Multilamellar Nanoparticles Self-Assembled from Opposite Charged

Article pubs.acs.org/JPCC

Multilamellar Nanoparticles Self-Assembled from Opposite Charged Blends: Insights from Mesoscopic Simulation Shuyu Nie,†,∥ Xiaofang Zhang,†,∥ Ruxandra Gref,‡ Patrick Couvreur,§ Yu Qian,† and Lijuan Zhang*,† †

School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China Institute of Molecular Sciences, UMR CNRS 8214, Université Paris Sud, Orsay, France § Institute Galien, UMR CNRS 8612, Université Paris Sud, Chatenay Malabry, France ‡

ABSTRACT: Multilamellar nanoparticles (NPs) are spontaneously formed when mixing two components with opposite charges, meaningful for drug delivery. However, details of NPs association and mechanisms of this process remain largely unknown, due to the limitation of experimental technique. In this work, we use dissipative particle dynamics (DPD) simulation for the first time to determine the structure−property relationships of multilamellar NPs formed by charged blends. As a case study, a system with polyanionic fondparinux (Fpx) and cationic derivatives squalenoyl (CSq, including Sq+ and Sq++) in aqueous media is investigated, with a focus on the optimized formation condition and mechanism of regular spherical multilamellar NPs. In particular, we find that highly ordered multilamellar structures tend to form when the nonbonded interaction between Fpx−CSq and hydrophobic interaction contributed by CSq are well-balanced. The DPD results strongly agree with corresponding experimental results of this novel nanoparticulate drug carrier. This study could help develop promising multilamellar NPs formed by charged blends through self-assembly for drug delivery.

1. INTRODUCTION Multilamellar vesicles (MLV) also called “onion-type” nanoparticles (NPs) possess a layered structure similar to that of an onion.1−4 Due to the unique structure, multilamellar NPs have been widely studied in pharmaceutical field from the experimental point of view.5−7 So far, many multilamellar NPs reported in the literature are formed from amphiphilic polymers. In these cases, drugs distribute in different regions of multilamellar structure based on their compatibility with polymers.8−11 In recent years, another type of promising multilamellar NPs for drug delivery has been developed by ion pairing approach.12−14 In this approach, drug carriers and drugs generally contain oppositely charged groups, and they are able to associate with each other to form multilamellar NPs.15−17 Among these promising multilamellar NPs, it is worth mentioning a recent work by Gref et al. dealing with the efficient encapsulation of a challenging highly charged drug, fondaparinux (Fpx).17 Fpx is a synthetic analogue of the antithrombin-binding pentasaccharide derived from heparin, to treat short- and medium-term thromboembolic disease. However, it is of very low bioavailability administrated via oral route.18 To address this issue and develop an oral form for Fpx, this polyanionic pentasaccharide has been associated with cationic squalenyl derivatives (CSq, including Sq+ and Sq++), known for their excellent oral bioavailability. Gref et al. have shown that multilamellar nanoparticulate carriers were selfassembled upon both charged groups and hydrophobic interactions between Fpx and Sq+, and the resulting multilamellar NPs dramatically increased the oral bioavailability of Fpx. However, owning to the limitation of experimental © XXXX American Chemical Society

technique, there was no detailed investigation on the association mechanism of the multilamellar NPs. Meanwhile, how polar groups and hydrophobic components affect the multilamellar structure of NPs, and what factors may induce the morphological outcomes of self-assembled macromolecules were not explored nor discussed in depth. If these issues are solved, it will greatly improve the understanding of structure− property relationship of potential multilamellar drug delivery vehicles assembled by charged blends. To overcome the limitation inherent in experiments, computational simulations have become powerful numerical experiments for providing detailed information on experimental systems in recent decades, including dynamics, distributions, and ordering of morphologies.2,19−25 Dissipative particle dynamics (DPD), proposed by Hoogerbrugge and Koelman26 in 1992 and revised by Español and Warren,27 is an effective coarse-grained simulation method to explore the phase behavior of soft matter systems. DPD provides a straightforward mesoscopic insight into the macro scale experimental system. Some DPD simulation studies have explored the microphase separation behavior of amphiphilic polymers that form multilamellar NPs in the presence of solvents.2,28,29 For instance, Chang et al. used DPD simulations to investigate the self-assembly behavior of amphiphilic comb-like graft copolymers containing a hydrophobic backbone and pH-responsive hydrophilic side chains in selective solvent, which form Received: April 21, 2015 Revised: August 11, 2015

A

DOI: 10.1021/acs.jpcc.5b03833 J. Phys. Chem. C XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry C

Figure 1. Molecular structures and coarse-grained models of (A) Fpx, (B) water, (C) Sq+, and (D) Sq++.

multilamellar vesicles in certain conditions.30 However, to the best of our knowledge, no simulation study has investigated the microphase separation behavior and formation of multilamellar NPs of charged blends. The goal of this computational study is to examine the association behavior and mechanisms of self-assembled multilamellar NPs from charged blends for drug delivery. For a case study, the Fpx−CSq charged blending system is explored by simulation using DPD method. Fpx served as a model drug, whereas two squalenyl derivatives, bearing one or two terminal cationic groups (Sq+/Sq++), are used as carrier materials in the simulations. The main objective of the current work is to achieve a qualitative understanding of effects of Fpx:CSq molar ratio, concentration, and hydrophobic chain length of CSq on morphological outcomes of self-assembled NPs. The work focuses on the formation process, optimized conditions, and the impact of polar groups and hydrophobic chains in the formation of multilamellar NPs. Our study illustrates that it is possible to address the nanoscale confinement in experiments, in favor of understanding the structure−property relationship of potential multilamellar drug delivery vehicles.

random force (FijR).33,34 Thus, the total force on bead i is described as fi =

(2)

i≠j

The conservation force for nonbonded particles is defined by soft repulsion. The dissipative force corresponding to a frictional force depends both on the position and relative velocities of the beads. The random force is a random interaction between bead i and its neighbor bead j. All forces vanish beyond a certain cutoff radius rc, whose value is usually set to 1 unit of length in simulations. The forces above are given by the following formulas:35 ⎧ ⎪ aij(1 − rij)riĵ (rij < 1) FCij = ⎨ ⎪ 0 (rij ≥ 1) ⎩

FijD = −

2. SIMULATION METHODS 2.1. DPD Theory. DPD simulation is a coarse-grained simulation method suitable for larger time and space scale. In this method, a set of soft interacting particles are used to simulate a fluid system. Each particle represents a group of atoms or a volume of fluid that is large on the atomistic scale but is still macroscopically small. All beads comply with Newton’s equations of motion:31,32 dri dv = vi, mi i = fi dt dt

∑ (FCij + FijD + FijR )

FijR =

σ(ω(rij))2 2kT

(vij·riĵ )riĵ

(3)

(4)

σω(rij)riĵ ζ δt

(5)

where aij is the strength of the repulsive interaction and depends on the species of particles i and j; rij = ri − rj, rij = |rij|, r̂ij = rij/rij, vij = vi − vj; σ is the noise strength; ζ denotes a randomly fluctuating variable with zero mean and unit variance; δt is the time step of simulation; k is the Boltzmann constant; T is the system temperature. The r-dependent weight function ω(r) = 1 − r for r < 1 and ω(r) = 0 for r ≥ 1. In addition, an extra spring force (FiS) is introduced to describe the constraint between the bonded particles in molecules. A simple harmonic force law is used for this force on particle i:

(1)

where ri, vi, mi, and fi denote the position vector, velocity, mass and total force on the particle i, respectively. All the physical quantities in DPD method are presented in reduced units for simplicity. The force between each pair of beads is a sum of a conservative force (FijC), a dissipative force (FijD), and a

FSi =

∑ C rij j

B

(6) DOI: 10.1021/acs.jpcc.5b03833 J. Phys. Chem. C XXXX, XXX, XXX−XXX

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Table 1. Interaction Parameters aij between Different Beads Used in the Simulations

where C is the spring constant and set to be 4.0 in our simulations according to the study by Groot and Warren, resulting in a slightly smaller distance for bonded beads than for nonbonded ones.19 The interaction repulsion aij between beads i and j depends on the underlying atomistic interaction that is linearly related to the Flory−Huggins parameters (χij) as given in eq 7.36,37 aij = aii + 3.27χij (7) where aii is equal to 78. For binary components i and j, the Flory−Huggins parameter χij can be estimated by eq 8.38 χij =

ΔEmix Vr RTϕϕ V i j

A

B

C

S

P

P+

W

A B C S P P+ W

78.0 78.5 76.5 94.7 74.4 55.7 106.9

78.0 90.9 82.2 74.6 52.0 103.2

78.0 88.2 107.1 62.8 79.2

78.0 103.9 46.5 79.0

78.0 105.2 125.0

78.0 82.6

78.0

energy convergence threshold of 1 × 10−4 kcal·mol−1 and a force convergence of 0.005 kcal·mol−1·A−1. The van der Waals interactions are calculated with a cutoff of 12.5 Å, a spline width of 1 Å, and a buffer width of 0.5 Å. Moreover, the Ewald summation with an accuracy of 0.001 kcal·mol−1 is used to calculate the Coulombic interactions. For a pure component, 5 ns MD equilibrium simulation runs at isothermal and isobaric (NPT) conditions, with the temperature and pressure maintained at 298 K by Nosé thermostat and 1 bar by Andersen method. For binary components, 5 ns MD equilibrium simulation runs at isothermal and isochoric (NVT) conditions with the temperature maintained at 298 K. The potential energies of pure and binary components are calculated from the MD simulations and used for eqs 8 and 9. DPD simulations are performed in the Mesocite module of Materials Studio 5.5 software. A cubic simulation box of 37 × 37 × 37 rc3 with periodic boundary conditions is applied in all directions, which are sufficient to avoid finite size effects. According to our investigation, a dimensionless time step of 0.05tc and 400,000 simulation steps are applied to obtain equilibrium, which is decided after we prolonged the simulation steps and found the structure of the NPs structure did not change appreciably. rc and tc are DPD length and time unit, respectively. In this work, the average volume of beads is 100 Å3. Since the bead density is 3 used in this work, namely, a cube of rc3 contained three beads,21,35 the cutoff radius rc is calculated to be rC = (3 × 100)1/3= 6.7 Å. The time unit tC = rC(m/(kBT))1/2 = 0.004 ns. DPD simulations are performed on the systems in Section 3.2 to 3.5 with the composition described in Table 2. In all the following figures the water beads are concealed for clarity. The simulation results of this study are repeatable and conclusive, confirmed by the structurally similar NPs obtained from the systems with different initial configurations (different initial particle positions and random initial velocities), namely, in all our DPD simulations, the macromolecule CSq and Fpx are homogeneously mixed in water at 0 simulation step.

(8)

where R is the gas constant and T is temperature; φi and φj are the volume fractions of components i and j, respectively; V is total volume and Vr is reference volume; and ΔEmix is the mixing energy of the binary components. ΔEmix = Eij − (Ei + Ej)

aij

(9)

where Eij is the potential energy of binary mixture, and Ei and Ej are the potential energies of pure components i and j, respectively. In our DPD study, the COMPASS force field is applied on all the components in which the total potential energy E is expressed E = Ebonded + Enonbond + Ecross, where the sum of bonded energy Ebonded includes bond stretching energy, bending energy, dihedral torsion energy and out-of-plane energy. The sum of nonbonded energy (Enonbond) contains van der Waals energy and electrostatic energy (Coulombic interaction). Ecross is the energy of cross terms between any two bonded items in the COMPASS. Therefore, the electrostatic interaction of components is contained in the repulsion parameters calculated by eqs 7−9. 2.2. Coarse-Grained Models and Input Parameters. In this study, DPD simulations are employed in three cases: pure Sq+/Sq++/Fpx and Fpx−Sq+ and Fpx−Sq++ blends in aqueous solution. Coarse-grained models of the components are shown in Figure 1. The molecular structure of Fpx (Figure 1A) is divided into four types of beads (denoted by A, B, C and S; C and S represent the charged groups −COO− and −SO3−, respectively), which are in pink, purple, light green, and dark green colors, respectively. The number of A, B, C, and S beads are 6, 4, 2, and 8 in one Fpx molecule, respectively. Sq+ (Figure 1B) and Sq++ (Figure 1C) are divided into two types of beads denoted by P+ (dark blue) and P (light blue): one P+ and five P beads in Sq+, while two P+ and four P beads in one Sq++ molecule. Three water molecules are coarse-grained into one bead (denoted by W) (Figure 1D). The mass and radius of each bead are 90 amu and 2.8 Å. According to the coarse-grained models of Fpx, Sq+, Sq++, and water molecules, we carry out molecular dynamics (MD) simulations on the pure and binary components to obtain the Flory−Huggins parameters. Either pure or binary mixture system is constructed by the Amorphous Cell module in Materials Studio 5.5 (Accelrys Inc.). The interaction parameters aij between different beads used in the simulations are calculated by eqs 7 and 8, as listed in Table 1. It should be noted that Fpx and CSq contain charged groups C, S, and P+. To electrically neutralize the charges on the components, sodium/chloride ions are included in the system of C, S, or P+. To eliminate unfavorable contacts, the initial configurations are subjected to 10,000 steps of energy minimization with an

3. RESULTS AND DISCUSSION 3.1. Morphologies of Aqueous Solution Containing Pure Sq+, Sq++, or Fpx. In order to explore the morphologies of pure CSq NPs, DPD simulations are employed in the aqueous solution with pure Sq+ or Sq++. The volume concentration of pure Sq+ or Sq++ system is 5%. The simulation results are shown in Figure 2. As shown in Figure 2A, Sq+ molecules are able to selfassemble into NPs at a relative low concentration. Each Sq+ molecule has five strongly hydrophobic P beads (the interaction parameter between P and W beads is 125.0), which tend to form nanoassemblies resulting from Sq+−Sq+ hydrophobic interaction. Since the hydrophobic chains have weak affinity C


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polar beads C and S. Hence, Fpx is a highly hydrophilic molecule in general in which greater affinity with water hampers the formation of nanoassemblies. 3.2. Effect of Molar Ratio on Morphologies of Fpx− CSq NPs. A regular multilamellar (“onion-type”) structure is supposedly a key factor for ideal stability and drug loading capability of multilamellar NPs. This structure is closely related to the concentration ratio of components. In order to verify the optimal molar ratio of Fpx to Sq+ to form multilamellar NPs, the morphologies assembled from Fpx−Sq+ charged blends with the Fpx:Sq+ molar ratios of 1:1, 1:2, 1:4, 1:6, 1:10, and 1:20 are studied. The corresponding Fpx:Sq+ volume fraction ratios are 10.77%:3.23%, 8.75%:5.25%, 6.36%:7.64%, 5%:9%, 3.5%:10.5%, and 2%:12%, respectively (total volume fraction of Fpx and Sq+ is fixed at 14%). The results are shown in Figure 3A−F. For clarity and comparison, cross-section views of the corresponding NPs are also given. As shown in Figure 3, NPs are formed at Fpx:Sq+ molar ratio 1:1 (Figure 3A) with a large number of Fpx molecules dissociating in water. Moreover, more NPs are observed compared to other systems with different Fpx:Sq+ molar ratios after the same equilibrium time (when increasing the Sq+ amount, the association between Fpx and Sq+ dramatically increases; this is consistent with the previously published data showing lower association efficiency at 1:1 molar ratio as compared to 1:617). Since the Fpx concentration is at a high level, the polar groups of Fpx are much more than that of Sq+, thus only a certain quantity of Fpx associate with Sq+ through attraction. As a result, the remaining Fpx, which cannot be encapsulated by Sq+, diffuse in water due to their strong hydrophilicity. The outer layer of the NPs is formed by Fpx, which generates repulsive interaction among other NPs and the dissociative Fpx; therefore, more NPs and many dissociative Fpx are observed in the system. According to the cross-section view of NPs (Figure 3A), the outline of which is not smooth but close to a spherical structure, and the internal cross-linking Fpx divide Sq+ into irregular microregions. With regard to the system with Fpx:Sq+ molar ratio of 1:2 (Figure 3B), many Fpx remain dissociated in water, but the number of nonassociated Fpx molecules dramatically decreases since more Fpx molecules are able to interact with an increased quantity of Sq+. Further increasing the amount of Sq+ (Fpx:Sq+ molar ratio of 1:4) (Figure 3C) decreases the quantity of dissociative Fpx continuously and the distribution of Fpx inside the NPs becomes more regular but not quite orderly. When the

Table 2. Composition of the Systems in Sections 3.2 to 3.5 components (volume concentration (%)) section

Fpx

Sq+

3.2

10.77 8.75 6.36 5.00 3.50 2.00 10.77 8.75 5.00 3.50 5 1.0 2.5 5.0 7.5 10.0 15.0 5 5

3.23 5.25 7.64 9.00 10.50 12.00

3.3 3.4

3.5

Sq++

total volume fraction (%)

molar ratio (Fpx:CSq)

14

1:1 1:2 1:4 1:6 1:10 1:20 1:1 1:2 1:6 1:10 1:6 1:6

3.23 5.25 9.00 10.50 9 1.8 4.6 9.0 13.5 18.0 27.0 9

14 2.8 7.1 14 21 28 42 14

1:6

9

with water, high interfacial energy generates. Hence in order to lower the high interfacial energy between hydrophobic chains and water, the hydrophobic chains tend to curl up and get close to each other, decreasing exposure to solvent as much as possible.39 As a consequence, the nanoassemblies spontaneously formed. Similarly, Sq++ can also aggregate into nanoassemblies as a result of the hydrophobic interaction of the hydrophobic chains (Figure 2B). However, some Sq++ molecules dissociate in water, which may be attributed to the stronger hydrophilicity developed by two polar groups P+ in Sq++ compared to Sq+. Additionally, the ion−dipole interaction of Sq++ is stronger than Sq+ in a polar solvent, thus the Sq++ assemblies are not as stable as the Sq+ ones. DPD simulations are also carried out in the aqueous solution with pure Fpx (5% volume concentration), and the result is shown in Figure 2C. Aggregates are unable to form from Fpx, even though this macromolecule has ten hydrophobic beads (A and B, see Figure 1). Indeed, the hydrophobic interaction developed by beads A and B are overcome by the abundant

Figure 2. Morphologies of aqueous solution contain pure (A) Sq+, (B) Sq++, or (C) Fpx. D


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Figure 3. (A−F) Morphologies and cross-section views of Fpx−Sq+ NPs with different molar ratios. (G) Supramolecular organization of Fpx:Sq+ NPs at a molar ratio of 1:6 (adapted with permission from ref 17): cryo-TEM image (left) and transmission electron microscopy (TEM) after freezefracture (right). Bar represents 100 nm.

molar ratio of Fpx:Sq+ reaches 1:6 (Figure 3D), few Fpx dissociate in water and highly ordered multilamellar spherical NPs are formed. The NPs are composed of alternating layers of hydrophilic Fpx and hydrophobic Sq+, and the polar beads C and S in Fpx are closely grouped with the polar beads P+ in Sq+ through nonbonded attraction. However, as Sq+ further increases (Fpx:Sq+ molar ratio of 1:10 and 1:20, Figure 3E,F), the multilamellar structure of NPs become irregular again. This is likely because the high Sq+ concentration induces strong interfacial energy of the hydrophobic chains and solvent, so more hydrophobic chains tend to curl and aggregate. Meanwhile, it is insufficient to sequester the hydrophobic chains from solvent by Fpx as its concentration is relatively small. Therefore, in order to maintain the stability of the NPs

and lower the interfacial energy of the hydrophobic chains, more Fpx tend to stay as the outer protective hydrophilic layer. Consequently, Sq+ molecules show an irregular distribution, apart from each other inside the NPs. The simulation results are in perfect agreement with the experimental results of Gref et al.17 in which the NPs prepared using Sq+ were successful, and the optimal preparation conditions were obtained with a Fpx to Sq+ molar ratio of 1:6 (with small mean diameter, large zeta potential, and low polydispersity index of the NPs). The corresponding supramolecular organization images of Fpx:Sq+ NPs at a molar ratio 1:6 are given as Figure 3G. Moreover, the DPD simulations provide detailed morphologies and possible explanations to the experiments. E


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Figure 4. (A)-(D) Morphologies and cross-section views of Fpx−Sq++ NPs with different molar ratios; (E) Typical TEM images showing the supramolecular organization of Fpx:Sq++ NPs at a molar ratio 1:6. Bar represents 100 nm.

Figure 5. Schematic drawing of Fpx:CSq molar ratio on the formation of multilamellar NPs.

Similarly, to investigate the influence of Fpx:Sq++ molar ratio on the morphology of relevant self-assembled NPs, we perform

DPD simulations on the charged blending systems with Fpx:Sq++ molar ratios of 1:1, 1:2, 1:6, and 1:10, respectively, F


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Figure 6. (A−G) Morphologies and cross-section views of Fpx−Sq+ NPs during the formation process of different simulation time. (H) Crosssection view of NP with only Fpx shown in 300 000 steps.

the corresponding Fpx:Sq++ volume fraction ratios of which are 10.77%:3.23%, 8.75%:5.25%, 5%:9%, and 3.5%:10.5% (total volume fraction of Fpx and Sq++ is fixed at 14%). The morphologies of Fpx−Sq++ NPs are shown in Figure 4A−D, and the corresponding cross-section profiles are also given for clarity and comparison. According to Figure 4, despite the differences, Fpx and Sq++ are able to self-assemble into NPs under any molar ratios. As shown in Figure 4A, compared to the other three cases, dissociative Fpx are observed with Fpx:Sq++ molar ratio of 1:1 when the system reaches equilibrium, but the quantity of dissociative Fpx is remarkably smaller than that of Fpx−Sq+ system (Fpx:Sq+ = 1:1). Since one Sq++ molecule contains two polar beads (P+), Sq++ is able to attract more Fpx compared to Sq+ under the same ratio through attraction. As for the systems with Fpx:Sq++ molar ratios of 1:2, 1:6, and 1:10 (Figure 4B− D), it is in clear contrast to Sq+, where no multilamellar structures are obtained under any Fpx:Sq++ molar ratio. As shown in the cross-section views in Figure 4, only NP structures with random combination of Fpx and Sq++ result. This demonstrates that the molar ratio has little influence on the formation of Fpx:Sq++ multilamellar NPs, in that CSq are more solvophilic when two polar groups P+ are closely located. Moreover, the hydrophobic interaction generated by Sq++ molecules is relatively weak because the hydrophobic chain of

Sq++ is short. Thus, the interfacial energy between hydrophobic chain and solvent is smaller, tending to form NPs of disordered structure associating with Fpx due to entropic effect. Consistent with Gref’s experiments, the NPs prepared with Fpx and Sq++ were also less stable than Fpx−Sq+ NPs (with large mean diameter and higher polydispersity index).17 Moreover, TEM observations clearly revealed that Fpx−Sq++ NPs could not form “onion-type” structures regardless of the molar ratio (a typical result is shown in Figure 4E). According to the above study, Sq+ is more appropriate for encapsulating Fpx among the two investigated CSq. For clear illustration, we show the schematic drawing of the effect of Fpx:CSq molar ratio (which is changed with the altered concentration of CSq) on the formation of Fpx−CSq multilamellar NPs in Figure 5. With low Sq+ concentration, Fpx and Sq+ cannot form multilamellar NPs, but Sq+ microregions can be seen inside the NPs. When the amount of Sq+ reaches an optimal value, highly ordered multilamellar NPs are formed, resulting from the polar groups and hydrophobic interaction between Fpx and Sq+. However, the multilamellar structure disappeared as Sq+ concentration further increases, and the NPs formed in this case mainly consist of Sq+ with few Fpx distributing randomly inside. In clear contrast to Sq+, Fpx−Sq++ NPs always appear disordered under any Fpx:Sq++ molar ratios. G


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The Journal of Physical Chemistry C Based on the above findings, the optimal molar ratio and volume fraction of Fpx−Sq+ system are 1:6 and 5%:9%, respectively, allowing the formation of NPs with highly ordered multilamellar spherical structures. More important, the results reveal that the formation of multilamellar NPs depends greatly on the molar ratio of Fpx and CSq, and the multilamellar structure is hard to be organized by remaining Fpx or CSq. 3.3. Formation of Fpx−Sq+ Multilamellar NPs. To explore the detailed formation process of the multilamellar NPs, we perform simulation on the Fpx−Sq+ aqueous solution where the volume ratios of Fpx, Sq+, and water are 5%, 9%, and 86%, respectively (under the Fpx:Sq+ optimized molar ratio 1:6). Representative snapshots from the formation of Fpx−Sq+ multilamellar NPs and the corresponding cross-section profiles are shown in Figure 6. As shown in Figure 6A, the components are randomly distributed in water at the initial state of the simulation. With the evolution of simulation, the molecules first aggregate to form small clusters caused by the interaction among beads (Figure 6B). The small clusters then collide and gradually form larger nanoassemblies (Figure 6C−F). Finally a NP is formed after stabilization (Figure 6G). As seen in the cross-section profiles, Fpx and the charged groups of Sq+ distribute on the surface of small clusters, while the hydrophobic chains of Sq+ distribute inside the clusters (Figure 6B). With collision and aggregation of the small clusters, a portion of Fpx gradually diffuse into the clusters, and the discontinuous Fpx inner layer extends to form a closed one eventually, resulting in two Sq+ microregions (Figure 6C−F). As the simulation increases to 200,000 steps (Figure 6F), the size of the NP does not change significantly, but the inner structure remains irregular. As the formation process further proceeds, the inner Fpx layer of NP becomes increasingly clear, and a regular multilamellar structure appears at 300,000 steps (Figure 6G). According to Figure 6G, the detailed morphology of multilamellar structure is revealed: Owning to the strong repulsion with water generated by hydrophobic chains (which consist of P beads), Sq+ distribute inside the NP forming hydrophobic layers to decrease contact with water. While Fpx spread around the surface of NP forming a hydrophilic outer layer, for the abundant polar groups (C and S beads) show good affinity with water. As a consequence, the Gibbs energy is lowered in favor of the stability of the system.39 However, the attraction between Fpx and Sq+ allows Fpx to diffuse into the NPs, the polar groups P+ of Sq+ distribute on the outer side of Sq+ layers associating with Fpx through dipole attraction, and thus, alternative layers are organized in the NPs. In our DPD simulation, the total energy changes in the formation of Fpx−Sq+ NPs is decreased from 5.983 × 105 to 4.401 × 105 kcal·mol−1, indicating that the self-assembly of Fpx and Sq+ is thermodynamically favorable. The ordered morphological outcome can be explained by the entropic effect as well. The loss of entropy associated with the assembly of ordered NPs is more than compensated for by the gain in entropy associated with the increase in free volume of water molecules (before the formation of NPs, the free volume of water molecules is smaller since Fpx and Sq+ dissociate in water).40 Therefore, the overall entropy of the system increases. In general, Fpx and Sq+ assemble into NPs is a process that energy decreases and entropy increases, thus the system tends to be thermodynamically stable. To clearly observe the distribution of Fpx inside the multilamellar NP, cross-section view of the NP with only Fpx shown is given (Figure 6H).

Based on the above analysis, spherical NPs with stable multilamellar structure: Fpx shell−Sq+ layer−Fpx layer−Sq+ microregion self-assemble under optimized conditions when the system reaches equilibrium. Generally, the formation of Fpx−Sq+ multilamellar NPs experiences three phases: (I) Formation of small clusters. (II) Small clusters aggregate into large clusters and Fpx gradually diffuse into the clusters. (III) Generation of Fpx inner layer and Sq+ microregions and stabilization of multilamellar structure. In addition, the formation mechanism of Fpx−Sq+ multilamellar NPs is discussed: (I) The hydrophobic interaction of Sq+ attributes to the self-assembly of NPs. (II) The nonbonded interaction of polar groups among Fpx and Sq+ determines the spontaneous association of Fpx and Sq+. To further demonstrate the structure of Fpx−Sq+ multilamellar NPs, the radial distribution function (RDF) is used to analyze the distribution of different beads in the NPs. The RDF is defined as38 gij(r ) =

⟨ΔNij(r → r + Δr )⟩V 4πr 2ΔrNN i j

(10)

where ⟨ΔNij(r → r + Δr)⟩ is the ensemble averaged number of bead j around bead i within the volume of a shell from r to r + Δr; V is the volume of system; Ni and Nj represent the number of beads i and j, respectively. Herein, the RDF curves between P and C beads, P and S beads, P+ and C beads, and P+ and S beads are acquired as shown in Figure 7, demonstrating the

Figure 7. RDF curves of different beads in Fpx and Sq+.

distributions of these contents in the NPs. g(r) is the distribution function, and r values corresponding to the peaks of RDF curve reflect the distance between two types of beads. Set RDF curves between P+ and S beads, for instance, the highest peak indicates that most S beads appear in the corresponding distance away from P+ beads. The relative position r between different beads also reflects the affinity between the beads. The RDF profile is calculated from the Fpx−Sq+ system of optimized molar ratio (Fpx:Sq+ = 1:6). The RDF results show a large difference between the P−C/S curves and P+−C/S curves. The P+−C and P+−S curves exhibit a sharp peak, indicating that C and S charged groups mainly distribute in the region formed by P+ charged groups. The peak value of P+−S curve is higher than that of P+−C since the number of S group is more compared to C group (one Fpx contains eight S beads and two C beads). However, the RDF curves of P−C and P−S similarly lack sharp peaks, suggesting that C and S charged groups distribute in the area far away from the P chains, which reflects the structural characteristic that C H


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Figure 8. Morphologies of Fpx−Sq+ charged blends with different concentrations: (A) Fpx:Sq+ = 1.0%:1.8%, (B) Fpx:Sq+ = 2.5%:4.5%, (C) Fpx:Sq+ = 5%:9%, (D) Fpx:Sq+ = 7.5%:13.5%, (E) Fpx:Sq+ = 10%:18%, (F) Fpx:Sq+ = 15%:27%.

and 9%, 7.5% and 13.5%, 10% and 18%, and 15% and 27%, respectively (Fpx:Sq+ = 1:6). The morphologies of the nanoassemblies are shown in Figure 8. For the equilibrium system with Fpx:Sq+ volume fraction of 1%:1.8% (Figure 8A), small spherical clusters are generated. The reason is discussed as follows: The small clusters are in a relatively long distance due to the low concentrations of Fpx and Sq+, so the interactions among the clusters are relatively weak, which is unfavorable for collision and further aggregation. As the volume concentration of Fpx and Sq+ increases to 2.5% and 4.5% (Figure 8B), the clusters tend to aggregate into a large spherical NP when the system reaches equilibrium. The interaction among the clusters may strengthen with higher concentration, thus the clusters are easy to collide and further aggregate. However, although multilamellar structure appears under this concentration, the inner Fpx layer is still not highly ordered enough. With regard to the system with Fpx:Sq+ volume fraction of 5%:9% (Figure 8C), a spherical NP is assembled with a larger size and represents a highly ordered multilamellar structure as discussed previously. Nevertheless, when the volume concentration of Fpx and Sq+ continuously increases to 7.5% and 13.5% (Figure 8D), the morphology of nanoassemblies is no longer spherical but appears columnar, which attribute to the collision and aggregation of NPs in high concentration. Further increasing volume concentrations of Fpx and Sq+ to 10% and 18% (Figure 8E), the column structure transforms into a more complex irregular one, and a lamellar structure appears when the volume concentrations of Fpx and Sq+ reach 15% and 27% (Figure 8F). Notably, despite the differences, the nanoassemblies obtained in the above systems (except for the systems with the Fpx:Sq+ volume concentration

and S charged groups tend to distribute in the exterior of the regions formed by P chains since they have poor affinity. The RDF results also reflect the compatibility between different components; thus, the effect of the interaction parameters on the formation of multilamellar NPs can be further analyzed. The RDF curves of P+−C and P+−S are similar, indicating that the compatibility between P+ and C/S are alike. While the similarity of P−C and P−S curves represent similar strong repulsive interaction between P and C/S beads. According to the interaction parameters listed in Table 1, C and S have a good compatibility with P+ (aC−P+ = 62.8, aS−P+ = 46.5); these interaction parameters are remarkably smaller than those of P (aC−P = 107.1, aS−P = 103.9). The RDF results are consistent with the interaction parameters illustrating that the structure of the NPs is significantly influenced by the components compatibility. Indeed, the parameters in Table 1 include various interactions between different components mainly attributed by their structural properties. Therefore, we further analyze the RDF outcomes through the structural properties of the components. Since groups C and S carry negative charges, electrostatic attraction and charge−dipole interaction are generated between C/S and the positive charged group P+, thus showing good compatibility. By contrast, P is nonpolar; thus, it shows repulsive interaction with polar groups C/S and P+ despite of the relatively weak dispersion and induction interaction. 3.4. Effect of Concentration on Morphologies of Fpx− Sq+ Charged Blends. To examine the optimized concentration of the formation of Fpx−Sq+ multilamellar NPs in aqueous solution, we perform simulations on the systems with Fpx:Sq+ volume fractions of 1.0% and 1.8%, 2.5% and 4.5%, 5% I


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Figure 9. Morphologies and cross-section views of Fpx−Sq+ NPs formed by Sq+ with different lengths of hydrophobic chain (A) P = 5, (B) P = 7, (C) P = 9, and (D) P = 13.

Figure 10. Morphologies and cross-section views of Fpx−Sq++ NPs formed by Sq++ with different lengths of hydrophobic chain (A) P = 4, (B) P = 6, (C) P = 8, and (D) P = 12.

of their nanoassemblies. This result verifies that Fpx:Sq+ volume concentration of 5%:9% applied in our study is optimal for the formation of spherical NPs with perfect multilamellar structure. 3.5. Effect of Hydrophobic Chain Length of CSq on Formation of Fpx−CSq Multilamellar NPs. To examine the significance of hydrophobic interaction provided by the hydrophobic chains of CSq on the formation of multilamellar NPs, DPD simulations are carried out in the systems with CSq of various hydrophobic chain lengths (the molecule should be

of 1.0% and 1.8%) have similarity that the surface is formed by Fpx and Sq+ distributed inside, to decrease the interfacial energy of the hydrophobic interaction generated by P chains. While a portion of Fpx diffuse into the nanoassemblies associating with Sq+ in the presence of the nonbonded interaction, to maintain the stability of system. In summary, increasing the concentrations of Fpx and Sq+ result in self-assembled nanoassemblies that display spherical, columnar, and lamellar structures in turn. The volume concentrations of Fpx and Sq+ greatly impact the morphology J


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Figure 11. Schematic drawing of hydrophobic interaction on the formation of multilamellar NPs.

to generate. With reference to Sq++ containing eight P beads (Figure 10C), the NP formed tends to appear as a multilamellar structure although the inner Fpx layer remains unapparent enough. Of particular interest, the NP possessing a highly ordered multilamellar structure is formed, while Sq++ contains 12 P beads (Figure 10D). As the hydrophobic chain length of Sq++ gradually increases, the hydrophobic interaction of Sq++ is enhanced accordingly, thus the hydrophobic chains tend to aggregate into regions to lower the interfacial energy. As a consequence, the P-hydrophobic chains become the center protected by polar P+-groups and hydrophilic Fpx through nonbonded interaction. To sum up, the hydrophobic interaction and nonbonded interaction play an outstanding role for Fpx−Sq++ NPs transforming from disordered to highly organized structure. To better illustrate the effect of hydrophobic interaction on the formation of multilamellar NPs, the schematic drawing of the structural transformation of NPs as the hydrophobic chain lengths in CSq changed is provided in Figure 11. For Fpx−Sq+, Fpx and Sq+ are capable of forming multilamellar NPs under proper concentration, but the multilamellar structure is gradually destroyed as the length of hydrophobic chain increases. Ultimately, “crew-cut micelle-like” NPs with a shell−core two layer structure tend to form. With regard to Fpx−Sq++, NPs present disordered structures when the hydrophobic chain of Sq++ is short, while highly ordered multilamellar NPs appear as the hydrophobic chain gradually lengthens. This part of exploration reveals that the hydrophobic interaction provided by CSq has a significant influence on the formation of multilamellar NPs. Summarize the above findings, the formation of multilamellar NPs prepared by ion pairing approach is attributed to the joint effect of the nonbonded interaction (provided by polar groups between Fpx−CSq) and the hydrophobic interaction of hydrophobic chain (contributed by CSq). Only when these two interactions reach a beneficial state for the thermodynamic stability of the system, highly ordered multilamellar NPs are capable to be organized.

called terpene when the hydrophobic chain length of squalene is changed. However, the molecules with longer hydrophobic chains remain to be denoted by CSq (Sq+ and Sq++) here for simplicity). The volume concentration of Fpx:CSq is set to 5%:9%. Figure 9 shows the stable morphologies assembled from Fpx−Sq+ charged blends with different hydrophobic chain lengths of Sq+ (the numbers of hydrophobic bead P are 5, 7, 9, and 13, respectively). Cross-section profiles of NPs are also given in Figure 9 for clarity of the inner structures. For the system of Sq+ with five P beads (Figure 9A), which has been discussed in a previous study, few Fpx dissociate in water, and the formed NPs possess a highly ordered multilamellar structure. As the P beads of Sq+ increase to 7 (Figure 9B), some Fpx dissociate into water and the quantity of Fpx inside NP decreases, leading to discontinuous Fpx inner layer. The reason may be that as the hydrophobic chain lengthens, the polar groups of Sq+ accordingly decrease, and the NP interior presents stronger hydrophobicity, which induces the nonbonded attraction between Sq+ and Fpx; thus, more Fpx dissociate into water. With regard to the system of Sq+ with nine P beads (Figure 9C), the number of dissociative Fpx increases and the Fpx inner layer of NPs continuously disintegrates. Finally, when the P beads of Sq+ increase to 13 (Figure 9D), the quantity of dissociative Fpx does not increase significantly, which may result from the increased specific surface areas as the number of NPs increases; thus, more Fpx can be attracted to the surface. The NPs increase may ascribe to the stronger repulsion between NPs since more Fpx are absorbed on their surface after the disintegration of Fpx inner layer. In this case, few Fpx distribute inside the NPs (which is denoted by “crew-cut micelle-like” nanoassemblies) possessing only a hydrophilic shell and a hydrophobic core, i.e., a shell− core structure. Similarly, to verify the hydrophobic interaction provided by the hydrophobic chains of Sq++ plays a key role in the formation of multilamellar NPs, the morphologies of NPs formed by Fpx and Sq++ with different numbers of P beads (P = 4, 6, 8, and 12) are investigated, as shown in Figure 10. DPD simulations are engaged in the systems with Fpx:Sq++ volume concentration of 5%:9%. Cross-section profiles of NPs are also given in Figure 10 for clarity of the inner structures. The NP formed by Sq++ (P = 4) shown in Figure 10A has been discussed in the previous simulation that the inner structure is disordered. When the number of P bead in Sq++ increases to six (Figure 10B), the Sq++ microregions of NP start

4. CONCLUSIONS Dissipative particle dynamics (DPD) simulation is applied for the first time to investigate the self-assembly behavior of the multilamellar NPs formed by charged blends for drug delivery. Our simulation addresses the nanoscale confinement in experiments and reveals a wealth of self-assembly morphologies of the Fpx−CSq (including Sq+ and Sq++) aqueous solution are K


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examined. The simulation results are in perfect agreement with experimental findings, helping to understand the structure− property relationship of the experimental system. For the Fpx− Sq+ system, the optimized Fpx:Sq+ molar ratio and volume fraction are 1:6 and 5%:9%, respectively, resulting in highly regular multilamellar spherical NPs. However, the multilamellar structure gradually disappears as the hydrophobic chain of Sq+ lengthens. For the Fpx−Sq++ system, multilamellar NPs cannot be formed under any molar ratios when the hydrophobic chain of Sq++ is short (P = 4). Of particular interest, multilamellar structures are organized as the hydrophobic chain of Sq++ stretches to a proper length. Based on the simulation results, the formation process and mechanism of multilamellar NPs are discussed, which is attributed to the joint effect of the nonbonded interaction provided by the polar groups between Fpx−CSq and the hydrophobic interaction contributed by the hydrophobic chain of CSq. This study offers a theoretical guide to control the morphologies of multilamellar NPs and paves the way toward the design of novel nanoparticulate drug carriers with tailored multilamellar structures developed by ion pairing approach.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel/Fax: +86-20-87112046. Author Contributions ∥

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by National Natural Science Foundation of China (No.91434125), Team Project of Natural Science Foundation of Guangdong Province, China (No.S2011030001366), Specialized Research Fund for the Doctoral Program of Higher Education of China (No.20130172110009), Science and Technology Plan Project of Guangdong Province, China (No.2013B010404006), Fundamental Research Funds for the Central Universities, China (2014ZP0020), and European grants FP7-PEOPLE-ITN 2013 N 608407 and ERC project “Ternanomed” FP7/20072013 N 249835.

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Multilamellar Nanoparticles Self-Assembled from Opposite Charged

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