Self-Assembly of Two Agents in a Core-Shell-Corona Multicompartment Micelle Studied by Dissipative Particle Dynamics Simulations

Self-Assembly of Two Agents in a Core-Shell-Corona

Multicompartment Micelle Studied by Dissipative

Particle Dynamics Simulations

Jun Xia, Chongli Zhong*

Department of Chemical Engineering, The Key Lab of Bioprocess of Beijing, Beijing University of Chemical Technology,Beijing 100029, P. R. ChinaFax: þ86-10-64419862; E-mail: [email protected]

Received: June 14, 2006; Revised: July 25, 2006; Accepted: July 26, 2006; DOI: 10.1002/marc.200600411

Keywords: block copolymers; computer modeling; density distribution; dissipative particle dynamics; multicompartmentmicelle

Introduction

Multicompartment micelles, introduced about ten years

ago, can provide interesting morphologies for nanotechno-

logy.[1–3] To date various multicompartment micelles have

been designed and investigated,[3–8] and increasing atten-

tion is being paid to their potential applications as nano-

containers to solubilize two or more incompatible agents

within separate nanoscopic compartments.[9] The core-

shell-corona micelle is a simple morphology of multi-

compartment micelles that can be formed from linear ABC

triblock copolymers. These ‘three-layer’ micelles have

been used in the development of new nanotechnological

applications, such as drug delivery and catalysis.[10–12]

To date, investigations on the simultaneous storage of two

kinds of hydrophobic agents in core-shell-corona micelles

are very scarce, to which molecular simulation is a powerful

tool that can give insight into molecular-level details of the

extent and the locus of solubilization. However, to date, no

such simulation studies have been performed.

To have a molecular understanding of the solubilization

of two or more agents in multicompartment micelles, the

Summary: Dissipative particle dynamics simulations areperformed on the distributions of two agents in a core-shell-corona multicompartment micelle. The simulated resultsshow that when the agents are weakly hydrophobic, theirdistributions in the multicompartment micelle are largelyaffected by the interactions between the agents and theblocks; while for strongly hydrophobic agents, the self-assembly of solubilized species in the micelle is also affected

largely by the interactions between the species. This workconfirms that a multicompartment micelle can store twoagents within separate nanoscopic compartments simulta-neously, and shows that the distributions of the agents can betailored easily by changing the interactions presented. Thisprovides molecular-level information that is useful for thefuture rational design of new micellar systems with tailoredproperties.

Simulated cross sections of the multicompartment micelles with strongly hydrophobicsolubilized agents (the solvent and block A are omitted for clarity, block B is dark gray,block C is light gray, agent P is white, and agent Q is black).

Macromol. Rapid Commun. 2006, 27, 1654–1659 � 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

1654 DOI: 10.1002/marc.200600411 Communication

dissipative particle dynamics (DPD) technique is employed

here to study the self-assembly of two agents in a core-shell-

corona multicompartment micelle, to which particular

attention is paid to the influences of the interactions bet-

ween the agents as well as between the agents and the

blocks.

Experimental Part

Dissipative Particle Dynamics (DPD) Method

The DPD method, originally developed by Hoogerbrugge andKoelman,[13,14] is a mesoscopic simulation technique that canbe used to study systems over greater length and time scalesthan are accessible in classical molecular dynamics and MonteCarlo simulations, and this larger scale simulation is veryimportant for investigating the behavior of polymers. TheDPD method has been successfully used to study the micro-structures and properties of polymers in the bulk state and insolvent.[15–24] Details of the DPD method are given by Grootand co-workers.[15,25]

Models and Parameters

In this work, multicompartment micelles formed from linearABC triblock copolymers in water were studied. Block A wasdefined to be hydrophilic, block B weakly hydrophobic, andblock C strongly hydrophobic. The ABC copolymer chain wasmodeled as a 10þ 8þ 2 spring-bead chain that was denotedA10B8C2. The two hydrophobic agents, denoted as P and Q, aswell as the solvent (denoted as S) were modeled as single DPDbeads. Furthermore, agent P was compatible with block B,while agent Q was compatible with block C.

There were six components in the system, and thus there werea total of 15 pairs of DPD parameters (aij) to describe theinteractions between the components in the system. As a result,some parameters had to be fixed and the study focused on theeffects of the other ones. In this work, the influence of theinteractions between the agents as well as between the agentsand the blocks were of interest. Therefore, the interactionsbetween the blocks and those between the blocks and the solventwere fixed. This was equivalent to studying the assembly ofvarious agents in a given micelle. The DPD parameters for themwere selected asaAS¼ 25,aBC¼ 60,aAB¼ aBS¼ 40, andaAC¼aCS¼ 90 to make the A10B8C2 copolymers assemble into core–shell–corona multicompartment micelles in water. Since agentP was compatible with block B, and agent Q was compatiblewith block C, aBP¼aCQ¼ 25 was set. According to the study ofGroot and Warren,[25] the bead density in the simulations can beeither 3 or 5. It was set to 3 in this work so that less computationalefforts were required. To make sure this selection did not affectthe simulation results, some parallel simulations using a beaddensity of 5 were carried out to demonstrate that the choice ofbead density did not affect the main results and the conclusionsderived. For a bead density of 3, the repulsion parameterbetween like particles was aii¼ 25 according to the work ofGroot and Madden.[15]

Simulation Details

The DPD simulations were performed in a cubic cell of size25� 25� 25 rc

3, which contained a total of about 47 000 DPDbeads. Periodic boundary conditions were applied and thevolume fraction of the copolymer was set to be 0.1 to ensure thesystem could form enough micelles. The volume fractions ofthe two hydrophobic agent beads were identical and they wereboth set to 0.01. For convenience, the cut-off radius rc, theparticle mass m, and kBTwere all taken as unity. The time stepDt was taken as 0.05, and adjacent particles in the polymerchain interacted via a linear spring with a harmonic springconstant of 4.0. The number of DPD steps carried out for a DPDsimulation in this work was (2–4)� 105, and depended on thesystem concerned as previously reported.[16–19]

Results and Discussion

Validation of the DPD Method

Although the DPD technique has been used successfully to

describe the formation of multicompartment micelles from

star triblock copolymers[18] and linear pentablock copoly-

mers in water,[19] as well as the cooperative self-assembly

of nanoparticle mixtures in block copolymers[17] in our

previous work, it is further validated for describing solubili-

zation in micelles by comparison with the Monte Carlo

(MC) simulations of Xing and Mattice[26] in this work. They

investigated the solubilization of insoluble agents (IA) in

A5B10A5 micelles where the volume fraction of solubilizate

varied from 0.0078 to 0.125, the polymer volume fraction

was 0.04, and a total of 128 chains were considered. Their

simulations show that a transition of a micellar structure

into a droplet microemulsion occurs as more IA is added to

the system. Our DPD simulations can reproduce their

observations under similar conditions. This, together with

our previous work,[17–19] indicates that the DPD technique

is reliable for studying the self-assembly of agents in multi-

compartment micelles.

Self-Assembly of Two Agents inMulticompartment Micelles

Here the focus is on the investigation of the effects of the

interactions between the agents as well as between the

agents and the blocks on the self-assembly of the two agents

in multicompartment micelles. Even so, there are a total of 7

pairs of DPD parameters to be considered. Therefore, case

studies must be performed, and two such cases are explored:

one is the case of weakly hydrophobic agents (weak solubi-

lization), and the other that of strongly hydrophobic agents

(strong solubilization).

Case 1. Weakly Hydrophobic Agents

Aweakly hydrophobic agent is defined here by setting their

interactions with the hydrophilic species (block A and

Self-Assembly of Two Agents in a Core-Shell-Corona Multicompartment Micelle Studied by . . . 1655

Macromol. Rapid Commun. 2006, 27, 1654–1659 www.mrc-journal.de � 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

water) as equal to that of the interactions of the weakly

hydrophobic block B with the hydrophilic species, thus,

aAP¼aPS¼ aAQ ¼ aQS¼ 40. To study the effects of the

interactions between the solubilizates and the blocks, two

series of simulations are performed: one is the case that the

repulsion strength between the two solubilizates is weak

(aPQ¼ 30), and the other is the case that strong repulsion

exists between the two agents (aPQ¼ 60). The repulsion is

varied between the two agents and the incompatible blocks

from 30 to 60, that is, aBQ¼ aCP¼ 30–60.

The simulated density profiles for the weak repulsion of

the two agents (aPQ¼ 30) and aBQ¼ aCP ¼ 30 (also weak

repulsion between the two agents with the incompatible

blocks) are shown in Figure 1a. Obviously, agent Q distri-

butes throughout block C with slight accumulation at the

interface of blocks B and C. Agent P, on the other hand,

distributes throughout block B with preferential occupation

of the center of the shell formed by block B. A direct

visualization of the simulated multicompartment micelle

with the two agents is given in Figure 1c. When the repul-

sion between the agents and the incompatible blocks

is increased to 60, that is aBQ¼ aCP¼ 60, although agent

Q still distributes throughout block C, it accumulates in the

center of the core formed by block C (Figure 1b and 1d)

instead of the interface as before (Figure 1c). The distri-

bution of agent P, however, is not largely influenced,

although agent P is no longer observed in block C because

of the strong repulsion.

Furthermore, DPD simulations of a strong repulsion be-

tween the two agents (aPQ¼ 60) are performed by varying

aBQ¼ aCP from 30 to 60. The simulated density profiles are

nearly identical to those of weak repulsion between the two

agents (aPQ¼ 30). It seems for weakly hydrophobic agents

(weak solubilization) that the localization of the solubili-

zates in multicompartment micelles is more significantly

affected by the chemistries of the blocks, and the effects of

the chemistries of the agents are less important because of

the small quantities of the solubilizates.

Case 2: Strongly Hydrophobic Agents

The self-assembly of strongly hydrophobic agents is investi-

gated by setting the interactions of the two agents with the

hydrophilic species equal to that of the strongly hydrophobic

Figure 1. a,b) Simulated density profiles for weakly hydrophobic agents solubilized in a core–shell–corona multicompartment micelle. c,d) Simulated cross sections of the multicompartmentmicelles with solubilized agents. (c) corresponds to (a) and (d) corresponds to (b) (the solvent andblock Awere omitted for clarity, block B is dark gray, block C is light gray, agent P is white, and agentQ is black).

1656 J. Xia, C. Zhong


block C with the hydrophilic species, that is, aAP¼ aPS¼aAQ¼ aQS¼ 90. Again, two cases are studied: weak (aPQ¼30) and strong (aPQ¼ 60) repulsion between the two agents.

The simulated density profiles for aPQ¼ aBQ¼ aCP¼ 30,

aPQ¼ 30, and aBQ¼ aCP¼ 60 are shown in Figure 2a and b,

respectively. Figure 2a shows that agent Q distributes uni-

formly in block C, while agent P concentrates more

preferably at the interface of blocks B and C. This is quite

different from Figure 1a, where weakly hydrophobic agents

are considered, which indicates that the hydrophobicity of

the solubilizates significantly affects their distributions in

multicompartment micelles. When the repulsion strength

between the two agents and the incompatible blocks is

increased to aBQ¼ aCP¼ 60, as depicted in Figure 2b, the

concentration of block C in the center of the core decreases

with an increase in concentration of agent Q in the center.

Meanwhile, for agent P, the change in distribution is not

large, which is similar to the case of the weakly hydro-

phobic agents. A comparison of Figure 1b and Figure 2b

shows that the distribution of agent Q is more sensitive to

the interactions within the micellar system. To have a direct

visualization of the structures of the multicompartment

micelles with agents, the cross sections of the micelles

corresponding to Figure 2a and b are shown in Figure 3a and

b, respectively.

DPD simulations for a strong repulsion between the two

agents (aPQ¼ 60) have been further performed by varying

aBQ¼ aCP from 30 to 60. In the case of aBQ¼ aCP¼ 30, as

shown in Figure 2c, agent Q concentrates more in the center

of the core, a feature that is quite different from the distri-

bution shown in Figure 2a. This illustrates that for strongly

hydrophobic agents, the repulsion between the agents also

influences their distributions, possibly mainly because of

the large quantities of solubilizates present. Although agent

P also tends to accumulate in the center of block B, the

change in distribution is not significant as compared to the

one in Figure 2a.

The DPD simulation results for aBQ¼ aCP¼ 60 are

shown in Figure 2d. Obviously, by increasing the repulsion

strength between the agents and the incompatible blocks,

agent Q accumulates strongly in the center of the core with

C blocks being pushed away from the center. This illustrates

that in the case of strong solubilization, a transition of

a micellar structure into a droplet microemulsion may

occur in multicompartment micellar systems like the

one observed in normal micellar systems by Xing and

Mattice.[26] As shown in Figure 2d and 3d, in the case of

strong repulsion between the agents and the incompatible

blocks, agent P also tends to concentrate in the center of the

shell, that is, both agents can accumulate in the centers of

the compatible blocks.

The above simulations show that for strongly hydro-

phobic agents, in contrast to case 1, the self-assembly of the

agents are affected largely by both the interactions between

the agents and that between the agents and the incompatible

blocks.

Figure 2. Simulated density profiles for strongly hydrophobic agents solubilized in a core–shell–corona multicompartment micelle.



Evolution of a Multicompartment Micelle withTwo Agents Solubilized

It is both interesting and important to reveal the formation

process of multicompartment micelles with solubilized

agents, which can be realized by examining the snapshots of

the density profiles of the evolution process. In this work,

the evolution of the multicompartment micelle that corres-

ponds to Figure 3d is adopted as an example, and the

corresponding simulated snapshots of density profiles are

shown in Figure 4. Obviously, at the beginning all the

hydrophobic components aggregate in the central area of

the ‘nucleus’, whereas the solvent in the central region of

the nucleus remains high in density and the hydrophilic

block (block A) has a low density in the central region

(t¼ 25). The B blocks are then pushed away from the center

Figure 3. Simulated cross sections of the multicompartment micelles with solubilizedagents corresponding to Figure 2 (the solvent and block Awere omitted for clarity, block B isdark gray, block C is light gray, agent P is white, and agent Q is black).

Figure 4. Evolution process of the multicompartment micelle that corresponds to Figure 2d and 3d.

1658 J. Xia, C. Zhong


by C blocks and agent Q to form the inner shell of the micelle

(t¼ 100), and the block B compatible agent (agent P) moves

to the shell with further evolution (t¼ 250). During this pro-

cess, water molecules are pushed away from the center and

the hydrophilic blocks gradually form the corona. Further-

more, agent Q pushes C blocks away from the center of the

core to accumulate in the center, and C blocks form a shell-

like structure that surrounds the accumulated agent Q with a

low concentration in the center to form the structure shown in

Figure 3d.

Conclusion

The DPD simulations show that a multicompartment

micelle can store two or more agents within separate nano-

scopic compartments simultaneously, and the distributions

of the agents can be tailored by changing the interactions

between incompatible species. For weakly hydrophobic

agents, the interactions between the agents and the blocks

play an important role, while for strongly hydrophobic

agents, the interactions between the agents also has a large

influence. The simulated results elucidate the relation be-

tween the distributions of agents in a multicompartment

micelle to the interactions present in the system, which

provides useful information for developing new nanocon-

tainers that may deliver two or more agents simultaneously.

Acknowledgements: The financial support of the NSFC(20476003) and the Specialized Research Fund for the DoctoralProgram ofHigher Education of China (20040010002) are greatlyappreciated.

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Self-Assembly of Two Agents in a Core-Shell-Corona Multicompartment Micelle Studied by Dissipative Particle Dynamics Simulations