Article pubs.acs.org/Langmuir
Formation and Structural Characteristics of Thermosensitive Multiblock Copolymer Vesicles Shiying Ma,†,‡ Mengying Xiao,† and Rong Wang*,† †
Department of Polymer Science and Engineering, State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, China ‡ College of Chemistry and Chemical Engineering, Taishan University, Taian 271021, China S Supporting Information *
ABSTRACT: The spontaneous vesicle formation of ABABAtype amphiphilic multiblock copolymers bearing thermosensitive hydrophilic A-block in a selective solvent is studied using dissipative particle dynamics (DPD) approach. The formation process of vesicle through nucleation and growth pathway is observed by varying the temperature. The simulation results show that spherical micelle takes shape at high temperature. As temperature decreases, vesicles with small aqueous cavity appear and the cavity expands as well as the membrane thickness decreases with the temperature further decreasing. This finding is in agreement with the experimental observation. Furthermore, by continuously varying the temperature and the length of the hydrophobic block, a phase diagram is constructed, which can indicate the thermodynamically stable region for vesicles. The morphological phase diagram shows that vesicles can form in a larger parameter scope. The relationship between the hydrophilic and hydrophobic block length versus the aqueous cavity size and vesicle size are revealed. Simulation results demonstrate that the copolymers with shorter hydrophobic blocks length or the higher hydrophilicity are more likely to form vesicles with larger aqueous cavity size and vesicle size as well as thinner wall thickness. However, the increase in A-block length results to form vesicles with smaller aqueous cavity size and larger vesicle size.
■
INTRODUCTION Vesicles possess hollow structure with a hydrophobic bilayer membrane and hydrophilic internal and external coronas.1−6 Because of the unique structure, vesicles have attracted considerable attention for their potential applications, such as gene and drug delivery, microcapsules, nanoreactors, cell membrane mimetic, synthetic organelles, and so forth.7−11 Vesicles have the advantage of simultaneously delivering hydrophilic components in their aqueous cavities and hydrophobic components within their membranes.12 So the size of the vesicle, especially the aqueous cavity size, and the thickness of the membrane play important roles in the encapsulation efficiency during the delivery process. The vesicular characteristics, including size, wall thickness and empirical relationships between wall thickness and the molecular weight of the copolymers have been found in many experimental studies.12−14 Eisenberg et al.15 have studied the sizes of PS-b-PAA vesicles in solution and found the sizes of vesicles can be controlled through changing the water content. However, most of these studies have focused on the wall thickness of vesicles13,14,16 and studies on the computer simulation of how to control the aqueous cavity size and vesicle size are seldom reported. Detailed investigations about the influence on aqueous cavity size and vesicle size are still needed, which could be of great importance to provide guidance for generating polymer vesicles and facilitating the further applications. © 2013 American Chemical Society
The structural properties of vesicles can be affected by many factors, such as temperature and hydrophobic/hydrophilic length. Thermosensitive polymers are one particular type of the various stimulus-responsive polymers that have been studied extensively over the last decades.17−20 Jiang and coworkers21 investigated the self-assembly of a thermosensitive amphiphilic hydrogen-bonded interpolymer HPC-PAA complex and found that the formation of vesicle follows the nucleation and growth mechanism. Recently, Winnik et al.22 studied the effect of heating rate on the pathway for vesicle formation of thermosensitive diblock copolymer. Lian et al.23 found that the amphiphilic asymmetric macromolecular brush bearing PEO and PS-b-PNIPAM side chain on PGMA backbone can self-assemble into vesicles in aqueous solution and the temperature exerted a significant influence on the structure and morphology of vesicle. The above mentioned thermosensitive polymers solution exhibit a LCST at which a polymer solution undergoes a phase transition from a soluble to an insoluble state when the temperature is raised. Although the transition is attributed to the change in the hydrophilic− hydrophobic balance of the polymer with respect to its interaction with a hydrogen-bonding solvent, the detail of the Received: October 28, 2013 Revised: November 28, 2013 Published: December 4, 2013 16010
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
of simplicity, the masses of the particles are set to 1, so that the force acting on a particle equals to its acceleration. There are three types of forces acting on a particle, including the conservative force (FCij ), dissipative force (FDij ), and random force (FRij ). The total force is a pairwise additive force and acts over all particles within a cutoff radius rC. Thus, the total force on particle i is given by
readjustment and the change in size of aggregates with the temperature are still unclear. Therefore, a more detailed investigation about the effect of temperature on the resulting aggregated morphologies self-assembled by thermosensitive polymers and the characteristic properties remain an essential work. In recent years, the investigations on amphiphilic multiblock copolymers have increased rapidly. Menger et al.24 examined the self-assembly of six penta-segmented block amphiphiles and found the segmentation can have a dramatic effect upon solute properties, including solubility, propensity to self-assembly, aggregation number, and cooperativity. Sommerdijk et al.25 investigated the self-assembly of an amphiphilic multiblock copolymer containing rigid semiconductor segments, which formed a variety of well-defined morphologies such as vesicles, micellar rods, and helices upon aggregation in water-based solvent systems. Patrickios et al.26 studied the aqueous micellization behavior of five linear amphiphilic multiblock copolymers, which self-assembled into flowerlike micelles. Recently, Sun et al.27 applied the Brownian dynamics simulation to study the self-assembly structures of an amphiphilic multiblock copolymer in dilute solution. They observed various structures including single-flower micelle, multiflower micelle, and single or multibridge structures. Despite these previous studies, due to the difficulty of synthesizing of well-defined multiblock copolymers few systematic studies on the self-assembly of amphiphilic multiblock copolymers have been reported. In this paper, we implemented dissipative particle dynamics (DPD) approach to study the formation and structure of vesicles self-assembled from ABABA-type amphiphilic multiblock copolymers, where A is hydrophilic and B is hydrophobic. The effects of temperature and hydrophobic block length on morphologies of the aggregates were examined. Moreover, the aqueous cavity size, membrane thickness, and size of vesicle were analyzed in detail. The relationship between the size of vesicles and the block length and the solubility of hydrophilic blocks were revealed.
fi ⃗ =
R
(2)
The conservative force is a soft repulsive potential between different particles ⎛ rij ⎞ C Fij⃗ = aij⎜1 − ⎟riĵ rC ⎠ ⎝
(3)
where aij is the repulsive interaction parameter between particle i and j, ri⃗ j = ri⃗ − rj⃗ , rij = |ri⃗ j|, r̂ij = ri⃗ j/rij, and rC is the cutoff radius. The dissipative force is a friction force that tries to reduce velocity differences between DPD particles. D
Fij⃗ = −γω 2(rij)(riĵ ·vij⃗ )riĵ
(4)
where γ is the friction coefficient governing the magnitude of the dissipative force, vi⃗ j = vi⃗ − vj⃗ . The weight function ω(rij) provides the range of interaction for DPD particle ⎧ 1 − rij ⎪ rij < rC ω(rij) = ⎨ rC ⎪ rij ≥ rC ⎩ 0
(5)
The random force compensates the loss of energy due to the dissipative force reducing the relative momentum R
Fij⃗ = σω(rij)θijriĵ
(6)
where σ is the noise amplitude that controls the intensity of the random force. θij is a randomly fluctuating variable with normal distribution. The values of friction coefficient and noise magnitude are related by
SIMULATION METHOD A. DPD Method. DPD simulation technique was invented and developed for simulating hydrodynamic behavior by Hoogerbrugger and Keolman28 in 1992 and successfully applied by Groot and Warren29 in 1997. It is a coarse-grained, mesoscopic simulation technique and has been extensively employed to study the self-assembly behavior of amphiphilic block copolymer in dilute solution,30−32 the microstructure and microphase separation of polymer melts,33−35 vesicle fusion and fission,36−39 and vesicle formation mechanisms.40,41 Because of the use of soft, short-ranged interparticle forces and a momentum-conserving thermostat, DPD method can correctly simulate complex fluid systems. In DPD, similar to coarsegrained molecular dynamics (MD), each DPD particle that interacts via an effective force field combines several atoms or atomic groups. All the particles obey Newton’s equations of motion29 f⃗ dvi⃗ = i dt mi
D
+ Fij⃗ + Fij⃗ )
j≠i
■
d ri ⃗ = v⃗, dt
C
∑ (Fij⃗
σ 2 = 2γkBT
(7)
where kB is the Boltzmann’s constant and T is the equilibrium temperature. In our simulation, the units of mass, length, time, and energy are scaled by the particle mass m, cutoff distance rC, time τ, and thermal energy kBT, respectively. The time unit τ is defined as τ = (mrC2 /kBT)1/2.The remaining simulation parameters are σ = 3.0, γ = 4.5, Δt = 0.03τ. In addition, we employ the finitely extensible nonlinear elastic (FENE) potential between the consecutive particles42 ⎧ 2⎤ ⎡ ⎪− 1 kR 2 ln⎢1 − ⎛⎜ rij ⎞⎟ ⎥ r < R ⎪ 0 ij 0 ⎢⎣ ⎝ R 0 ⎠ ⎥⎦ VFENE(rij) = ⎨ 2 ⎪ ⎪ rij ≥ R 0 ∞ ⎩
(8)
We choose k = 30 and R0 = 1.5rC. The value of FENE spring k is strong enough to make bond crossings energetically infeasible. B. Model and Condition. In the simulation, we consider the amphiphilic multiblock copolymer synthesized by Jiang et al.21 to mimic the HPC-PAA copolymer qualitatively, a model polymer AmBnAmBnAm with hydrophilic A beads and hydro-
(1)
where ri⃗ , vi⃗ , mi, and fi⃗ denote the position, velocity, mass of the ith particle, and the acting force on it, respectively. For the sake 16011
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 1. Snapshots showing the aggregates formed by A1B8A1B8A1 multiblock copolymers with aBS = 75 and different aAS = 65 (a), 60 (b), 40 (c), and 20 (d). For a better understanding, the enlarged slices of aggregates are also given. The hydrophilic and hydrophobic beads are marked in green and red, respectively.
vesicle size are revealed. In addition, the detailed molecular packing in the vesicle membrane was also demonstrated. A. Effect of Temperature on the Formation of Vesicles. 1. Comparison between Experiments and Simulations. HPC is a thermosensitive polysaccharide with low critical solution temperature in aqueous solution (41 °C). Complexation between HPC and PAA further decrease the phase-transition temperature of HPC.45 On the basis of CLSM images, it is concluded that HPC-PAA vesicles were formed through nucleation and growth pathway with the temperature decreases when the polymerization of AA was stopped. The general character of the experimental observation is that the temperature can influence the pathway of vesicle formation. The influence of temperature on thermosensitive block HPC can be revealed through the solvent quality, so it can be represented by the interaction parameter between the solvent and thermosensitive block in DPD simulations. In other words, the value of aAS rises with the increase of temperature.43 It is note worthy that all the interaction parameters between solvent and polymer (HPC segments, complexed HPC-PAA segments) may change with temperature. However, HPC segments exhibit a remarkable hydration-dehydration change in the temperature variation process,45 especially around the LCST which can indicate a significant change in the interaction parameter of solvent-HPC (aAS). The hydrophobicity of complexed HPCPAA segments (aBS) only have a slightly change during the process of temperature variation. Therefore, for simplicity, only aAS was varied to investigate the effect of temperature on the morphology and formation of vesicle. Figure 1 shows the morphologies of the A1B8A1B8A1 assemblies with different interaction parameters aAS. Figure 1a shows the spherical micelle forms with higher aAS = 65. As the aAS decreases, small hollow center appears in the spherical micelle when the aAS = 60 and the cavity expands and the membrane thickness decreases further with aAS = 40 and 20. Furthermore, we also investigated the kinetic evolution of the vesicular morphologies. The snapshots showing the aggregated morphologies are given in Supporting Information Figure S1. The kinetic evolution process is consistent with that mentioned above. During the kinetic process, the hydrophilicity of A-blocks is gradually enhanced, thereby leading to reassembly of copolymers into the vesicles to reduce the interfacial energy when lowering the
phobic B is proposed. Solvent beads (denoted by S) are included explicitly in the simulation, but they are not shown in the following figures for simplicity and clarity. The simulations of 81 000 DPD particles at a number density 3 were performed in a cube box with a size of 30 × 30 × 30 with periodic boundary conditions. A cube box with a size of 20 × 20 × 20 was also adopted in order to clearly analyze the vesicle properties, such as the aqueous cavity size, membrane thickness, and vesicle size. The different size of boxes does not affect the formation of aggregations except the number of aggregates in the boxes.43 The copolymer volume fraction is 0.1 unless otherwise stated. The interaction parameter aij is determined by the characteristic of the beads (either hydrophilic or hydrophobic).44 We take the interaction parameter between the same type of beads to be aii = 25 (measured in unit of kBT), and the interaction parameter between the hydrophilic and hydrophobic beads to be aij = 50. That is, the interaction parameter aAA, aBB, aSS are set to be 25, and aAB is set to be 50. In this work, each simulation takes at least 1 × 106 steps so that the simulation system can achieve an equilibrium state. More than 10 simulations with different initial conditions were carried out to ensure the equilibrium is independent upon the initial conditions.
■
RESULTS AND DISCUSSION
In this study, dissipative particle dynamics is applied to investigate the morphological aggregates and thermosensitive behaviors of multiblock copolymers in selective solvent. The structural characteristics of vesicles formed by multiblock copolymers are also investigated. The simulation results are given in two parts. First, comparisons between our simulation results and the experimental findings were proposed to elucidate the validity of our model multiblock copolymer and simulation approach. The formation of vesicles through a nucleation and growth pathway with temperature was also observed. The morphological phase diagram of A1BnA1BnA1 was obtained to demonstrate the effects of temperature and B-block lengths. The second part describes the effects of hydrophilic and hydrophobic block length on the structural characteristics of vesicles. The relationship between the hydrophilic and hydrophobic block length versus the aqueous cavity size and 16012
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 2. Radial density function of (a) the hydrophilic block ΦA(r), and (b) the hydrophobic block ΦB(r) plotted as a function of the distance r from the mass center of the aggregates at aAS = 20 (solid), 40 (dash), and 60 (dash dot) for A1B8A1B8A1 at aBS = 75. Note that normalizations have been chosen such that 4π∫ R0 ϕA(r)r2 dr = NAagg, the total number of hydrophilic beads in the selected aggregate, and 4π∫ R0 ϕB(r)r2 dr = NBagg, the total number of hydrophobic beads in the selected aggregate.
value of aAS. The process of vesicles formation is consistent with the experimental observation.21 Figure 2 shows the variation of the densities of block A and block B with the distance from the mass center of the vesicles formed by A1B8A1B8A1 with interaction parameter aAS = 60, 40, and 20. We can find hydrophilic block A gradually moves away from the center of the vesicle with the decrease in aAS, which indicates the cavity size of the vesicle growing larger. The variation of block B is similar to block A (Figure 2b). The simulation results indicate that the cavity volume and vesicle size gradually increase with decreasing aAS. Moreover, the cavity size grows more significantly than the vesicle size, which can also be verified by the following Figure 5. 2. Effect of Temperature and Hydrophobic Block Length. In order to investigate the effects of the temperature and the hydrophobic B-block length, a morphological phase diagram is constructed with aAS and A1BnA1BnA1 as shown in Figure 3.
order to reduce the interfacial energy of spherical micelles. Note that for shorter B blocks the solvent has a stronger influence on the hydrophilic segments due to the higher fraction of hydrophilic A-block, resulting in vesicle formation when aAS is smaller than 50. However, as the B-block length becomes longer, vesicles form with larger region of aAS because the solvent has a slight influence on the hydrophilic blocks with the lower fraction. On the other hand, from the phase diagram we can find that multiblock copolymers with different hydrophobic block length easily self-assemble to vesicles in a large parameter scope. In addition, we analyzed the structural characteristics of vesicles formed at different aAS. As shown in Figure 4, the
Figure 4. Schematic illustration of a typical vesicle. Rin is the cavity radius, d is the wall thickness of the hydrophobic membrane, and Rout is the vesicle size.
vesicle size is defined as the outer radius Rout, and the aqueous cavity size is defined as the inner radius Rin, and the wall thickness d is determined by the difference between the outer and inner hydrophobic membranes. Here, the outer or inner radii are defined as the average distance from the center of mass of the vesicle to the last bead of tail. The wall thickness d is the thickness of hydrophobic membrane.16,46 The changes in the vesicle size (Rout), wall thickness (d), and aqueous volume or the cavity size (Rin) are then analyzed for vesicle characteristics based on different interaction parameter aAS. Figure 5 presents plots of relationship between vesicular radius, membrane thickness, and interaction parameter aAS. We choose 30 samples of vesicles formed by the copolymer with
Figure 3. Morphological phase diagram of aggregates formed by copolymer A1BnA1BnA1 as a function of temperature (aAS) and hydrophobic block length (n) with aBS = 75.
From the figure, we can only see two types of aggregates, spherical micelles and vesicles. In general, vesicles take shape at small values of aAS and spherical micelles develop for large aAS. It is clear that spherical micelles form when the hydrophilic Ablock are not rather hydrophilic (that is, as temperature exceeds the LCST and thus large aAS). At the temperature below the LCST, A-block is soluble in solvent and vesicles can form in 16013
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 6. Relationship between the average vesicular radius and Bblock length with aAS = 25 and aBS = 75 for multiblock copolymer (A1BnA1BnA1). The hydrophilic and hydrophobic beads are marked in green and red, respectively. Here, the number concentration of copolymer is fixed.
Figure 5. Relationship between the averaged vesicular radius and interaction parameter aAS with aBS = 75 obtained from the multiblock copolymer A1B8A1B8A1. Note that the number concentration of copolymer is fixed.
A ratio increases. Vesicles decrease the interfacial area of the inner and outer of vesicle through shrinking and densely packing in order to reduce the interfacial energy between the solvent and the inner or outer surface of vesicle. Moreover, it is clear that the membrane thickness increases with increasing of the B-block length. It is in agreement with the previous experimental and theoretical findings.16,23,47 For the sake of understanding the vesicles in details and demonstrating the inner structure diversity, the density distributions of A and B blocks for two typical vesicles are plotted in Figure 7. Figure 7a,b shows radial density distributions of vesicles from A1B4A1B4A1 and A1B12A1B12A1 copolymers, respectively. As can be seen from Figure 7a, the density of A-block reaches a maximum and gradually decreases with the distance r. The hydrophobic membrane thickness is to lower to segregate the hydrophilic block locating in the outer and inner surface of the vesicle. However, the density of Ablock appears two peaks with the distance r in Figure 7b. This indicates that with the increase of B-block length, the membrane thickness also increases. Moreover, the density of B-block is larger and closer to the center of vesicle for A1B12A1B12A1 copolymer than that for A1B4A1B4A1 copolymer. This also indicates that the cavity size decreases with the increase of B-block length. 2. Effect of Hydrophilic Block Length. Figure 8 presents the variation of the averaged radius of vesicles with different Ablock length for a series of A m B 8 A m B 8 A m multiblock copolymers. The quantified aqueous cavity size and vesicle size with different A-block length are given in Supporting Information Table S3. From the figure, we can see that the inner radius (Rin) of vesicle decreases and the outer radius (Rout) of vesicle increases with the increasing of the A-block length. The increase of the A-block length enhances the solubility of copolymers, and the hydrophilic blocks prefer to segregate to reduce the repulsive interactions among the outer and inner chains. Then, we analyzed the block density variation from the mass center of the vesicles in order to get more deep insight into the structure of vesicles. The typical results of A-block density ΦA(r) and B-block density ΦB(r) for the two vesicles are presented in Figure 9. It can be seen that the densities for blocks A and B in the vesicle center are zero. Two peaks for the curve of A-block are corresponding to the densities of A-block at inner surface and outer surface of the vesicle, respectively. Moreover, we can find that the density of A-block in vesicle
interval of 1 × 103 DPD steps after achieving the equilibrium state for each system and computed the average distances of inner radius, outer radius, and wall thickness, respectively. The quantified aqueous cavity size, membrane thickness, and vesicle size with different solvent-A block interactions are given in Supporting Information Table S1. As can be seen from Figure 5, the radii of the cavity and the vesicle both gradually decrease with increasing aAS. As mentioned above, the increase in aAS results in a strengthened repulsive interaction between the hydrophilic blocks and solvent. As the interaction parameter aAS increases, the solvent gradually becomes insoluble for hydrophilic segments and the hydrophilic segments begin to shrink in the corona and pack more densely to reduce the interfacial energy of the vesicle, leading to the contraction of the vesicle. However, the membrane thickness gradually increases with an increase in solvent-A-block interaction (aAS). For a larger value of aAS, the hydrophilic segments are insoluble in the solvent and partly move into the membrane of vesicle in order to minimize the interfacial energy, resulting in the increase of the membrane thickness. The increasing trend of the membrane thickness with the increase of aAS is consistent with the experimental observations.23 The variations of aqueous cavity size and vesicle size as well as the membrane thickness are consistent with the results in Figure 2. These simulation results indicate that the temperature is an effective factor in the structural characteristics of vesicles. B. Structural Characteristics of Vesicles. Polymer vesicles not only encapsulate soluble substance in their cavities but also accumulate insoluble substance in their shells. Furthermore, the large cavity of vesicle may deliver larger and more hydrophilic drugs. The size of the cavity and the thickness of the membrane for vesicles determine the encapsulation efficiency for hydrophilic and hydrophobic drugs. In the following section, we present the effect of hydrophilic and hydrophobic block length on structural properties of vesicles, such as the size of the cavity and the membrane thickness. 1. Effect of Hydrophobic Block Length. Figure 6 shows the averaged aqueous cavity size of vesicles and vesicle size as a function of B-block length. The quantified aqueous cavity size and vesicle size with different B-block length are given in Supporting Information Table S2. From the figure, we can see that the cavity size and the vesicle size decrease with the increase of B-block length. This is due to the increase of the hydrophilic segments in the inner and outer of vesicle as the B/ 16014
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 7. Radial density distributions of the hydrophilic A-block and the hydrophobic B-block with aAS = 25 and aBS = 75 for vesicles self-assembled from (a) A1B4A1B4A1 and (b) A1B12A1B12A1 with the distance r from the mass center of the aggregates.
blocks in a copolymer molecule and one of them locating in the middle of the copolymer, the packing mode of multiblock copolymer consisting of vesicle is much more complex compared with diblock or triblcok copolymers and other types of block copolymers. We observed and analyzed the packing modes of polymer chains from simulation structures of vesicles. An illustration of the chain packing in a typical vesicle is given in Figure 10. There are three packing modes in the
Figure 8. Variation of averaged radius of vesicles with different A-block length for multiblock copolymer (AmB8AmB8Am) with aAS = 25 and aBS = 75. The hydrophilic and hydrophobic beads are marked in green and red, respectively. Here, the number concentration of copolymer is fixed.
formed by A1B8A1B8A1 is obviously lower than that in vesicle formed by A4B8A4B8A4. From the peak position for curve of Ablock, the inner and outer hydrophilic membrane thickness of vesicle formed by A4B8A4B8A4 is greater than that of vesicle formed by A1B8A1B8A1, which is in agreement with the results shown in Figure 8. The packing modes of polymer chains within the vesicle membrane are also investigated. Because of three hydrophilic
Figure 10. Illustration of the packing modes of polymer chains within the vesicle membrane. The circle represents the membrane of vesicle.
vesicle membrane that are defined as m-type, v-type, and htype, respectively. In m-type mode, the hydrophobic segments are embedded in the vesicle membrane. The hydrophilic
Figure 9. Radial density distributions of the hydrophilic A-block and the hydrophobic B-block with aAS = 25 and aBS = 75 for vesicles self-assembled from (a) A1B8A1B8A1 and (b) A4B8A4B8A4 with the distance r from the mass center of the aggregates. 16015
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir segments locate simultaneously on the inner or outer surfaces of the vesicle membrane. In v-type mode, the two hydrophobic segments simultaneously bridge through the vesicle membrane, and the middle and end of hydrophilic segments locate on outside and inside hydrophilic surfaces of the vesicle respectively or vice versa. In h-type mode, one hydrophobic segment is embedded in the vesicle membrane and the other hydrophobic segment penetrates the vesicle membrane; the two ends of the copolymer locate on different hydrophilic surfaces of the vesicle.
■
CONCLUSIONS
■
ASSOCIATED CONTENT
ACKNOWLEDGMENTS
■
REFERENCES
We thank Professor Xiqun Jiang for his providing the experimental work and valuable discussions. This work was financially supported by the National Natural Science Foundation of China (Grants 21074053 and 51133002) and National Basic Research Program of China (Grant 2010CB923303).
(1) Soo, P. L.; Eisenberg, A. Preparation of Block Copolymer Vesicles in Solution. J. Polym. Sci., Part B: Polym. Phys. 2004, 42, 923− 938. (2) Discher, D. E.; Eisenberg, A. Polymer Vesicles. Science 2002, 297, 967−973. (3) Shen, H. W.; Eisenberg, A. Control of Architecture in BlockCopolymer Vesicles. Angew. Chem., Int. Ed. 2000, 39, 3310−3312. (4) Yu, K.; Eisenberg, A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution. Macromolecules 1998, 31, 3509−3518. (5) Zhang, L. F.; Eisenberg, A. Multiple Morphologies and Characteristics of “Crew-Cut” Micelle-Like Aggregates of Polystyrene-b-Poly(acrylic acid) Diblock Copolymers in Aqueous Solutions. J. Am. Chem. Soc. 1996, 118, 3168−3181. (6) Zhang, L. F.; Eisenberg, A. Multiple Morphologies of Crew-Cut Aggregates of Polystyrene-b-Poly(acrylic acid) Block-Copolymers. Science 1995, 268, 1728−1731. (7) Tanner, P.; Baumann, P.; Enea, R.; Onaca, O.; Palivan, C.; Meier, W. Polymeric Vesicles: From Drug Carriers to Nanoreactors and Artificial Organelles. Acc. Chem. Res. 2011, 44, 1039−1049. (8) Brinkhuis, R. P.; Rutjes, F. P. J. T.; van Hest, J. C. M. Polymeric Vesicles in Biomedical Applications. Polym. Chem. 2011, 2, 1449− 1462. (9) Walde, P.; Cosentino, K.; Engel, H.; Stano, P. Giant Vesicles: Preparations and Applications. ChemBioChem. 2010, 11, 848−865. (10) LoPresti, C.; Lomas, H.; Massignani, M.; Smart, T.; Battaglia, G. Polymersomes: Nature Inspired Nanometer Sized Compartments. J. Mater. Chem. 2009, 19, 3576−3590. (11) Liu, Z.; Jiang, Z. B.; Yang, H.; Bai, S. M.; Wang, R.; Xue, G. Crowding Agent Induced Phase Transition of Amphiphilic Diblock Copolymer in Solution. Chin. J. Polym. Sci. 2013, 11, 1491−1500. (12) Battaglia, G.; Ryan, A. J. Bilayers and Interdigitation in Block Copolymer Vesicles. J. Am. Chem. Soc. 2005, 127, 8757−8764. (13) Azzam, T.; Eisenberg, A. Control of Vesicular Morphologies through Hydrophobic Block Length. Angew. Chem., Int. Ed. 2006, 45, 7443−7447. (14) Bermudez, H.; Brannan, A. K.; Hammer, D. A.; Bates, F. S.; Discher, D. E. Molecular Weight Dependence of Polymersome Membrane Structure, Elasticity, and Stability. Macromolecules 2002, 35, 8203−8208. (15) Luo, L. B.; Eisenberg, A. Thermodynamic Size Control of Block Copolymer Vesicles in Solution. Langmuir 2001, 17, 6804−6811. (16) Xiao, M. Y.; Liu, J. N.; Yang, J. X.; Wang, R.; Xie, D. Q. Biomimetic Membrane Control of Block Copolymer Vesicles with Tunable Wall Thickness. Soft Matter 2013, 9, 2434−2442. (17) Dimitrov, I.; Trzebicka, B.; Muller, A.; Dworak, A.; Tsvetanov, C. B. Thermosensitive Water-Soluble Copolymers with Doubly Responsive Reversibly Interacting Entities. Prog. Polym. Sci. 2007, 32, 1275−1343. (18) Meng, F. H.; Zhong, Z. Y.; Feijen, J. Stimuli-Responsive Polymersomes for Programmed Drug Delivery. Biomacromolecules 2009, 10, 197−209. (19) Cai, C. H.; Zhang, L. S.; Lin, J. P.; Wang, L. Q. Self-Assembly Behavior of pH- and Thermosensitive Amphiphilic Triblock Copolymers in Solution: Experimental Studies and Self-Consistent Field Theory Simulations. J. Phys. Chem. B 2008, 112, 12666−12673. (20) Gil, E. S.; Hudson, S. M. Stimuli-Reponsive Polymers and Their Bioconjugates. Prog. Polym. Sci. 2004, 29, 1173−1222.
The formation and structural characteristics of vesicle formed by amphiphilic multiblock copolymer ABABA in a selective solvent are explored by dissipative particle dynamics method, which can provide valuable microscopic insights and complement the deficiency of experimental studies. In order to confirm the validity of our DPD model of multiblock copolymer, our simulation findings are compared with the experimental results by Jiang et al. The influence of temperature on HPC is realized by the solvent property (aAS), where lower temperature can depict good solvent (smaller aAS) and higher temperature can indicate poor solvent (larger aAS). On the basis of the variation of solvent quality for A-block, our simulations of the multiblock copolymers show that the vesicle formed through nucleation and growth mechanism. This finding is in agreement with the experimental observation. We also analyzed the structure property of vesicles formed at different temperatures. It is found that the vesicle size and cavity size both decrease with increasing temperature and the membrane thickness grows with the increase of temperature. The structure of the vesicle formed by multiblock copolymer with various hydrophilic or hydrophobic block lengths is also studied. Simulation results reveal that the ratio of hydrophilic/ hydrophobic block and the hydrophilicity of A-block largely affect the aqueous cavity size, membrane thickness, and vesicle size. The copolymers with shorter hydrophobic blocks length or the higher hydrophilicity are more likely to form vesicles with larger aqueous cavity size and vesicle size as well as thinner wall thickness. However, the increase in A-block length results in forming vesicles with smaller aqueous cavity size and larger vesicle size. The polymer chains packing mode within the vesicle membrane is also investigated. It was observed that the structure of amphiphilic copolymer has a large impact on the packing mode of polymer chains. Thus, the findings presented in this paper might provide a new approach for preparing sizecontrolled polymer vesicles.
S Supporting Information *
Figure of the dynamics evolution process of vesicle and tables of quantified aqueous cavity size, membrane thickness, and vesicle size of vesicles. This material is available free of charge via the Internet at http://pubs.acs.org.
■
■
Article
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The authors declare no competing financial interest. 16016
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
(21) Qian, H. Q.; Yao, W.; Yu, S. L.; Chen, Y.; Wu, W.; Jiang, X. Q. Spontaneous Formation of Giant Polymer Vesicles through a Nucleation and Growth Pathway. Chem. Asian J. 2012, 7, 1875−1880. (22) Korchagina, E. V.; Qiu, X. P.; Winnik, F. M. Effect of Heating Rate on the Pathway for Vesicle Formation in Salt-Free Aqueous Solutions of Thermosensitive Cationic Diblock Copolymers. Macromolecules 2013, 46, 2341−2351. (23) Lian, X. M.; Wu, D. X.; Song, X. H.; Zhao, H. Y. Synthesis and Self-Assembly of Amphiphilic Asymmetric Macromolecular Brushes. Macromolecules 2010, 43, 7434−7445. (24) Menger, F. M.; Lu, H.; Lundberg, D. A-B-A-B-A Block Amphiphiles. Balance Between Hydrophilic and Hydrophobic Segmentation. J. Am. Chem. Soc. 2007, 129, 272−273. (25) Sommerdijk, N. A. J. M.; Holder, S. J.; Hiorns, R. C.; Jones, R. G.; Nolte, R. J. M. Self-Assembled Structures From an Amphiphilic Multiblock Copolymer Containing Rigid Semiconductor Segments. Macromolecules 2000, 33, 8289−8294. (26) Hadjiantoniou, N. A.; Triftaridou, A. I.; Kafouris, D.; Gradzielski, M.; Patrickios, C. S. Synthesis and Characterization of Amphiphilic Multiblock Copolymers: Effect of the Number of Blocks on Micellization. Macromolecules 2009, 42, 5492−5498. (27) Zhang, J.; Lu, Z. Y.; Sun, Z. Y. Self-Assembly Structures of Amphiphilic Multiblock Copolymer in Dilute Solution. Soft Matter 2013, 9, 1947−1954. (28) Hoogerbruggge, P. J.; Koelman, J. M. V. A. Simulating Microscopic Hydrodynamic Phenomena with Dissipative Particle Dynamics. Europhys. Lett. 1992, 19, 155−160. (29) Groot, R. D.; Warren, P. B. Dissipative Particle Dynamics: Bridging the Gap Between Atomistic and Mesoscopic Simulation. J. Chem. Phys. 1997, 107, 4423−4435. (30) Wang, H.; Liu, Y. T.; Qian, H. J.; Lu, Z. Y. Dissipative Particle Dynamics Simulation Study on Complex Structure Transitions of Vesicles Formed by Comb-Like Block Copolymers. Polymer 2011, 52, 2094−2101. (31) He, P. T.; Li, X. J.; Kou, D. Z.; Deng, M. G.; Liang, H. J. Complex Micelles from the Self-Assembly of Amphiphilic Triblock Copolymers in Selective Solvents. J. Chem. Phys. 2010, 132, 204905. (32) Li, X. J.; Pivkin, I. V.; Liang, H. J.; Karniadakis, G. E. Shape Transformations of Membrane Vesicles from Amphiphilic Triblock Copolymers: A Dissipative Particle Dynamics Simulation Study. Macromolecules 2009, 42, 3195−3200. (33) Gavrilov, A. A.; Kudryavtsev, Y. V.; Khalatur, P. G.; Chertovich, A. V. Microphase Separation in Regular and Random Copolymer Melts by DPD Simulations. Chem. Phys. Lett. 2011, 503, 277−282. (34) Tang, Y. H.; He, Y. D.; Wang, X. L. Effect of Adding a Second Diluent on the Membrane Formation of Polymer/Diluent System via Thermally Induced Phase Separation: Dissipative Particle Dynamics Simulation and Its Experimental Verification. J. Membr. Sci. 2012, 409, 164−172. (35) He, Y. D.; Tang, Y. H.; Wang, X. L. Dissipative Particle Dynamics Simulation on the Membrane Formation of PolymerDiluent System via Thermally Induced Phase Separation. J. Membr. Sci. 2011, 368, 78−85. (36) Grafmuller, A.; Shillcock, J.; Lipowsky, R. The Fusion of Membranes and Vesicles: Pathway and Energy Barriers from Dissipative Particle Dynamics. Biophys. J. 2009, 96, 2658−2675. (37) Yamamoto, S.; Hyodo, S. Budding and Fission Dynamics of Two-Component Vesicles. J. Chem. Phys. 2003, 118, 7937−7943. (38) Wu, S. G.; Guo, H. X. Simulation Study of Protein-Mediated Vesicle Fusion. J. Phys. Chem. B 2009, 113, 589−591. (39) Liu, Y. T.; Zhao, Y.; Liu, H.; Liu, Y. H.; Lu, Z. Y. Spontaneous Fusion between the Vesicles Formed by A2n(B2)n Type Comb-Like Block Copolymers with a Semiflexible Hydrophobic Backbone. J. Phys. Chem. B 2009, 113, 15256−15262. (40) Xiao, M. Y.; Xia, G. J.; Wang, R.; Xie, D. Q. Controlling the SelfAssembly Pathways of Amphiphilic Block Copolymers into Vesicles. Soft Matter 2012, 8, 7865−7874. (41) Chen, H. Y.; Ruckenstein, E. Self-Assembly of π-Shaped Copolymers. Soft Matter 2012, 8, 1327−1333.
(42) Kroger, M.; Hess, S. Rheological Evidence for a Dynamical Crossover in Polymer Melts via Nonequilibrium Molecular Dynamics. Phys. Rev. Lett. 2000, 85, 1128−1131. (43) Chang, H. Y.; Lin, Y. L.; Sheng, Y. J. Multilayered Polymersome Formed by Amphiphilic Asymmetric Macromolecular Brushes. Macromolecules 2012, 45, 4778−4789. (44) Chen, H. Y.; Ruckenstein, E. Nanoparticle Aggregation in the Presence of a Block Copolymer. J. Chem. Phys. 2009, 131, 244904. (45) Lu, X. H.; Hu, Z. B.; Schwartz, J. Phase Transition Behavior of Hydroxypropylcellulose under Interpolymer Complexation with Poly(acrylic acid). Macromolecules 2002, 35, 9164−9168. (46) Lin, C. M.; Li, C. S.; Sheng, Y. J.; Wu, D. T.; Tsao, H. K. SizeDependent Properties of Small Unilamellar Vesicles Formed by Model Lipids. Langmuir 2012, 28, 689−700. (47) Ma, L.; Eisenberg, A. Relationship between Wall Thickness and Size in Block Copolymer Vesicles. Langmuir 2009, 25, 13730−13736.
16017
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Formation and Structural Characteristics of Thermosensitive Multiblock Copolymer Vesicles Shiying Ma,†,‡ Mengying Xiao,† and Rong Wang*,† †
Department of Polymer Science and Engineering, State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, China ‡ College of Chemistry and Chemical Engineering, Taishan University, Taian 271021, China S Supporting Information *
ABSTRACT: The spontaneous vesicle formation of ABABAtype amphiphilic multiblock copolymers bearing thermosensitive hydrophilic A-block in a selective solvent is studied using dissipative particle dynamics (DPD) approach. The formation process of vesicle through nucleation and growth pathway is observed by varying the temperature. The simulation results show that spherical micelle takes shape at high temperature. As temperature decreases, vesicles with small aqueous cavity appear and the cavity expands as well as the membrane thickness decreases with the temperature further decreasing. This finding is in agreement with the experimental observation. Furthermore, by continuously varying the temperature and the length of the hydrophobic block, a phase diagram is constructed, which can indicate the thermodynamically stable region for vesicles. The morphological phase diagram shows that vesicles can form in a larger parameter scope. The relationship between the hydrophilic and hydrophobic block length versus the aqueous cavity size and vesicle size are revealed. Simulation results demonstrate that the copolymers with shorter hydrophobic blocks length or the higher hydrophilicity are more likely to form vesicles with larger aqueous cavity size and vesicle size as well as thinner wall thickness. However, the increase in A-block length results to form vesicles with smaller aqueous cavity size and larger vesicle size.
■
INTRODUCTION Vesicles possess hollow structure with a hydrophobic bilayer membrane and hydrophilic internal and external coronas.1−6 Because of the unique structure, vesicles have attracted considerable attention for their potential applications, such as gene and drug delivery, microcapsules, nanoreactors, cell membrane mimetic, synthetic organelles, and so forth.7−11 Vesicles have the advantage of simultaneously delivering hydrophilic components in their aqueous cavities and hydrophobic components within their membranes.12 So the size of the vesicle, especially the aqueous cavity size, and the thickness of the membrane play important roles in the encapsulation efficiency during the delivery process. The vesicular characteristics, including size, wall thickness and empirical relationships between wall thickness and the molecular weight of the copolymers have been found in many experimental studies.12−14 Eisenberg et al.15 have studied the sizes of PS-b-PAA vesicles in solution and found the sizes of vesicles can be controlled through changing the water content. However, most of these studies have focused on the wall thickness of vesicles13,14,16 and studies on the computer simulation of how to control the aqueous cavity size and vesicle size are seldom reported. Detailed investigations about the influence on aqueous cavity size and vesicle size are still needed, which could be of great importance to provide guidance for generating polymer vesicles and facilitating the further applications. © 2013 American Chemical Society
The structural properties of vesicles can be affected by many factors, such as temperature and hydrophobic/hydrophilic length. Thermosensitive polymers are one particular type of the various stimulus-responsive polymers that have been studied extensively over the last decades.17−20 Jiang and coworkers21 investigated the self-assembly of a thermosensitive amphiphilic hydrogen-bonded interpolymer HPC-PAA complex and found that the formation of vesicle follows the nucleation and growth mechanism. Recently, Winnik et al.22 studied the effect of heating rate on the pathway for vesicle formation of thermosensitive diblock copolymer. Lian et al.23 found that the amphiphilic asymmetric macromolecular brush bearing PEO and PS-b-PNIPAM side chain on PGMA backbone can self-assemble into vesicles in aqueous solution and the temperature exerted a significant influence on the structure and morphology of vesicle. The above mentioned thermosensitive polymers solution exhibit a LCST at which a polymer solution undergoes a phase transition from a soluble to an insoluble state when the temperature is raised. Although the transition is attributed to the change in the hydrophilic− hydrophobic balance of the polymer with respect to its interaction with a hydrogen-bonding solvent, the detail of the Received: October 28, 2013 Revised: November 28, 2013 Published: December 4, 2013 16010
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
of simplicity, the masses of the particles are set to 1, so that the force acting on a particle equals to its acceleration. There are three types of forces acting on a particle, including the conservative force (FCij ), dissipative force (FDij ), and random force (FRij ). The total force is a pairwise additive force and acts over all particles within a cutoff radius rC. Thus, the total force on particle i is given by
readjustment and the change in size of aggregates with the temperature are still unclear. Therefore, a more detailed investigation about the effect of temperature on the resulting aggregated morphologies self-assembled by thermosensitive polymers and the characteristic properties remain an essential work. In recent years, the investigations on amphiphilic multiblock copolymers have increased rapidly. Menger et al.24 examined the self-assembly of six penta-segmented block amphiphiles and found the segmentation can have a dramatic effect upon solute properties, including solubility, propensity to self-assembly, aggregation number, and cooperativity. Sommerdijk et al.25 investigated the self-assembly of an amphiphilic multiblock copolymer containing rigid semiconductor segments, which formed a variety of well-defined morphologies such as vesicles, micellar rods, and helices upon aggregation in water-based solvent systems. Patrickios et al.26 studied the aqueous micellization behavior of five linear amphiphilic multiblock copolymers, which self-assembled into flowerlike micelles. Recently, Sun et al.27 applied the Brownian dynamics simulation to study the self-assembly structures of an amphiphilic multiblock copolymer in dilute solution. They observed various structures including single-flower micelle, multiflower micelle, and single or multibridge structures. Despite these previous studies, due to the difficulty of synthesizing of well-defined multiblock copolymers few systematic studies on the self-assembly of amphiphilic multiblock copolymers have been reported. In this paper, we implemented dissipative particle dynamics (DPD) approach to study the formation and structure of vesicles self-assembled from ABABA-type amphiphilic multiblock copolymers, where A is hydrophilic and B is hydrophobic. The effects of temperature and hydrophobic block length on morphologies of the aggregates were examined. Moreover, the aqueous cavity size, membrane thickness, and size of vesicle were analyzed in detail. The relationship between the size of vesicles and the block length and the solubility of hydrophilic blocks were revealed.
fi ⃗ =
R
(2)
The conservative force is a soft repulsive potential between different particles ⎛ rij ⎞ C Fij⃗ = aij⎜1 − ⎟riĵ rC ⎠ ⎝
(3)
where aij is the repulsive interaction parameter between particle i and j, ri⃗ j = ri⃗ − rj⃗ , rij = |ri⃗ j|, r̂ij = ri⃗ j/rij, and rC is the cutoff radius. The dissipative force is a friction force that tries to reduce velocity differences between DPD particles. D
Fij⃗ = −γω 2(rij)(riĵ ·vij⃗ )riĵ
(4)
where γ is the friction coefficient governing the magnitude of the dissipative force, vi⃗ j = vi⃗ − vj⃗ . The weight function ω(rij) provides the range of interaction for DPD particle ⎧ 1 − rij ⎪ rij < rC ω(rij) = ⎨ rC ⎪ rij ≥ rC ⎩ 0
(5)
The random force compensates the loss of energy due to the dissipative force reducing the relative momentum R
Fij⃗ = σω(rij)θijriĵ
(6)
where σ is the noise amplitude that controls the intensity of the random force. θij is a randomly fluctuating variable with normal distribution. The values of friction coefficient and noise magnitude are related by
SIMULATION METHOD A. DPD Method. DPD simulation technique was invented and developed for simulating hydrodynamic behavior by Hoogerbrugger and Keolman28 in 1992 and successfully applied by Groot and Warren29 in 1997. It is a coarse-grained, mesoscopic simulation technique and has been extensively employed to study the self-assembly behavior of amphiphilic block copolymer in dilute solution,30−32 the microstructure and microphase separation of polymer melts,33−35 vesicle fusion and fission,36−39 and vesicle formation mechanisms.40,41 Because of the use of soft, short-ranged interparticle forces and a momentum-conserving thermostat, DPD method can correctly simulate complex fluid systems. In DPD, similar to coarsegrained molecular dynamics (MD), each DPD particle that interacts via an effective force field combines several atoms or atomic groups. All the particles obey Newton’s equations of motion29 f⃗ dvi⃗ = i dt mi
D
+ Fij⃗ + Fij⃗ )
j≠i
■
d ri ⃗ = v⃗, dt
C
∑ (Fij⃗
σ 2 = 2γkBT
(7)
where kB is the Boltzmann’s constant and T is the equilibrium temperature. In our simulation, the units of mass, length, time, and energy are scaled by the particle mass m, cutoff distance rC, time τ, and thermal energy kBT, respectively. The time unit τ is defined as τ = (mrC2 /kBT)1/2.The remaining simulation parameters are σ = 3.0, γ = 4.5, Δt = 0.03τ. In addition, we employ the finitely extensible nonlinear elastic (FENE) potential between the consecutive particles42 ⎧ 2⎤ ⎡ ⎪− 1 kR 2 ln⎢1 − ⎛⎜ rij ⎞⎟ ⎥ r < R ⎪ 0 ij 0 ⎢⎣ ⎝ R 0 ⎠ ⎥⎦ VFENE(rij) = ⎨ 2 ⎪ ⎪ rij ≥ R 0 ∞ ⎩
(8)
We choose k = 30 and R0 = 1.5rC. The value of FENE spring k is strong enough to make bond crossings energetically infeasible. B. Model and Condition. In the simulation, we consider the amphiphilic multiblock copolymer synthesized by Jiang et al.21 to mimic the HPC-PAA copolymer qualitatively, a model polymer AmBnAmBnAm with hydrophilic A beads and hydro-
(1)
where ri⃗ , vi⃗ , mi, and fi⃗ denote the position, velocity, mass of the ith particle, and the acting force on it, respectively. For the sake 16011
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 1. Snapshots showing the aggregates formed by A1B8A1B8A1 multiblock copolymers with aBS = 75 and different aAS = 65 (a), 60 (b), 40 (c), and 20 (d). For a better understanding, the enlarged slices of aggregates are also given. The hydrophilic and hydrophobic beads are marked in green and red, respectively.
vesicle size are revealed. In addition, the detailed molecular packing in the vesicle membrane was also demonstrated. A. Effect of Temperature on the Formation of Vesicles. 1. Comparison between Experiments and Simulations. HPC is a thermosensitive polysaccharide with low critical solution temperature in aqueous solution (41 °C). Complexation between HPC and PAA further decrease the phase-transition temperature of HPC.45 On the basis of CLSM images, it is concluded that HPC-PAA vesicles were formed through nucleation and growth pathway with the temperature decreases when the polymerization of AA was stopped. The general character of the experimental observation is that the temperature can influence the pathway of vesicle formation. The influence of temperature on thermosensitive block HPC can be revealed through the solvent quality, so it can be represented by the interaction parameter between the solvent and thermosensitive block in DPD simulations. In other words, the value of aAS rises with the increase of temperature.43 It is note worthy that all the interaction parameters between solvent and polymer (HPC segments, complexed HPC-PAA segments) may change with temperature. However, HPC segments exhibit a remarkable hydration-dehydration change in the temperature variation process,45 especially around the LCST which can indicate a significant change in the interaction parameter of solvent-HPC (aAS). The hydrophobicity of complexed HPCPAA segments (aBS) only have a slightly change during the process of temperature variation. Therefore, for simplicity, only aAS was varied to investigate the effect of temperature on the morphology and formation of vesicle. Figure 1 shows the morphologies of the A1B8A1B8A1 assemblies with different interaction parameters aAS. Figure 1a shows the spherical micelle forms with higher aAS = 65. As the aAS decreases, small hollow center appears in the spherical micelle when the aAS = 60 and the cavity expands and the membrane thickness decreases further with aAS = 40 and 20. Furthermore, we also investigated the kinetic evolution of the vesicular morphologies. The snapshots showing the aggregated morphologies are given in Supporting Information Figure S1. The kinetic evolution process is consistent with that mentioned above. During the kinetic process, the hydrophilicity of A-blocks is gradually enhanced, thereby leading to reassembly of copolymers into the vesicles to reduce the interfacial energy when lowering the
phobic B is proposed. Solvent beads (denoted by S) are included explicitly in the simulation, but they are not shown in the following figures for simplicity and clarity. The simulations of 81 000 DPD particles at a number density 3 were performed in a cube box with a size of 30 × 30 × 30 with periodic boundary conditions. A cube box with a size of 20 × 20 × 20 was also adopted in order to clearly analyze the vesicle properties, such as the aqueous cavity size, membrane thickness, and vesicle size. The different size of boxes does not affect the formation of aggregations except the number of aggregates in the boxes.43 The copolymer volume fraction is 0.1 unless otherwise stated. The interaction parameter aij is determined by the characteristic of the beads (either hydrophilic or hydrophobic).44 We take the interaction parameter between the same type of beads to be aii = 25 (measured in unit of kBT), and the interaction parameter between the hydrophilic and hydrophobic beads to be aij = 50. That is, the interaction parameter aAA, aBB, aSS are set to be 25, and aAB is set to be 50. In this work, each simulation takes at least 1 × 106 steps so that the simulation system can achieve an equilibrium state. More than 10 simulations with different initial conditions were carried out to ensure the equilibrium is independent upon the initial conditions.
■
RESULTS AND DISCUSSION
In this study, dissipative particle dynamics is applied to investigate the morphological aggregates and thermosensitive behaviors of multiblock copolymers in selective solvent. The structural characteristics of vesicles formed by multiblock copolymers are also investigated. The simulation results are given in two parts. First, comparisons between our simulation results and the experimental findings were proposed to elucidate the validity of our model multiblock copolymer and simulation approach. The formation of vesicles through a nucleation and growth pathway with temperature was also observed. The morphological phase diagram of A1BnA1BnA1 was obtained to demonstrate the effects of temperature and B-block lengths. The second part describes the effects of hydrophilic and hydrophobic block length on the structural characteristics of vesicles. The relationship between the hydrophilic and hydrophobic block length versus the aqueous cavity size and 16012
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 2. Radial density function of (a) the hydrophilic block ΦA(r), and (b) the hydrophobic block ΦB(r) plotted as a function of the distance r from the mass center of the aggregates at aAS = 20 (solid), 40 (dash), and 60 (dash dot) for A1B8A1B8A1 at aBS = 75. Note that normalizations have been chosen such that 4π∫ R0 ϕA(r)r2 dr = NAagg, the total number of hydrophilic beads in the selected aggregate, and 4π∫ R0 ϕB(r)r2 dr = NBagg, the total number of hydrophobic beads in the selected aggregate.
value of aAS. The process of vesicles formation is consistent with the experimental observation.21 Figure 2 shows the variation of the densities of block A and block B with the distance from the mass center of the vesicles formed by A1B8A1B8A1 with interaction parameter aAS = 60, 40, and 20. We can find hydrophilic block A gradually moves away from the center of the vesicle with the decrease in aAS, which indicates the cavity size of the vesicle growing larger. The variation of block B is similar to block A (Figure 2b). The simulation results indicate that the cavity volume and vesicle size gradually increase with decreasing aAS. Moreover, the cavity size grows more significantly than the vesicle size, which can also be verified by the following Figure 5. 2. Effect of Temperature and Hydrophobic Block Length. In order to investigate the effects of the temperature and the hydrophobic B-block length, a morphological phase diagram is constructed with aAS and A1BnA1BnA1 as shown in Figure 3.
order to reduce the interfacial energy of spherical micelles. Note that for shorter B blocks the solvent has a stronger influence on the hydrophilic segments due to the higher fraction of hydrophilic A-block, resulting in vesicle formation when aAS is smaller than 50. However, as the B-block length becomes longer, vesicles form with larger region of aAS because the solvent has a slight influence on the hydrophilic blocks with the lower fraction. On the other hand, from the phase diagram we can find that multiblock copolymers with different hydrophobic block length easily self-assemble to vesicles in a large parameter scope. In addition, we analyzed the structural characteristics of vesicles formed at different aAS. As shown in Figure 4, the
Figure 4. Schematic illustration of a typical vesicle. Rin is the cavity radius, d is the wall thickness of the hydrophobic membrane, and Rout is the vesicle size.
vesicle size is defined as the outer radius Rout, and the aqueous cavity size is defined as the inner radius Rin, and the wall thickness d is determined by the difference between the outer and inner hydrophobic membranes. Here, the outer or inner radii are defined as the average distance from the center of mass of the vesicle to the last bead of tail. The wall thickness d is the thickness of hydrophobic membrane.16,46 The changes in the vesicle size (Rout), wall thickness (d), and aqueous volume or the cavity size (Rin) are then analyzed for vesicle characteristics based on different interaction parameter aAS. Figure 5 presents plots of relationship between vesicular radius, membrane thickness, and interaction parameter aAS. We choose 30 samples of vesicles formed by the copolymer with
Figure 3. Morphological phase diagram of aggregates formed by copolymer A1BnA1BnA1 as a function of temperature (aAS) and hydrophobic block length (n) with aBS = 75.
From the figure, we can only see two types of aggregates, spherical micelles and vesicles. In general, vesicles take shape at small values of aAS and spherical micelles develop for large aAS. It is clear that spherical micelles form when the hydrophilic Ablock are not rather hydrophilic (that is, as temperature exceeds the LCST and thus large aAS). At the temperature below the LCST, A-block is soluble in solvent and vesicles can form in 16013
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 6. Relationship between the average vesicular radius and Bblock length with aAS = 25 and aBS = 75 for multiblock copolymer (A1BnA1BnA1). The hydrophilic and hydrophobic beads are marked in green and red, respectively. Here, the number concentration of copolymer is fixed.
Figure 5. Relationship between the averaged vesicular radius and interaction parameter aAS with aBS = 75 obtained from the multiblock copolymer A1B8A1B8A1. Note that the number concentration of copolymer is fixed.
A ratio increases. Vesicles decrease the interfacial area of the inner and outer of vesicle through shrinking and densely packing in order to reduce the interfacial energy between the solvent and the inner or outer surface of vesicle. Moreover, it is clear that the membrane thickness increases with increasing of the B-block length. It is in agreement with the previous experimental and theoretical findings.16,23,47 For the sake of understanding the vesicles in details and demonstrating the inner structure diversity, the density distributions of A and B blocks for two typical vesicles are plotted in Figure 7. Figure 7a,b shows radial density distributions of vesicles from A1B4A1B4A1 and A1B12A1B12A1 copolymers, respectively. As can be seen from Figure 7a, the density of A-block reaches a maximum and gradually decreases with the distance r. The hydrophobic membrane thickness is to lower to segregate the hydrophilic block locating in the outer and inner surface of the vesicle. However, the density of Ablock appears two peaks with the distance r in Figure 7b. This indicates that with the increase of B-block length, the membrane thickness also increases. Moreover, the density of B-block is larger and closer to the center of vesicle for A1B12A1B12A1 copolymer than that for A1B4A1B4A1 copolymer. This also indicates that the cavity size decreases with the increase of B-block length. 2. Effect of Hydrophilic Block Length. Figure 8 presents the variation of the averaged radius of vesicles with different Ablock length for a series of A m B 8 A m B 8 A m multiblock copolymers. The quantified aqueous cavity size and vesicle size with different A-block length are given in Supporting Information Table S3. From the figure, we can see that the inner radius (Rin) of vesicle decreases and the outer radius (Rout) of vesicle increases with the increasing of the A-block length. The increase of the A-block length enhances the solubility of copolymers, and the hydrophilic blocks prefer to segregate to reduce the repulsive interactions among the outer and inner chains. Then, we analyzed the block density variation from the mass center of the vesicles in order to get more deep insight into the structure of vesicles. The typical results of A-block density ΦA(r) and B-block density ΦB(r) for the two vesicles are presented in Figure 9. It can be seen that the densities for blocks A and B in the vesicle center are zero. Two peaks for the curve of A-block are corresponding to the densities of A-block at inner surface and outer surface of the vesicle, respectively. Moreover, we can find that the density of A-block in vesicle
interval of 1 × 103 DPD steps after achieving the equilibrium state for each system and computed the average distances of inner radius, outer radius, and wall thickness, respectively. The quantified aqueous cavity size, membrane thickness, and vesicle size with different solvent-A block interactions are given in Supporting Information Table S1. As can be seen from Figure 5, the radii of the cavity and the vesicle both gradually decrease with increasing aAS. As mentioned above, the increase in aAS results in a strengthened repulsive interaction between the hydrophilic blocks and solvent. As the interaction parameter aAS increases, the solvent gradually becomes insoluble for hydrophilic segments and the hydrophilic segments begin to shrink in the corona and pack more densely to reduce the interfacial energy of the vesicle, leading to the contraction of the vesicle. However, the membrane thickness gradually increases with an increase in solvent-A-block interaction (aAS). For a larger value of aAS, the hydrophilic segments are insoluble in the solvent and partly move into the membrane of vesicle in order to minimize the interfacial energy, resulting in the increase of the membrane thickness. The increasing trend of the membrane thickness with the increase of aAS is consistent with the experimental observations.23 The variations of aqueous cavity size and vesicle size as well as the membrane thickness are consistent with the results in Figure 2. These simulation results indicate that the temperature is an effective factor in the structural characteristics of vesicles. B. Structural Characteristics of Vesicles. Polymer vesicles not only encapsulate soluble substance in their cavities but also accumulate insoluble substance in their shells. Furthermore, the large cavity of vesicle may deliver larger and more hydrophilic drugs. The size of the cavity and the thickness of the membrane for vesicles determine the encapsulation efficiency for hydrophilic and hydrophobic drugs. In the following section, we present the effect of hydrophilic and hydrophobic block length on structural properties of vesicles, such as the size of the cavity and the membrane thickness. 1. Effect of Hydrophobic Block Length. Figure 6 shows the averaged aqueous cavity size of vesicles and vesicle size as a function of B-block length. The quantified aqueous cavity size and vesicle size with different B-block length are given in Supporting Information Table S2. From the figure, we can see that the cavity size and the vesicle size decrease with the increase of B-block length. This is due to the increase of the hydrophilic segments in the inner and outer of vesicle as the B/ 16014
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
Figure 7. Radial density distributions of the hydrophilic A-block and the hydrophobic B-block with aAS = 25 and aBS = 75 for vesicles self-assembled from (a) A1B4A1B4A1 and (b) A1B12A1B12A1 with the distance r from the mass center of the aggregates.
blocks in a copolymer molecule and one of them locating in the middle of the copolymer, the packing mode of multiblock copolymer consisting of vesicle is much more complex compared with diblock or triblcok copolymers and other types of block copolymers. We observed and analyzed the packing modes of polymer chains from simulation structures of vesicles. An illustration of the chain packing in a typical vesicle is given in Figure 10. There are three packing modes in the
Figure 8. Variation of averaged radius of vesicles with different A-block length for multiblock copolymer (AmB8AmB8Am) with aAS = 25 and aBS = 75. The hydrophilic and hydrophobic beads are marked in green and red, respectively. Here, the number concentration of copolymer is fixed.
formed by A1B8A1B8A1 is obviously lower than that in vesicle formed by A4B8A4B8A4. From the peak position for curve of Ablock, the inner and outer hydrophilic membrane thickness of vesicle formed by A4B8A4B8A4 is greater than that of vesicle formed by A1B8A1B8A1, which is in agreement with the results shown in Figure 8. The packing modes of polymer chains within the vesicle membrane are also investigated. Because of three hydrophilic
Figure 10. Illustration of the packing modes of polymer chains within the vesicle membrane. The circle represents the membrane of vesicle.
vesicle membrane that are defined as m-type, v-type, and htype, respectively. In m-type mode, the hydrophobic segments are embedded in the vesicle membrane. The hydrophilic
Figure 9. Radial density distributions of the hydrophilic A-block and the hydrophobic B-block with aAS = 25 and aBS = 75 for vesicles self-assembled from (a) A1B8A1B8A1 and (b) A4B8A4B8A4 with the distance r from the mass center of the aggregates. 16015
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir segments locate simultaneously on the inner or outer surfaces of the vesicle membrane. In v-type mode, the two hydrophobic segments simultaneously bridge through the vesicle membrane, and the middle and end of hydrophilic segments locate on outside and inside hydrophilic surfaces of the vesicle respectively or vice versa. In h-type mode, one hydrophobic segment is embedded in the vesicle membrane and the other hydrophobic segment penetrates the vesicle membrane; the two ends of the copolymer locate on different hydrophilic surfaces of the vesicle.
■
CONCLUSIONS
■
ASSOCIATED CONTENT
ACKNOWLEDGMENTS
■
REFERENCES
We thank Professor Xiqun Jiang for his providing the experimental work and valuable discussions. This work was financially supported by the National Natural Science Foundation of China (Grants 21074053 and 51133002) and National Basic Research Program of China (Grant 2010CB923303).
(1) Soo, P. L.; Eisenberg, A. Preparation of Block Copolymer Vesicles in Solution. J. Polym. Sci., Part B: Polym. Phys. 2004, 42, 923− 938. (2) Discher, D. E.; Eisenberg, A. Polymer Vesicles. Science 2002, 297, 967−973. (3) Shen, H. W.; Eisenberg, A. Control of Architecture in BlockCopolymer Vesicles. Angew. Chem., Int. Ed. 2000, 39, 3310−3312. (4) Yu, K.; Eisenberg, A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution. Macromolecules 1998, 31, 3509−3518. (5) Zhang, L. F.; Eisenberg, A. Multiple Morphologies and Characteristics of “Crew-Cut” Micelle-Like Aggregates of Polystyrene-b-Poly(acrylic acid) Diblock Copolymers in Aqueous Solutions. J. Am. Chem. Soc. 1996, 118, 3168−3181. (6) Zhang, L. F.; Eisenberg, A. Multiple Morphologies of Crew-Cut Aggregates of Polystyrene-b-Poly(acrylic acid) Block-Copolymers. Science 1995, 268, 1728−1731. (7) Tanner, P.; Baumann, P.; Enea, R.; Onaca, O.; Palivan, C.; Meier, W. Polymeric Vesicles: From Drug Carriers to Nanoreactors and Artificial Organelles. Acc. Chem. Res. 2011, 44, 1039−1049. (8) Brinkhuis, R. P.; Rutjes, F. P. J. T.; van Hest, J. C. M. Polymeric Vesicles in Biomedical Applications. Polym. Chem. 2011, 2, 1449− 1462. (9) Walde, P.; Cosentino, K.; Engel, H.; Stano, P. Giant Vesicles: Preparations and Applications. ChemBioChem. 2010, 11, 848−865. (10) LoPresti, C.; Lomas, H.; Massignani, M.; Smart, T.; Battaglia, G. Polymersomes: Nature Inspired Nanometer Sized Compartments. J. Mater. Chem. 2009, 19, 3576−3590. (11) Liu, Z.; Jiang, Z. B.; Yang, H.; Bai, S. M.; Wang, R.; Xue, G. Crowding Agent Induced Phase Transition of Amphiphilic Diblock Copolymer in Solution. Chin. J. Polym. Sci. 2013, 11, 1491−1500. (12) Battaglia, G.; Ryan, A. J. Bilayers and Interdigitation in Block Copolymer Vesicles. J. Am. Chem. Soc. 2005, 127, 8757−8764. (13) Azzam, T.; Eisenberg, A. Control of Vesicular Morphologies through Hydrophobic Block Length. Angew. Chem., Int. Ed. 2006, 45, 7443−7447. (14) Bermudez, H.; Brannan, A. K.; Hammer, D. A.; Bates, F. S.; Discher, D. E. Molecular Weight Dependence of Polymersome Membrane Structure, Elasticity, and Stability. Macromolecules 2002, 35, 8203−8208. (15) Luo, L. B.; Eisenberg, A. Thermodynamic Size Control of Block Copolymer Vesicles in Solution. Langmuir 2001, 17, 6804−6811. (16) Xiao, M. Y.; Liu, J. N.; Yang, J. X.; Wang, R.; Xie, D. Q. Biomimetic Membrane Control of Block Copolymer Vesicles with Tunable Wall Thickness. Soft Matter 2013, 9, 2434−2442. (17) Dimitrov, I.; Trzebicka, B.; Muller, A.; Dworak, A.; Tsvetanov, C. B. Thermosensitive Water-Soluble Copolymers with Doubly Responsive Reversibly Interacting Entities. Prog. Polym. Sci. 2007, 32, 1275−1343. (18) Meng, F. H.; Zhong, Z. Y.; Feijen, J. Stimuli-Responsive Polymersomes for Programmed Drug Delivery. Biomacromolecules 2009, 10, 197−209. (19) Cai, C. H.; Zhang, L. S.; Lin, J. P.; Wang, L. Q. Self-Assembly Behavior of pH- and Thermosensitive Amphiphilic Triblock Copolymers in Solution: Experimental Studies and Self-Consistent Field Theory Simulations. J. Phys. Chem. B 2008, 112, 12666−12673. (20) Gil, E. S.; Hudson, S. M. Stimuli-Reponsive Polymers and Their Bioconjugates. Prog. Polym. Sci. 2004, 29, 1173−1222.
The formation and structural characteristics of vesicle formed by amphiphilic multiblock copolymer ABABA in a selective solvent are explored by dissipative particle dynamics method, which can provide valuable microscopic insights and complement the deficiency of experimental studies. In order to confirm the validity of our DPD model of multiblock copolymer, our simulation findings are compared with the experimental results by Jiang et al. The influence of temperature on HPC is realized by the solvent property (aAS), where lower temperature can depict good solvent (smaller aAS) and higher temperature can indicate poor solvent (larger aAS). On the basis of the variation of solvent quality for A-block, our simulations of the multiblock copolymers show that the vesicle formed through nucleation and growth mechanism. This finding is in agreement with the experimental observation. We also analyzed the structure property of vesicles formed at different temperatures. It is found that the vesicle size and cavity size both decrease with increasing temperature and the membrane thickness grows with the increase of temperature. The structure of the vesicle formed by multiblock copolymer with various hydrophilic or hydrophobic block lengths is also studied. Simulation results reveal that the ratio of hydrophilic/ hydrophobic block and the hydrophilicity of A-block largely affect the aqueous cavity size, membrane thickness, and vesicle size. The copolymers with shorter hydrophobic blocks length or the higher hydrophilicity are more likely to form vesicles with larger aqueous cavity size and vesicle size as well as thinner wall thickness. However, the increase in A-block length results in forming vesicles with smaller aqueous cavity size and larger vesicle size. The polymer chains packing mode within the vesicle membrane is also investigated. It was observed that the structure of amphiphilic copolymer has a large impact on the packing mode of polymer chains. Thus, the findings presented in this paper might provide a new approach for preparing sizecontrolled polymer vesicles.
S Supporting Information *
Figure of the dynamics evolution process of vesicle and tables of quantified aqueous cavity size, membrane thickness, and vesicle size of vesicles. This material is available free of charge via the Internet at http://pubs.acs.org.
■
■
Article
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Notes
The authors declare no competing financial interest. 16016
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
Langmuir
Article
(21) Qian, H. Q.; Yao, W.; Yu, S. L.; Chen, Y.; Wu, W.; Jiang, X. Q. Spontaneous Formation of Giant Polymer Vesicles through a Nucleation and Growth Pathway. Chem. Asian J. 2012, 7, 1875−1880. (22) Korchagina, E. V.; Qiu, X. P.; Winnik, F. M. Effect of Heating Rate on the Pathway for Vesicle Formation in Salt-Free Aqueous Solutions of Thermosensitive Cationic Diblock Copolymers. Macromolecules 2013, 46, 2341−2351. (23) Lian, X. M.; Wu, D. X.; Song, X. H.; Zhao, H. Y. Synthesis and Self-Assembly of Amphiphilic Asymmetric Macromolecular Brushes. Macromolecules 2010, 43, 7434−7445. (24) Menger, F. M.; Lu, H.; Lundberg, D. A-B-A-B-A Block Amphiphiles. Balance Between Hydrophilic and Hydrophobic Segmentation. J. Am. Chem. Soc. 2007, 129, 272−273. (25) Sommerdijk, N. A. J. M.; Holder, S. J.; Hiorns, R. C.; Jones, R. G.; Nolte, R. J. M. Self-Assembled Structures From an Amphiphilic Multiblock Copolymer Containing Rigid Semiconductor Segments. Macromolecules 2000, 33, 8289−8294. (26) Hadjiantoniou, N. A.; Triftaridou, A. I.; Kafouris, D.; Gradzielski, M.; Patrickios, C. S. Synthesis and Characterization of Amphiphilic Multiblock Copolymers: Effect of the Number of Blocks on Micellization. Macromolecules 2009, 42, 5492−5498. (27) Zhang, J.; Lu, Z. Y.; Sun, Z. Y. Self-Assembly Structures of Amphiphilic Multiblock Copolymer in Dilute Solution. Soft Matter 2013, 9, 1947−1954. (28) Hoogerbruggge, P. J.; Koelman, J. M. V. A. Simulating Microscopic Hydrodynamic Phenomena with Dissipative Particle Dynamics. Europhys. Lett. 1992, 19, 155−160. (29) Groot, R. D.; Warren, P. B. Dissipative Particle Dynamics: Bridging the Gap Between Atomistic and Mesoscopic Simulation. J. Chem. Phys. 1997, 107, 4423−4435. (30) Wang, H.; Liu, Y. T.; Qian, H. J.; Lu, Z. Y. Dissipative Particle Dynamics Simulation Study on Complex Structure Transitions of Vesicles Formed by Comb-Like Block Copolymers. Polymer 2011, 52, 2094−2101. (31) He, P. T.; Li, X. J.; Kou, D. Z.; Deng, M. G.; Liang, H. J. Complex Micelles from the Self-Assembly of Amphiphilic Triblock Copolymers in Selective Solvents. J. Chem. Phys. 2010, 132, 204905. (32) Li, X. J.; Pivkin, I. V.; Liang, H. J.; Karniadakis, G. E. Shape Transformations of Membrane Vesicles from Amphiphilic Triblock Copolymers: A Dissipative Particle Dynamics Simulation Study. Macromolecules 2009, 42, 3195−3200. (33) Gavrilov, A. A.; Kudryavtsev, Y. V.; Khalatur, P. G.; Chertovich, A. V. Microphase Separation in Regular and Random Copolymer Melts by DPD Simulations. Chem. Phys. Lett. 2011, 503, 277−282. (34) Tang, Y. H.; He, Y. D.; Wang, X. L. Effect of Adding a Second Diluent on the Membrane Formation of Polymer/Diluent System via Thermally Induced Phase Separation: Dissipative Particle Dynamics Simulation and Its Experimental Verification. J. Membr. Sci. 2012, 409, 164−172. (35) He, Y. D.; Tang, Y. H.; Wang, X. L. Dissipative Particle Dynamics Simulation on the Membrane Formation of PolymerDiluent System via Thermally Induced Phase Separation. J. Membr. Sci. 2011, 368, 78−85. (36) Grafmuller, A.; Shillcock, J.; Lipowsky, R. The Fusion of Membranes and Vesicles: Pathway and Energy Barriers from Dissipative Particle Dynamics. Biophys. J. 2009, 96, 2658−2675. (37) Yamamoto, S.; Hyodo, S. Budding and Fission Dynamics of Two-Component Vesicles. J. Chem. Phys. 2003, 118, 7937−7943. (38) Wu, S. G.; Guo, H. X. Simulation Study of Protein-Mediated Vesicle Fusion. J. Phys. Chem. B 2009, 113, 589−591. (39) Liu, Y. T.; Zhao, Y.; Liu, H.; Liu, Y. H.; Lu, Z. Y. Spontaneous Fusion between the Vesicles Formed by A2n(B2)n Type Comb-Like Block Copolymers with a Semiflexible Hydrophobic Backbone. J. Phys. Chem. B 2009, 113, 15256−15262. (40) Xiao, M. Y.; Xia, G. J.; Wang, R.; Xie, D. Q. Controlling the SelfAssembly Pathways of Amphiphilic Block Copolymers into Vesicles. Soft Matter 2012, 8, 7865−7874. (41) Chen, H. Y.; Ruckenstein, E. Self-Assembly of π-Shaped Copolymers. Soft Matter 2012, 8, 1327−1333.
(42) Kroger, M.; Hess, S. Rheological Evidence for a Dynamical Crossover in Polymer Melts via Nonequilibrium Molecular Dynamics. Phys. Rev. Lett. 2000, 85, 1128−1131. (43) Chang, H. Y.; Lin, Y. L.; Sheng, Y. J. Multilayered Polymersome Formed by Amphiphilic Asymmetric Macromolecular Brushes. Macromolecules 2012, 45, 4778−4789. (44) Chen, H. Y.; Ruckenstein, E. Nanoparticle Aggregation in the Presence of a Block Copolymer. J. Chem. Phys. 2009, 131, 244904. (45) Lu, X. H.; Hu, Z. B.; Schwartz, J. Phase Transition Behavior of Hydroxypropylcellulose under Interpolymer Complexation with Poly(acrylic acid). Macromolecules 2002, 35, 9164−9168. (46) Lin, C. M.; Li, C. S.; Sheng, Y. J.; Wu, D. T.; Tsao, H. K. SizeDependent Properties of Small Unilamellar Vesicles Formed by Model Lipids. Langmuir 2012, 28, 689−700. (47) Ma, L.; Eisenberg, A. Relationship between Wall Thickness and Size in Block Copolymer Vesicles. Langmuir 2009, 25, 13730−13736.
16017
dx.doi.org/10.1021/la404157h | Langmuir 2013, 29, 16010−16017
