Cooperation of Amphiphilicity and Crystallization for Regulating the

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Cooperation of Amphiphilicity and Crystallization for Regulating the Self-Assembly of Poly(ethylene glycol)-block-poly(lactic acid) Copolymers Zhen Wang,† Yuanyuan Cao,† Jiaqi Song,† Zhigang Xie,*,‡ and Yapei Wang*,† †

Department of Chemistry, Renmin University of China, Beijing 100872, China State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Science, Changchun 130022, China

‡

ABSTRACT: Tuning the amphiphilicity of block copolymers has been extensively exploited to manipulate the morphological transition of aggregates. The introduction of crystallizable moieties into the amphiphilic copolymers also offers increasing possibilities for regulating self-assembled structures. In this work, we demonstrate a detailed investigation of the self-assembly behavior of amphiphilic poly(ethylene glycol)-block-poly(L-lactic acid) (PEG-b-PLLA) diblock copolymers with the assistance of a common solvent in aqueous solution. With a given length of the PEG block, the molecular weight of the PLA block has great effect on the morphologies of self-assembled nanoaggregates as a result of varying molecular amphiphilicity and polymer crystallization. Common solvents including N,N-dimethylformamide, dioxane, and tetrahydrofuran involved in the early stage of self-assembly led to the change in chain configuration, which further influences the self-assembly of block copolymers. This study expanded the scope of PLA-based copolymers and proposed a possible mechanism of the sphere-to-lozenge and platelet-to-cylinder morphological transitions.

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INTRODUCTION

Increasing attention has been paid to studies of the morphological transition of nanoaggregates resulting from some crystalline−amorphous copolymers having relatively shorter crystalline blocks and longer amorphous blocks that routinely form starlike aggregates, e.g., polyferrocenyldimethylsilane (PFDMS)-based diblock copolymers,17 polyferrocenylsilane (PFS)-based diblock copolymers,18 poly(caprolactone) (PCL)-based diblock copolymers,19 and poly(acrylonitrile) (PAN)-based diblock copolymers.20 Exploiting other amphiphilic copolymers with different crystalline segments or amorphous−crystalline ratios could help us to understand the cooperation of crystallization and amphiphilicity in the process of self-assembly. As a biocompatible and biodegradable polymer, poly(lactic acid) (PLA) has been broadly studied for many biomedical applications.21−23 Undoubtedly, more expansive applications for PLA could be exploited if diverse morphologies were engineered on the basis of the self-assembly methods. For example, excellent self-assembly behaviors of poly(L-lactide)-b-poly(acrylic acid) (PLLA-b-PAA) in aqueous solution have aroused wide concerns about the popularization and application of PLA-based diblock copolymers.24,25 More studies of PLA-based block copolymers are expected as we seek to understand the contributions of crystallization and amphiphilicity to the self-assembly of this particular class of

The self-assembly of block copolymers (BCPs) has attracted tremendous attention in the past few decades and has shown enormous potential in a wide variety of fields on account of its intrinsic simplicity for creating diverse nanoaggregates with well-defined morphologies.1−4 The manipulation and regulation of self-assembled morphologies are at the forefront of devising nanomaterials with distinguished performance and exclusive functions. Several methodologies that aim to regulate self-assembly have been exploited depending on the type of BCPs. Traditionally, it has been broadly classified that the selfassembly of amorphous−amorphous (AA) block copolymers can be controlled by tuning the amphiphilicity.5−12 Great concern has recently been raised for the self-assembly of crystalline−amorphous (CA) block copolymers. In comparison with AA block copolymers, the introduction of a crystalline segment into CA copolymers allows more parameters, including internal factors affecting amphiphilicity and external factors affecting crystallization, to be employed for directing the controlled self-assembly.13−15 Correspondingly, the increased number of tuning factors renders possibilities to create selfassembled nanoaggregates with more complicated morphologies, such as star-shaped supermicelles and hierarchical architectures.16 The consideration of both amphiphilicity and crystallization within a self-assembly process is becoming a research focus for preparing supramolecular materials with spatiotemporal characteristics. © 2016 American Chemical Society

Received: June 13, 2016 Revised: July 30, 2016 Published: August 5, 2016 9633

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copolymers, where m and n refer to the number of repeating unit of the PEG block and PLLA block, respectively, were synthesized by ring-opening polymerization. In terms of a given PEG block length (m is 113 specifically), the total molecular weight and block ratio of each PEG-b-PLLA diblock copolymer could be estimated by the integral difference between protons of PEG and PLLA based on 1H NMR results. As summarized in Figure 1 and Table 1, several PEG-b-PLLA diblock copolymers with different weight percentages of PLLA ranging from 34 to 93% were obtained.

polymers, thus building a road map among PLA crystallization, molecular amphiphilicity, and self-assembly morphology. Unlike previous examples using a shorter crystalline segment, crystalline−amorphous copolymers with a longer crystalline segment enabling crew cut-like aggregates come into focus in this work. Herein, a family of block copolymers by linking the PLLA polymer with a given length of hydrophilic poly(ethylene glycol) (PEG) were synthesized. Specifically, the self-assembly behaviors of these PEG-b-PLLA copolymers were systematically compared. The self-assembly of PEG-PLLA in aqueous solution was tailored by a common solvent that was ultimately dialyzed away. The PLLA molecular weight exhibited a notable effect on the lozenge-to-cylinder morphological transition as a result of the varying chain configuration and polymer crystallization.

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EXPERIMENTAL SECTION

Materials. Analytically pure organic solvents N,N-dimethylformamide (DMF), dioxane, and tetrahydrofuran (THF) were purchased from Beijing Chemical Works. Poly(ethylene glycol) methyl ether (average Mn ≈ 5000) and stannous 2-ethylhexanoate were purchased from Sigma-Aldrich. PEG was dried via azeotropic distillation in toluene before use. L-Lactide (LLA, Purac) was recrystallized from ethyl acetate under an argon atmosphere. Toluene was dried and distilled from sodium/benzophenone under a nitrogen atmosphere before use. Synthesis of PEG-b-PLLA Block Copolymers. A series of PEGb-PLLA with different block ratios were synthesized according to the method of ring-opening polymerization. The detailed procedure can be found in previous work.26 Preparation of Nanoaggregates by Self-Assembly. A series of PEG-b-PLLA copolymers with different block ratios were dissolved in a common solvent for both blocks (DMF, dioxane, or THF) at a concentration of 0.1 wt %. Subsequently, deionized water (3.0 mL) at a certain flow rate was added dropwise to the PEG-b-PLLA solution (1.0 mL) by a syringe pump (LongerPump LSP02-1B) with stirring. The resulting solution was placed in a dialysis bag (molecular-weight cutoff of 3500) and dialyzed against deionized water for 1 week to remove the common solvent. The yielded nanoaggregates were kept in water (4.0 mL) for further characterization. The fluorescence probing nanoaggregates were obtained by following the same self-assembly process as stated above, except for the addition of fluorescein sodium (FNa, 0.1 mg/mL) to the initial polymer solution. The nanoaggregates were dialyzed adequately against water and dispersed in water (4.0 mL) for further fluorescence analysis. Characterization. Transmission electron microscopy (TEM) observations were carried out by using a Hitachi H-7650 transmission electron microscope at an acceleration voltage of 80 kV. TEM samples were prepared by dropping the aggregate solution onto carbon-coated copper grids. The samples were negatively stained with phosphotungstic acid (PTA) for better contrast. Electron diffraction (ED) was recorded by a transmission electron microscope (Tecnai G2 F20 UTWIN) operated at an accelerating voltage of 120 kV. The d spacing was calibrated using a TiCl standard. Atomic force microscopy (AFM) studies were conducted on a Bruker Dimension Icon. The samples were prepared by dropping aggregate solutions onto a freshly cleaned mica plate. Differential scanning calorimetry (PerkinElmer DSC8000) was used to determine the enthalpy change of nanoaggregates at the melting point. The solid nanoaggregate samples were obtained via centrifugation and lyophilization. Fluorescence spectra were recorded on a Hitachi F-7000 fluorescence spectroscope. The samples for fluorescence measurements were prepared by adding nanoaggregates loaded with FNa (0.5 mL) to DI water (3.5 mL).

Figure 1. 1H NMR spectra of PEG-b-PLLA block copolymers with different block ratios in CDCl3: (a) PEG113-b-PLLA922, (b) PEG113-bPLLA465, (c) PEG113-b-PLLA312, (d) PEG113-b-PLLA131, and (e) PEG113-b-PLLA36.

Table 1. Molecular Weight of PEG-b-PLLA molar ratio

molecular weighta

materials

EG/LLA

PEG

PLLA

f (%)b

PEG113-b-PLLA922 PEG113-b-PLLA465 PEG113-b-PLLA312 PEG113-b-PLLA131 PEG113-b-PLLA36

113/922 113/465 113/312 113/131 113/36

5000 5000 5000 5000 5000

66 400 33 500 22 500 9400 2600

93 87 82 66 34

a

Molecular weight is determined by 1H NMR in CDCl3. bWeight percent of the hydrophobic PLLA block in copolymers.

Effect of Block Ratio on the Morphologies of Nanoaggregates. Five block copolymers with different hydrophobic PLLA chain lengths yet constant hydrophilic PEG chain lengths (PEG113-b-PLLA922, PEG113-b-PLLA465, PEG113-b-PLLA312, PEG113-b-PLLA131, and PEG113-b-PLLA36) were exploited to discern the effect of block ratios on the morphologies of nanoaggregates resulting from their selfassembly (Scheme 1). In terms of amphiphilic feature of PEGb-PLLA, the copolymer is anticipated to act like a surfactant in self-assembling into particular nanoaggregates in water. However, the poor solubility of PLLA segment hinders the copolymer from being assembled straightforwardly. A typical assembly of PEG-b-PLLA copolymers is tailored by a common solvent of DMF for both blocks, which is also miscible with water. Random copolymers dissolved in the common solvent tend to aggregate their hydrophobic PLLA segments upon the gradual addition of water. The assembly process lasts until the formation of thermodynamically stable nanoaggregates and can be fully stopped upon the removal of common solvent.

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RESULTS AND DISCUSSION Synthesis and Characterization of PEG-b-PLLA Diblock Copolymers. A series of PEGm-b-PLLAn diblock 9634

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Langmuir Scheme 1. Schematic Illustration of the Formation of PEGmb-PLLAn Nanoaggregates in Aqueous Solution with the Help of a Common Solvent

As observed by TEM in Figure 2, the self-assembly of block copolymers with a different molecular weight of PLLA block produced several nanoaggregates with different morphologies. PEG113-b-PLLA922, PEG113-b-PLLA465, and PEG113-b-PLLA312 with a long hydrophobic block are self-assembled into welldefined lozenge platelet-like aggregates (Figure 2a−c). Lozenge platelets are still the main aggregates resulting from the selfassembly of PEG113-b-PLLA131, whereas some worm-like aggregates coexist with them (Figure 2d). With a further decrease in PLLA length, more worm-like aggregates with an even longer aspect ratio appeared within the aggregates of PEG113-b-PLLA36 (Figure 2e). Apparently, a tendency toward the morphological transition from a lozenge shape to worm-like cylinders is anticipated upon shortening the PLLA block of PEG-b-PLLA copolymers (Figure 2f). To gain further insight into the details of nanoaggregates, their height profiles are analyzed under atomic force microscopy (AFM) observation. As shown in Figure 3, the lozenge platelet-like aggregates resulting from PEG113-bPLLA922, PEG113-b-PLLA465, PEG113-b-PLLA312, PEG113-bPLLA131, and PEG113-b-PLLA36 have a thicknesses of 11.1 ± 1.1, 11.2 ± 1.2, 10.9 ± 2.1, 10.6 ± 1.2, and 10.8 ± 1.8 nm, respectively. The aggregate thickness seems to be independent of the block ratio, suggesting that PLLA segments of five copolymers have adopted a similar packing mode in the self-

Figure 3. AFM images (a−e) and AFM height profiles (f−j) of aggregates resulting from five different PEG-b-PLLA diblock copolymers with the use of DMF as the common solvent: (a) PEG113-b-PLLA922, (b) PEG113-b-PLLA465, (c) PEG113-b-PLLA312, (d) PEG113-b-PLLA131, and (e) PEG113-b-PLLA36.

Figure 2. TEM images (a−e) and phase diagram (f) of aggregates resulting from five different PEG-b-PLLA diblock copolymers with the use of DMF as the common solvent: (a) PEG113-b-PLLA922, (b) PEG113-b-PLLA465, (c) PEG113-b-PLLA312, (d) PEG113-b-PLLA131, and (e) PEG113-bPLLA36. 9635

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the PEG amorphous layer is enhanced because of the increased chain density. The PLLA crystallization, which is weakened at the same time, is not able to hold all of the polymer chains in the platelet-like aggregates. Instead, worm-like aggregates with higher interfacial curvature appear. As estimated in Figure 3d,e, the cylindrical aggregate is supposed to have a starlike crosssection consisting of the PLLA core and PEG corona (Figure 5d,e).31 The PEG amorphous layer is about 1−3 nm, and the core diameter of cylindrical aggregates is about 18 ± 2 nm. In terms of the increased interfacial curvature, the gap between PEG chains is enlarged to reduce the interchain repulsion. Effect of Common Solvent on the Self-Assembly of PEG-b-PLLA Copolymers. The common solvent involved in the early stage of self-assembly has a great impact on the dimensions of the PEG block by changing the solvation of the polymer chain, which is crucial to the morphology of aggregates.32 To investigate the solvent effect, THF was attempted as the common solvent to tailor the self-assembly of PEG-b-PLLA instead of DMF as used above. In comparison, the solubility parameter of THF is more similar to that of PEG than to that of DMF (Table 2). In this regard, the PEG block

assembly process. According to previous studies, ordered packing of PLLA segments as a result of folded chain crystallization is proposed to understand the formation of particular platelet-like aggregates with a specific thickness.27 As shown in Figure 4, a representative electron diffraction (ED)

Figure 4. (a) Selected area and (b) corresponding electron diffraction pattern of PEG113-b-PLLA465 aggregates.

observation was performed on the nanoaggregates resulting from the self-assembly of PEG113-b-PLLA465. Ordered hexagonal diffraction spots suggest the existence of a PLLA crystal regardless of PEG crystallization in a water medium.28,29 The crystalline PLLA segment takes a 10/3 helical conformation, and the length of each repeat unit Lm is theoretically estimated as 0.288 nm.27 The length of a fully extended PLLA chain can be worked out by eq 1, L = Lm N

Table 2. Solubility Parameter of Solvents and Polymers

(1)

where N is the degree of polymerization. In this regard, the PLLA segments involved in five block copolymers of PEG113-bPLLA922, PEG113-b-PLLA465, PEG113-b-PLLA312, PEG113-bPLLA131, and PEG113-b-PLLA36 have lengths of 265.5, 133.9, 89.9, 37.7, and 10.4 nm, respectively. The PLLA chains should be folded in a crystalline state because most of them have a length larger than the thickness of platelet-like aggregates. As proposed in Figure 5, the chains in the lozenge platelet are

materials

solubility parameter (δ) ([MPa]1/2)

DMF THF dioxane water PEG PLLA

24.934 19.534 20.534 47.834 20.535 19.335

has a stronger interaction with THF and occupies a larger stereoscopic space. The repulsion between adjacent PEG blocks is supposed to be enhanced, thus propelling the formation of the curvature.33 As shown in Figure 6a, some spherical aggregates with high interfacial curvature in addition to platelet-like aggregates were observed for PEG113-b-PLLA922. This morphological transition satisfies the assumption that the enhanced polymer solvation is superior to chain crystallization for directing the self-assembly. However, such a morphological transition was not observed for block copolymers with a shorter PLLA, including PEG113-b-PLLA465 and PEG113-b-PLLA312. They formed only lozenge-shaped platelet aggregates. It is assumed that increasing PLLA molecular weight may delay the chain crystallization because of the enhanced chain entanglement. As summarized in Table 3, the degree of crystallization of three block copolymers, including PEG113-b-PLLA922, PEG113b-PLLA465, and PEG113-b-PLLA312, was represented by the enthalpy change at the melting point. Three block copolymers were solvated in different solvents and precipitated in water, going through a process like their self-assembly as stated above. For each block copolymer, the enthalpy change at the melting point is larger upon solvation by DMF than by THF and dioxane. For a given solvent, especially THF, PEG113-b-PLLA922 possesses a smaller enthalpy change at the melting point than do PEG113-b-PLLA465 and PEG113-b-PLLA312, indicating that extremely long PLLA is not crystallized adequately. Further shortening PLLA, the solvation effect by THF is not remarkable in that cylindrical aggregates coexist with platelet-like aggregates, as under the condition of DMF (Figure 6d,e). In the cases of PEG113-b-PLLA131 and PEG113-b-PLLA36, it is hypothesized that the self-assembly is mainly determined by

Figure 5. Block copolymer and chain arrangement of aggregates: (a) PEG113-b-PLLA922, (b) PEG113-b-PLLA465, (c) PEG113-b-PLLA312, (d) PEG113-b-PLLA131, and (e) PEG113-b-PLLA36.

possibly arranged in a sandwich structure consisting of a thin core layer of crystalline PLLA and two PEG amorphous layers.30 As for block copolymers with a longer PLLA segment, PEG chains are distributed on the surface of PLLA layer sparsely (Figure 5a−c). The formation of platelet-like aggregates is mainly contributed by the folding of PLLA chains. When the PLLA block is shorter, the repulsion within 9636

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Figure 6. TEM images (a−e) and phase diagram (f) of aggregates resulting from five different PEG-b-PLLA diblock copolymers with the use of THF as the common solvent: (a) PEG113-b-PLLA922, (b) PEG113-b-PLLA465, (c) PEG113-b-PLLA312, (d) PEG113-b-PLLA131, and (e) PEG113-b-PLLA36.

To further confirm the above assumption about the cooperation of amphiphilicity and crystallization, another good solvent for dioxane to PEG was used as the common solvent in the process of self-assembly. Dioxane has an identical solubility parameter to that of PEG, which allows adequate solvation of the PEG block. The enhanced polymer amphiphilicity as a result of sufficient stretching of the PEG block is expected to decide the self-assembly of block copolymers more than chain crystallization. As shown in Figure 7a, PEG113-b-PLLA922 completely self-assembles into spherical aggregates. Unlike the self-assembly with the use of DMF or THF as the common solvent, PEG113-b-PLLA465 and PEG113-b-PLLA312 are also formed into spherical aggregates

Table 3. Enthalpy Change of Nanoaggregates at the Melting Point ΔHm (J/g) DMF THF dioxane

PEG113-b-PLLA922

PEG113-b-PLLA465

PEG113-b-PLLA312

47.6 40.6 41.3

52.2 50.5 48.8

53.7 50.9 49.7

polymer amphiphilicity. Enhancing PEG repulsion or weakening PLLA crystallization with a change in common solvent does not cause a change in polymer amphiphilicity.

Figure 7. TEM images (a−e) and phase diagram (f) of aggregates resulting from five different PEG-b-PLLA diblock copolymers with the use of dioxane as the common solvent: (a) PEG113-b-PLLA922, (b) PEG113-b-PLLA465, (c) PEG113-b-PLLA312, (d) PEG113-b-PLLA131, and (e) PEG113-bPLLA36. 9637

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conducted with the help of common solvents. Several welldefined morphologies were obtained via changing block ratios or common solvents. Shortening the PLLA block caused a morphological transition from lozenge platelets to cylindrical micelles as a result of the enhanced repulsion within the corona layer of the PEG block. From another perspective, common solvent with a solubility parameter close to that of the PEG block tailored the lozenge platelet−vesicle transition. The change in block ratios or common solvents was proven to have a considerable impact on the polymer amphiphilicity and chain crystallization. The cooperation between polymer amphiphilicity and chain crystallization is supposed to be crucial to the chain organization during self-assembly. This study provides new inspiration for predicting and controlling the self-assembly of amphiphilic block copolymers. It is envisioned that more crystalline−amorphous copolymers can be attempted for preparing particular nanostructures on demand via regulating the amphiphilicity and crystallization.

(Figure 7b and c). It should be noted that platelet-like aggregates are almost disappeared and only a few are observed in PEG113-b-PLLA312. Cylindrical aggregates are still dominant in the self-assembly of PEG113-b-PLLA131 and PEG113-bPLLA36. In general, the morphologies assembled by crystalline− amorphous copolymers are determined by the balance between the chain crystallization and the configuration of the corona layer. The chain crystallization leads to the formation of crystal nuclei that activate further growth of the crystal interior of selfassembled aggregates.17,32 On the other hand, the dimension of the corona layer, either stretched or collapsed, is greatly influenced by the common solvent. For PEG-b-PLLA, the contribution of polymer amphiphilicity is limited if PEG repulsion is not strong enough to overcome the crystallization effect, yet it is improved when PEG is solvated adequately. Once the amphiphilicity becomes the driving force to direct the self-assembly, the morphologies of self-assembled aggregates mainly rely on the block ratio between PEG and PLLA, e.g., spherical particles for block copolymers with longer PLLA or cylindrical aggregates for block copolymers with shorter PLLA. According to previous work, decreasing the hydrophilic/ hydrophobic ratio of amphiphilic block copolymers facilitates the formation of vesicle-like aggregates, and increasing the hydrophilic/hydrophobic ratio generally leads to micelles.1 The spherical aggregates appearing in Figure 7a−c are considered to possess vesicle-like structures, and the cylindrical aggregates in Figure 7d,e are composed of worm-like micelles. To verify the vesicle structure, a probing dye of fluorescein sodium was loaded into the system during the self-assembly of PEG113-bPLLA922, PEG113-b-PLLA312, and PEG113-b-PLLA36. After dialysis, much of the dye was retained in the solution of spherical aggregates of PEG113-b-PLLA922, whereas little was left in the aggregates of PEG 113-b-PLLA36 because of the remarkable decrease in fluorescence intensity. The high loading of water-soluble dye reveals that the spherical aggregates should possess vesicle structure with a water pool in the interior (Figure 8).

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (51373197, 21422407, and 20876169).

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REFERENCES

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CONCLUSIONS In summary, a class of crystalline−amorphous PEG-PLLA copolymers were synthesized, and their self-assembly was

Figure 8. Fluorescence spectra (λex = 485 nm) of nanoaggregates loaded with fluorescein sodium. Dioxane is used as the common solvent. 9638

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DOI: 10.1021/acs.langmuir.6b02211 Langmuir 2016, 32, 9633−9639