Asymmetric Polymersomes from an Oil-in-Oil Emulsion: A Computer

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Asymmetric Polymersomes from Oil-inOil Emulsion: a computer simulation study Shanlong Li, Yinglin Zhang, Hong Liu, Chunyang Yu, Yongfeng Zhou, and Deyue Yan Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b02411 • Publication Date (Web): 31 Aug 2017 Downloaded from http://pubs.acs.org on September 5, 2017

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Asymmetric

Polymersomes

from

Oil-in-Oil

Emulsion: a computer simulation study Shanlong Li,a Yinglin Zhang,a Hong Liu,b Chunyang Yu*a, Yongfeng Zhou*a and Deyue Yana aSchool

of Chemistry & Chemical Engineering, State Key Laboratory of Metal Matrix

Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China, 200240. bInstitute

of Theoretical Chemistry, State Key Laboratory of Supramolecular Structure and

Materials, Jilin University, Changchun, China, 130021. KEYWORDS: asymmetric polymersome, dissipative particle dynamics, oil-in-oil emulsion

ABSTRACT: Asymmetric vesicles are valuable for understanding and mimicking the cell and practical biomedicine applications. Recently, a very straightforward methodology for fabricating asymmetric polymersome was developed by Lodge group through co-assembly of polystyrene-bpoly(ethylene oxide) (PS-b-PEO) and polybutadiene-b-poly(ethylene oxide) (PB-b-PEO) block copolymers at the interface of polystyrene/polybutadiene/chloroform (PS/PB/CHCl3) emulsion. However, the in-depth microscopic mechanism for the formation of asymmetric polymersomes remains unclear. To address this issue, in this paper, the co-assembly process for the formation of the asymmetric polymersomes in Asano’s experimental system was systematically investigated by employing dissipative particle dynamics (DPD) simulation. Our results definitely demonstrate the formation of the asymmetric polymersomes like that in the experiments, and that the bilayer formed through the folding and crossing each other of the PEO blocks. Besides, at the

1 ACS Paragon Plus Environment

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microscopic view, three stages can be discerned in the formation process: (1) the formation of micelles; (2) the micelles diffuse to the interface; (3) the micelles rearrange at the interface to form the asymmetric polymersome. Meanwhile, the incompatibility between PS, PB and PEO is proved to be the main driving force for asymmetric polymersome formation. Moreover, the effect of addition order of copolymers and the volume fraction of PEO blocks on the structure of the asymmetric polymersomes are also investigated. We find that the formation process is affected severely by the addition order, and adding PS-b-PEO first can make the asymmetric bilayer more perfect. Not only that, the perfect asymmetric polymersomes can only be formed when the volume fraction of PEO (fPEO) is greater than 0.55. We believe the present work can extend the knowledge on the self-assembly of asymmetric polymersomes, especially on the selfassembly mechanism.

1. INTRODUCTION

The compositional asymmetry is a key chemical feature of the eukaryotic plasma membrane, which means the two leaflets of the bilayer in biomembranes contain different lipids

1-3

to

maintain a different environment on cytosolic and extracellular sides. The membrane asymmetry plays a significant role in cell functions, such as cell morphogenesis2, vesicle formation4, 5, transmembrane interaction6, 7 and cell communication8. As an artificial model of the cell membrane, the synthetic asymmetric vesicles have attracted great interest in recent years. Many studies have shown that the asymmetric vesicles have unique properties in some application areas9-12, especially in biomedicine applications, like drug delivery13, 14 and control release15. Therefore, it is crucial to conveniently prepare synthetic asymmetric membrane for understanding and mimicking the cell and practical biomedicine applications.


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Up to now, several strategies have been developed to fabricate asymmetric vesicles. The first one was named as “inverse emulsion method” which was developed by Zhang et al.16 , Xiao et al.17 and Pautot et al.18, 19. In the method, they transferred water-in-oil emulsions across a wateroil interface to fabricate asymmetric liposomes. The water-in-oil emulsions were stabilized by the first lipid leaflet and the second lipid leaflet was formed at the interface between bulk water and bulk oil. While transferring across the second leaflet interface, the first one converts into asymmetric bilayer. Another approach to fabricate asymmetric vesicle is by employing microfluidics. For example, Fletcher et al20, 21 built asymmetric vesicles by using microfluidic jetting, in which they jet micro volumes of liquid through an asymmetric bilayer. Two water-inoil droplets containing different kinds of small vesicles were brought in contact to form an asymmetric bilayer. Then ejected the aqueous phase droplet across the bilayer resulted in an asymmetric vesicle. Paegel et al22 developed a microfluidic layer-by-layer assembly method, which was originated from layer-by-layer assembly19. The inner leaflet formed at the interface to stabilize the water droplets in oil of lipid 1. The outer leaflet assembled while replacing oil-lipid 1 by oil-lipid 2, followed flushing with an aqueous phase resulting in asymmetric vesicle. Because of the excellent controllability and designability of microfluidics system, the control of vesicle size and membrane composition becomes much easier, and various asymmetric vesicles can be designed. Recently, Asano et al. reported a facile route to fabricate asymmetric polymersomes by coassembly of AC (PS-b-PEO) and BC (PB-b-PEO) block polymers in oil-in-oil emulsions23, 24. In their works, two mutually immiscible block copolymers PS (15 wt%) and PB (15 wt%) were first dissolved in CHCl3 (70wt%) to fabricate oil-in-oil emulsions. Then by blending 0.5 wt% of both PS-b-PEO (SO) and PB-b-PEO (BO) in the oil-in-oil emulsions, SO and BO could assemble into


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polymersomes at the interface. In consideration of the evidence of confocal fluorescence microscopy (CFM), the authors inferred that the polymersomes featured asymmetric bilayer due to the immiscibility among PS, PB and PEO. It can be seen that in this work the formation of asymmetric polymersomes is very simple just by mixing different polymers in CHCl3. In addition, it’s straightforward to synthesize various diblock copolymers and convenient to tune their stoichiometry25, so this approach would be a particularly attractive and promising methodology to prepare multifunctional asymmetric polymersomes with different compositions. However, despite this experimental progress, the in-depth microscopic mechanism of the asymmetric polymersomes formation is still not clear. For example, how do the polymers coassemble into an asymmetric bilayer in microscopic view? What is the fine structure of asymmetric bilayer? What is the effect of fPEO on the aggregation behaviors? Insight into these problems will be favorable to extend this simple strategy widely. Owing to the fast dynamics, experimental studies on the co-assembly behaviors are restricted, while molecular simulation can provide valuable microscopic insights to experiments. For mesoscopic simulations of macromolecular morphological expressions, dissipative particle dynamics (DPD) simulation is currently the most popular simulation method for relevant length and time scales. It has been successfully applied to study self-assembly of macromolecules, such as self-assembly of vesicle26-28, micelle29-33 and nanotube34,

35

and morphology transition of

aggregates15, 36, 37. For example, Yamamoto and Hyodo studied the dynamic behavior of twocomponent vesicles38. Li and coworkers investigated the dynamic process of amphiphilic diblock copolymer vesicles39. Lu and co-workers studied the complex structure transitions of vesicles formed by comb-like block copolymers40. Liang and co-workers explored plenty kinds of amphiphilic triblock copolymer vesicles41. Sheng and co-workers investigated multilayered


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polymersome formed by amphiphilic asymmetric macromolecular brushes42. Our group revealed that amphiphilic hyperbranched polymers could self-assemble into vesicles through the bending of membrane30, 43-45. These successful works indicate that DPD simulation is a very promising method to investigate the self-assembly behaviors of amphiphilic polymers. In this article, the co-assembly of SO and BO at the interface of PS/PB/CHCl3 emulsion was systematically investigated by employing DPD simulations. As a proof to support experiments, the simulation results definitely demonstrate the formation of the asymmetric polymersomes. Moreover, detailed mechanism analyses indicate that three stages can be summarized during the formation of asymmetric polymersomes. In the meanwhile, the effects of addition order of copolymers and PEO volume fraction on the structure of asymmetry polymers were disclosed in detail. This work has provided an in-depth microscopic understanding on the asymmetric polymersomes. The article is organized as follows. The description of DPD simulation method is shown in Section 2. Section 3 contains three parts: (1) the co-assembly mechanism, (2) the effect of addition order of copolymers, and (3) the effect of PEO volume fraction. Finally, conclusions are given in Section 4. 2. EXPERIMENTAL SECTION The dissipative particle dynamics (DPD) method employed in this work is a particle-based mesoscale simulation technique that includes explicit solvents. It was first introduced by Hoogerbrugge and Koelman46 in 1992 and improved by Español and Warren47. In DPD method, one bead represents a group of atoms. The bead’s internal degrees of freedom are integrated out and replaced by converse pairwise dissipative and random forces. The detailed fundamental of DPD method was described in supporting information.


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System Parameters. As with the system studied by Asano et al23, there are PS, PB, SO and BO in CHCl3. The number-average molecular weights (Mn) of PS and PB are 9 kg/mol and 8 kg/mol, respectively. The diblock copolymers are respectively denoted as SO(x−y) and BO(x−y), where x represents Mn (kg/mol) of S or B block, and y represents Mn (kg/mol) of O block. In this work, the co-assembly of SO(9-33) and BO(8-35) in CHCl3 are the main objects of study as same as those used in the experiment. Therefore, there are four different species of DPD beads (Figure 1) which are cyan CHCl3 beads (W), yellow PS block beads (S), light blue PB block beads (B) and red PEO block beads (O). Table 1 lists the monomer volume and density of each component. Based on the equal volume assumption in DPD method, one W bead represents 10 CHCl3 molecules, while one S, B and O bead respectively represent 8 styrene monomers, 13 butadiene monomers and 23 ethylene oxide monomers. Thus, the diameter of one DPD bead in the current study is equal to about 13.6 Å.

Figure 1. Scheme diagrams of the realistic molecule structure and its corresponding DPD beads for CHCl3(W), PS(S), PB(B) and PEO(O). The repulsive interaction parameters (aij in eq S3) can be estimated from the χ-parameter in Flory-Huggins theory according to the study of Groot and Warren48 as equation S8. In this article, the χ-parameters between different species were estimated from the Blends module of Materials Studio49 from Accelrys Inc by using the COMPASS force field50. All the chosen parameters are


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shown in Table 2. We can see clearly that PS, PB and PEO are all miscible with CHCl3 while every two species are immiscible. Table 1. Monomer volume and density of each component. CHCl3 (W)

PS (S)

PB (B)

PEO (O)

Vmonomer (cm3/mol)

81.0

98.3

61.5

34.6

Density(g/cm3)

1.49

1.06

0.91

1.27

Table 2. Interaction parameters aij and χij (in parentheses) chose in this article. aij(χij)

CHCl3 (W)

CHCl3 (W)

25.00 (0.00)

PS (S)

25.18 (0.06)

25.00 (0.00)

PB (B)

26.16 (0.35)

43.85 (5.76)

25.00 (0.00)

PEO (O)

26.59 (0.49)

38.40 (4.10)

55.63 (9.37)

PS (S)

PB (B)

PEO (O)

25.00 (0.00)

Finally, all the DPD simulations were carried out in the NVT ensemble in a cubic box (60 × 60 × 60) under periodic boundary conditions. The system density is set to 3. For simplicity, the cutoff radius Rc, the bead mass m, and the temperature kBT are taken as the units of the simulations, i.e., Rc=m=kBT=1; thus, the time unit τ= (mRc2/kBT)1/2=1. Corresponding to the real system, a cube of volume Rc3 represents ρNm water molecules, and the physical volume of this cube equals 30 ρNm Å3. So, the length scale follows as Rc = 3.107(ρNm)1/3 [Å] = 15.8 Å. Integrated with a modified velocity-Verlet algorithm48 with ∆t = 0.02 and λ = 0.65, each simulation takes at least 2 × 106 time steps, and the first 2 × 105 time steps are for equilibration. Also, a series of simulations with different random seeds and for various box sizes were


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performed. It shows that the results are reproducible. All DPD simulations were carried out by using HOOMD package51, 52, and all figures of the molecular structures were created using the VMD program (v.1.9.3)53. 3. RESULTS AND DISCUSSIONS A. Phase Separation of PS and PB in CHCl3. Owing to the immiscibility, two phases would form while both PS and PB are dissolved into CHCl3 as observed in the experiment. Therefore, systematic studies of phase separation behavior were performed firstly in this work to verify the validity of the chosen parameters. Consistent with the experiment, the simulation system was composed of PS/PB/CHCl3 with 15/15/70 (wt%) of each component, and the corresponding number ratio was 18.4/21.5/60.1 (at%). As shown in Figure 2a, PS and PB aggregate separately and finally separated into two layer phases.

Figure 2. Phase separation of PS and PB in CHCl3 with various ratio; (a) Lamellar phase separation with 19/21 (at%); (b) PS-in-PB emulsion with 10/30 (at%); (c) PB-in-PS emulsion with 30/10 (at%). The yellow and light blue beads are PS and PB, respectively, and the CHCl3 beads are omitted for clarity. In experiments, the oil-in-oil emulsion was fabricated through stirring. In our simulation, the stirring process was mimicked by changing the ratio of the particle number of PS and PB. As can be seen in Figure 2b and 2c, the reduction of PS results in the formation of PS-in-PB emulsions


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in CHCl3 at the ratio of 10/30 (at%), while PB-in-PS emulsions can be formed at the ratio of 30/10 (at%). It should be noted that all the emulsions can be stable in CHCl3. Besides, there always exist about 2% PS in PB-rich phase or 2% PB in PS-rich phase, which is consistent with the experiments. It is quite remarkable that our simulation can well reproduce the experimental observation. Quantitatively, interfacial tension (IFT) was calculated (as shown in Figure S1) to describe the interfacial properties. The computing method of IFT can be seen in the supporting information. The obtained IFT value for PS/PB/CHCl3 system is 0.30 in DPD units, which corresponds to 0.49 mN/m in the real physical units. In contrast, the IFT value for PS/PB bulk system without solvent is 4.01, which corresponds to 6.59 mN/m. Evidently, the PS/PB/CHCl3 emulsion is a particular system with very low interfacial tension. Moreover, the interfacial density distribution was also studied to characterize the structure of the emulsion further, as shown in Figure S1b and S1d. According to the “90-90” criterion54 in which the interfacial thickness is defined as the distance between two positions where the densities of PS and PB reaches 90% of their own phase densities. The calculated interfacial thickness of PS/PB/CHCl3 was about 4.7rc, which is much higher than that in PS/PB bulk system (1.4rc). Here, it should be noted that the solvent was found to occupy the interfacial region and result in the solvent density at the interface was higher than the average level. Therefore, PS and PB particles were rare in the cross region and the IFT distributes uniformly across the whole system without any significant change at the interface (Figure S1b). All these results are supposed to be responsible for the low IFT value. B. Co-assembly of SO and BO into Asymmetric Polymersomes at the Interface of Emulsions. As mentioned above, both PS-in-PB and PB-in-PS emulsions are stable in CHCl3. The asymmetric polymersomes can be formed when SO and BO were added and co-assembled at


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Figure 3. Sequential cross-sectional snapshots of the formation process of asymmetric polymersome at the interface of PS-in-PB emulsion. (a) the initial state; (b) 6.0 ×104 time steps; (c) 1.1 ×105 time steps; (d) 1.8 ×105 time steps; (e) 2.9 ×105 time steps; (f) 1.0 ×106 time steps. Blue and green beads represent the S and B blocks of SO and BO copolymers, respectively, while yellow beads represent S beads of PS homopolymers. The CHCl3 and PB homopolymers beads are omitted for clarity. the interface of the emulsions. Figure 3 provides the formation process of asymmetric polymersome with a PS-core. In the initial state, PS-in-PB emulsion system is established, which has been proved to be very stable. Then SO and BO are added into the PB-rich phase as shown in Figure 3a. CHCl3 and PB are omitted for clarity, and to distinguish the same blocks of copolymers from homopolymers, blue and green color were respectively used to highlight S and B blocks of SO and BO copolymers. In a very short period of simulation time, SO and BO aggregate rapidly (Figure 3b and 3c), and then gather around the PS-core. Then an asymmetric


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bilayer gradually forms in the following one million time steps (Figure 3d-3f). Furthermore, as one can see in Figure 3c, the spherical PS-core is transformed into ellipsoidal shape because of the squeezing of SO and BO aggregates. But during the formation of the asymmetric bilayer shell, the PS-core gradually returns to the original spherical shape (Figure 3d-3f). In addition, the co-assembly of SO and BO at the interface of PB-in-PS emulsions was also carried out (Figure S2). The nearly identical process was observed in this system to form the asymmetric polymersome. The structure of final asymmetric polymersome was investigated in detail. As illustrated in Figure 4a and 4b, the S blocks of SO attach on the PS-core and constitute the inner layer of the asymmetry polymersome while the B blocks of BO form the outer layer of the polymersome. In the meanwhile, O blocks of both SO and BO concentrate in the middle layer as the “solvophobic wall” (which is immiscible with both PS-rich and PB-rich phase) of the bilayer. Besides, there always exists a few S blocks of SO (ca. 1.5 at%) in the outer layer because this part of S blocks cannot penetrate into the inner leaflet after the formation of the high-density barrier of O blocks. Furthermore, two copolymer molecules are extracted from the bilayer to show the arrangement of SO and BO in the membrane of the asymmetry polymersomes (Figure 4c). It’s obvious that the O blocks of SO and BO fold and cross each other in the membrane. And owing to being immiscible with S and B blocks, the density of O blocks in the middle of the bilayer is so high that a part of CHCl3 beads are forced out of the region where the solvent beads used to be in the majority. In the case of the PB-in-PS emulsion system, the structure of the asymmetric polymersome is nothing different from PS-in-PB emulsion system besides the compositions of the inner and outer leaflet (Figure S3).


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Figure 4. The detailed structure of asymmetric polymersome. (a) cross-sectional view of the whole system; (b) cross-sectional view of asymmetric bilayer; (c) the arrangement of SO and BO in the asymmetric bilayer; (d) the density distribution of each particle in the direction of R as shown in (b). Blue and green beads represent the S and B blocks of SO and BO copolymers, respectively, while yellow beads represent S beads of PS homopolymers and light cyan beads represent B beads of PB homopolymers. OS and OB highlight the O blocks of SO and BO, respectively. The CHCl3 beads are omitted for clarity. Furthermore, to clarify the mechanism of the formation of asymmetric polymersome systematically, the detailed process of each system performed above was studied step by step. The whole co-assembly process can be divided into three stages: (1) the formation of micelles; (2) the micelles diffuse to the interface; (3) the micelles rearrange at the interface to form the asymmetric polymersome. Figure 5 provides a schematic representation of the above process to show the formation process of the asymmetry polymersomes. For clarity, the PB phase and PS phase are represented with light blue square and yellow sphere, respectively. In stage 1, owing to the unfavorable interaction between B beads and S or O beads, most of the copolymers aggregate into SO/BO hybrid micelles while a few (ca. 2~5%) of them insert into the interface directly, as


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shown in Figure 5a to 5b. But why do the most of these amphiphilic molecules not diffuse into the interface of the emulsion directly? As discussed in section A, the IFT of PS/PB/CHCl3 emulsion is feeble, and the IFT level of the whole system is nearly uniform (Figure S1b). Thus, there is no driving force to make the copolymer molecules moving towards the interface. Therefore, only molecules close to the interface can diffuse into the cross region directly. It’s conceivable that the S blocks of SO insert into PS-core while O blocks of BO do, and occasionally, they stay together tail to tail, as illustrated in Figure 5b. Moreover, the critical micelle concentration (CMC) of the mixture of SO and BO (1:1) in PB-rich phase was calculated, it was about 0.5 at% (Figure S5). So most of SO and BO will aggregate into micelles at stage 1. In stage 2, these micelles diffuse randomly in the PB-rich phase, rather than diffuse directionally. Moreover, the micelles are more favorable to form large micelles through fusing with each other, because the PB blocks are too short to stabilize the micelles in PB-rich phase. But then, once the micelles enter the interfacial region, the exposed S and O blocks insert into the PS core immediately, which results in that the micelles are captured by the PS core as shown in Figure5c. On the other side, there also have some micelles stay far away from the PS core. Once the micelle was captured by the PS core, it begins to transform the shape to be adapted to the new surroundings. The micelles gradually transform from near sphere to asymmetric bilayer membrane through rearrangement of SO and BO along the PS core. Figure 5d provides the typical transformation process of micelle A, B and C in detail. First, around the contact region (dash line section in Figure 5d), the S blocks of copolymers tend to insert into the PS core while B blocks move away from it (because B and S blocks are immiscible). But at the same time, the O blocks of both SO and BO prefer to stay in the middle of PS and PB phase owing to the unfavorable interaction between O beads and S or B beads. Furthermore, with more and more


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SO molecules rearranged directionally to the inner part, the original spherical micelles gradually turn into a flat shape and finally transform into the bilayer. Besides, the micelles attached to the PS core could fuse with each other during the rearrangement, which makes the whole asymmetric bilayer much more complete. Finally, the asymmetric polymersome forms when the bilayer membrane encases the PS core completely (Figure 5e). Here, it should be noted that the formation process of the asymmetric polymersome in PB-in-PS emulsion system is similar to that in PS-in-PB emulsion system.

Figure 5. Scheme of the formation of asymmetric polymersome. (a) initial status; (b) stage 1: the formation of micelles; (c) stage 2: the diffusion of micelles; (d) stage 3: the rearrangement of micelles (micelle A, B and C are taken for representation and the dash line sections indicate the contact region); (e) the regular asymmetric polymersome. The PB phase and PS phase are represented with light blue square and yellow sphere, respectively. Blue, green and red line segments indicate the S, B and O blocks of copolymers, respectively.


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What’s more, to reveal the main driving force for the formation of the asymmetric polymersomes, the effects of aOS, aOB and aBS on the self-assembled morphologies were explored. The results were summarized in Figure S4. It showed that the asymmetric polymersomes could not form if we changed any repulsion interaction among them with a lower value of 30 (aOS = 30 or aOB = 30 or aBS = 30, meaning relative lower incompatibility between two polymer blocks), and the final aggregates are complex micelles instead. In contrast, similar to the results as shown in figure 4, asymmetric polymersomes were generated again if we changed any repulsion interaction among them with a higher value of 60 (aOS = 60 or aOB = 60 or aBS = 60, meaning relative higher incompatibility between two polymer blocks). These simulation results clearly support that the incompatibility between PS, PB and PEO is the main driving force for asymmetric polymersome formation. Base on the above results, we can conclude that the formation process of asymmetric polymersome consists of three stages: formation of micelles, diffusion of micelles and the rearrangement of micelles into bilayer, while the driving force for asymmetric polymersome formation is the unfavorable interaction between each pair of S, B and O beads. More specifically, the immiscibility between O blocks and PS or PB homopolymers results in the formation of the bilayer structure, while the unfavorable interaction between S and B beads leads to the formation of asymmetric structure. It is a key law for designing various asymmetric systems to meet different needs. C. Effect of the Addition Order of SO and BO. In PB-rich phase, SO and BO copolymers perform apparently distinct behaviors. To investigate the effect of the addition order of SO and BO, two two-step simulations were carried out. The first step was carried out in the size box of


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60 × 60 × 60Rc3 and then the box size was expanded to 80 × 80 × 80Rc3 for the addition of the second copolymer. Although asymmetric polymersomes were both obtained ultimately, different adding orders were employed in the two systems. In one case, SO copolymers are put into the PS-in-PB emulsion solely, followed by the addition of BO copolymers after the system reaches equilibrium (ca. 1 × 106 time steps) again. As one can see in Figure 6a, SO copolymers aggregate into micelles rapidly and finally stay inside the PS core. A similar phenomenon was also observed in the experiment of Asano et al23. They found that PEO homopolymers formed a separate phase within PS phase when added to the PS/PB/CHCl3 emulsions. The IFT of the PEO/PB/CHCl3 emulsion system was calculated to clarify this phenomenon. It’s about 1.15mN/m, which is about double of the value in PS/PB/CHCl3 system (0.49 mN/m). It’s unfavorable to create a new PEO/PB interface to replace the original PS/PB interface. Therefore, micelles of SO copolymers finally stay inside the PS core. The following added BO copolymers, which are similar to amphipathic molecules in PB phase, aggregate into micelles with O blocks core (Figure 6b and 6c1). An interesting phenomenon is that the O blocks inside the PS core are pulled out from the core. To study this process quantitatively, the changes of the density distribution of S (PS and S blocks of SO) and O (only the O blocks of SO) beads with the time steps are analyzed as shown in Figure 7, in which the center of mass of the PS core is set as the origin of R. In the equilibrium state of the first step, S beads mainly distribute in the center (R = 0~10) and outer shell (R = 19) of PS core, while O beads distribute widely in the PS core and the peak locate at R = 13. It is clear that the S beads gradually aggregate into the core, while O beads move to the outer shell. As shown in Figure 6c, with the BO micelles attaching to the PS core, O beads inside the PS core and BO micelles fuse together, resulting in that the O beads inside the


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PS core move toward the outer shell and stay together with the O blocks of BO. In the meanwhile, most of the S beads are aggregated in the center and formed a new PS core. It means that the O blocks of SO inside the PS core are pulled out by the BO micelles and ultimately make up an asymmetric bilayer.

Figure 6. Sequential cross-sectional snapshots of the two-step simulations: adding SO followed by BO. (a) addition of SO; (b) following addition of BO; (c) scheme of the formation process of asymmetric bilayer after adding BO. In a and b, blue and green beads indicate the S and B blocks of SO and BO copolymers, respectively, while S beads of PS homopolymers are yellow. The CHCl3 and PB homopolymers beads are omitted for clarity. In c, The PB phase and PS phase are represented with light blue square and yellow sphere, respectively. Blue, green and red line segments indicate the S, B and O blocks of copolymers, respectively.


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Figure 7. The variation of the density distribution of S and O beads with simulation time. (a) the density distribution of S beads (PS and S blocks of SO); (b) the density distribution of O beads (only O blocks of SO). The center of mass of PS core is set as the origin (R = 0). In the other case, reversely, BO copolymers were added first (Figure 8). Being similar with SO, spherical micelles form in PB phase. However, owing to the incompatibility between B and S beads, the O blocks in the core of the micelles are prevented from penetrating into the PS phase. So, all the micelles only attach on the PS core with a limited PEO-PS contact region, and the sphere shape is kept, as shown in Figure 8a. The similar phenomenon was also observed in the experiment of Asano et al23. Then, the following added SO copolymers are aggregated into micelles owing to the immiscibility between B and S or O blocks. As one can see in Figure 8c, once the SO micelles diffuse into the interfacial region, the O parts of SO micelles will fuse with that in BO micelles, which results in forming a new complex micelle at the interface. It is made of SO and BO copolymers. After that, with the S blocks penetrate into the PS core, the complex aggregation rearranges along the interface and gradually transform into asymmetric bilayer and finally results in the formation of the asymmetric polymersome.


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Figure 8. Sequential cross-sectional snapshots of the two-step simulations: adding BO followed by SO. (a) addition of BO; (b) following addition of SO; (c) scheme of the formation process of asymmetric bilayer after adding SO. In a and b, blue and green beads indicate the S and B blocks of SO and BO copolymers, respectively, while S beads of PS homopolymers are yellow. The CHCl3 and PB homopolymers beads are omitted for clarity. In c, The PB phase and PS phase are represented with light blue square and yellow sphere, respectively. Blue, green and red line segments indicate the S, B and O blocks of copolymers, respectively. As described above, the rearrangement of micelles at the interface plays a determining role in the formation of the asymmetric bilayer. The addition order of polymers will greatly affect the self-assembly dynamics. However, the gathering of the copolymers at the interface is mainly derived from the diffusion of the micelles, which is independent of the addition order. The unfavorable interaction between each pair of PS, PB and PEO beads leads to the micelle


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rearrangement, which drives the formation of the asymmetric polymersomes. What’s more, although the polymer addition order is different, the final self-assembled structures after equilibrium are the same as asymmetric polymersomes. However, there is some small difference. Adding SO copolymers first can effectively reduce the ratio of SO in the outer leaflet (about 0.3 at%) when compared with that of adding BO first (about 1.8 at%), which leads to perfecter asymmetric polymersomes. D. Effect of PEO Volume Fraction (fPEO). In the previous simulations, SO(9-33) and BO(835) with fPEO = 0.75 were used to fabricate asymmetric polymersomes. In this section, a series of copolymers (SO:BO = 1:1) with various fPEO were employed to explore the effect of fPEO on the formation of asymmetric polymersomes. The molecular weights of S blocks and B blocks are fixed at 9 kg/mol and 8 kg/mol, respectively, while fPEO varies from 0.15 to 0.75. What’s more, with the increase of polymer concentration, the weight fraction of the solvent of CHCl3 in the emulsion system decreases accordingly. The phase diagram is shown in Figure 9, from which one can see that there are mainly three regions. Figure 9b shows the typical structures of each region and its corresponding density distribution of S, B and O beads of the copolymers. With the increase of fPEO, the final structure changes from emulsion, irregular aggregate to asymmetric polymersome. Meanwhile, the decrease of the weight fraction of CHCl3 results in a little leftshift of the irregular aggregate region. As mention in section 3B, the first step of the formation of asymmetric polymersome is the formation of hybrid micelles. Different copolymers with different fPEO perform different behaviors in the first step, which results in the formation of different structures. In the first region of the phase diagram, with low fPEO, BO copolymers are dissolved in PB-rich phase while SO


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Figure 9. Effect of fPEO and the weight fraction of CHCl3 on the final structure. (a) phase diagram of final structures; (b) Cross-sectional view of each structure and the corresponding density distribution of S, B and O beads of the copolymers. Blue and green beads indicate the S and B blocks of SO and BO copolymers, respectively, while S beads of PS homopolymers are yellow and B beads of PB homopolymers are light blue. The CHCl3 beads are omitted for clarity. In distribution diagram, B* and S* represent the B and S blocks of SO and BO, respectively. The center of mass of PS core is set as the origin (R = 0). copolymers aggregate into SO micelles. Because the O blocks are miscible with CHCl3, SO and BO with such short O blocks are stable in each rich phase instead of aggregating into micelles. Therefore, SO micelles disassemble in the PS-rich phase and the whole system is still existed in the form of emulsion. The second region is much more like a transitional state. In this region, SO and BO copolymers aggregate into many kinds of micelles, which are SO micelles, BO micelles and SO/BO hybrid micelles. BO micelles and SO/BO hybrid micelles assemble at the interface region, while SO micelles are stable within PS core. Such transitional structures are uniformly


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called irregular aggregate. In the third region, all the copolymers with such long O blocks are aggregated into hybrid micelles and then can be assembled at the interface region, which results in the formation of asymmetric polymersomes. It can be seen that the unfavorable interaction between O and S or B beads plays a key role in the formation of the asymmetric bilayer. The volume fraction of PEO blocks in copolymers determines whether the asymmetric polymersome can be formed. Indeed, only SO and BO with high fPEO (about higher than 0.65) can form regular asymmetric bilayer at the interface. 4. CONCLUSIONS In summary, the formation process of asymmetric polymersome through co-assembly of SO and BO at the interface of PS/PB/CHCl3 emulsion was systematically investigated by employing DPD simulations. Our results definitely demonstrate the formation of the asymmetric polymersomes like that in the experiments, and that the bilayer formed through the folding and crossing each other of the PEO blocks. Besides, we find that there are three stages in the formation process of the asymmetric polymersomes: the formation of micelles, the diffusion of micelles and the rearrangement of micelles. Meanwhile, we found that the immiscibility among PS, PB, and PEO are the main driving force for the formation of asymmetric polymersome. Moreover, the effect of addition order of copolymers and the volume fraction of PEO blocks on the structure of the asymmetric polymersome are also investigated. We found that the formation process is affected seriously by the addition order, and adding PS-b-PEO first can make the asymmetric bilayer more regular. Furthermore, our results showed that the perfect asymmetric polymersomes could only be formed with high fPEO. We hope the current work can be served as theoretical guidance for fabricating various kinds of asymmetric polymersomes.


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ASSOCIATED CONTENT Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author E-mail: [email protected]; [email protected] 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. ACKNOWLEDGMENT This work was supported by Center for High-Performance Computing, Shanghai Jiao Tong University. We thank the National Basic Research Program (2013CB834506), National Natural Science Foundation of China (21404070, 21474062, 51773115, 21774077, 91527304), Program for Basic Research of Shanghai Science and Technology Commission (17JC1403400), and Program of Shanghai Subject Chief Scientist (15XD1502400) for financial support. REFERENCES (1) Bretscher, M. S. Asymmetrical Lipid Bilayer Structure for Biological Membranes. Nat. New Biol. 1972, 236, 11-12. (2) Devaux, P. F. Static and dynamic lipid asymmetry in cell membranes. Biochemistry 1991,


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Insert Table of Contents Graphic and Synopsis Here.

The formation mechanism of asymmetric polymersome at the interface of oil-in-oil emulsions was systematically disclosed by employing DPD simulations.


Asymmetric Polymersomes from an Oil-in-Oil Emulsion: A Computer

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