8.0 to 9.3 nm, while its Ls stayed nearly constant (∼0.6 nm) upon heating from 20 to 70 °C. This indicated that the core−shell micelle structure was preserved and did not disassociate upon heating. The τ values of the EG-L/D-0.3 (mD = 0.3) micelles were 2.15, 1.17, and 0.073, and their ε values were 0.008, 0.015, and 0.026 at 50, 60, and 70 °C, respectively. The decrease in τ and increase in ε with temperature demonstrated an enhancement in the intermicellar interactions and penetration with heating. Similar tendency was also observed for the homochiral and enantiomerically mixed micelles for other mD values (Figure S13). At the same temperature above Tcp, the intermicellar interactions and penetration enhanced with increasing crystallinity of the micelle core. As shown in Figure S14 and Table S4, at 70 °C, the correlation peak for the SAXS profile increased in magnitude; τ decreased from 5.25 to 0.065, and ε increased from 0.003 to 0.037 as mD varied from 0 to 0.5. However, Rc increased, and Ls stayed nearly constant as mD varied from 0 to 0.5, similar to the results measured below Tcp (Figure 3c). Based on these SAXS results, the thermoresponsivity of both homochiral and enantiomerically mixed copolymers was due to intermicellar aggregation at high temperature. This was also supported by the fluorescence results (Figure S15) in which the fluorescence intensity ratio decreased with heating due to the aggregation-induced quenching of the fluorescence.37

Figure 4. Fluorescence results for the copolymer micelles in dilute solution (0.5 wt %) with the presence of Nile red. (a) Temperaturedependent fluorescence spectra of EG-L-0.5 homochiral micelles; (b) temperature-dependent fluorescence spectra of EG-L/D-0.5 (mD = 0.5) enantiomerically mixed micelles; (c) fluorescence intensity difference between the micelle solutions measured at a certain temperature and 25 °C; and (d) separation efficacy of removing Nile red for copolymer micelles at 50, 55, and 60 °C.

solution had a strong fluorescence below Tcp, further demonstrating the formation of the micelle. However, the fluorescence intensities dropped with heating due to the gradual removal of Nile red. The maximum fluorescence intensity (at 630 nm) differences between the measured temperatures and 25 °C was plotted as a function of 360

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WAXD were measured at the BL19U2 and BL16B1 beamlines of SSRF, respectively.

temperature in Figure 4c. For both the homochiral and enantiomerically mixed micelles, the fluorescence intensity abruptly decreased after filtration above the Tcp, indicating that most of the Nile red was removed. Furthermore, the thermally induced fluorescence decrease for the enantiomerically mixed micelle was more distinct than that of the homochiral one. The separation efficacy of removing Nile red for the homochiral and enantiomerically mixed micelles were quantitatively evaluated (Figure 4d), as elaborated in Supporting Information. Separation efficacy depended strongly on the crystalline state of micelle core. At 50, 55, and 60 °C, the separation efficacies of enantiomerically mixed micelles were 68.8%, 81.3%, and 85.1%, while these values decreased to 46.4%, 63.1%, and 68.4% for the homochiral micelles, respectively. Therefore, SC crystallization in the micelle core improved the separation efficacy of copolymers above Tcp for the removal of hydrophobic pollutants from water, originating from the formation of larger micelles and the enhanced intermicellar aggregation above Tcp. In summary, we found a simple and effective method to tune the Tcp of thermoresponsive copolymers only by mixing L- and D-configured copolymers in dilute solution; the mixing ratio of the enantiomeric pair controlled the degree of SC crystallization of the hydrophobic blocks. The mechanism for the crystallization-tuned Tcp was elucidated. SC crystallization of the hydrophobic blocks led to formation of micelles with a larger core, Nagg, and ρc but a smaller SPEG, which facilitated the aggregation between micelles above Tcp due to improved intermicellar attractions. The SC crystallization in the micelle core also improved the separation efficacy of thermoresponsive copolymers for the removal of hydrophobic pollutants from water. Thus, besides the chemical structure, precise control over the physical structure (or condensed matter structure) of colloid particles is essential and effective for designing responsive micelle materials for practical applications.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.9b00125.

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REFERENCES

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Experimental details and characterization data (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Guorong Shan: 0000-0001-5676-6310 Pengju Pan: 0000-0001-6924-5485 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial supports of Natural Science Foundation of Zhejiang Province, China (LR16E030003) and Natural Science Foundation of China (21422406). SAXS and 361

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DOI: 10.1021/acsmacrolett.9b00125 ACS Macro Lett. 2019, 8, 357−362