Precisely Controlled Incorporation of Drug Nanoparticles in Polymer

In our simulation systems, there are four different types of DPD particles, .... to attractive van der Waals and polymer mediated depletion attraction...
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Precisely Controlled Incorporation of Drug Nanoparticles in Polymer Vesicles by Amphiphilic Copolymer Tethers Junying Yang,† Rong Wang,*,‡ and Daiqian Xie*,†

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†

Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China ‡ Key Laboratory of High Performance Polymer Materials and Technology of Ministry of Education, Department of Polymer Science and Engineering, State Key Laboratory of Coordination Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210023, P. R. China S Supporting Information *

ABSTRACT: In this paper, we describe the fabrication of nanoparticle (NP)-embedded nanovesicles by coassembly of diblock copolymer-tethered NPs and free diblock copolymers via the dissipative particle dynamics simulation technique. We use an improved quantitative model to characterize the angular and radial distributions of NPs within vesicle walls simultaneously. In a specific circumstance, the NPs can be localized in the central portion of the vesicle walls, which is in excellent agreement with the experimental work. On the basis of this model, we find that the distributions of the NPs can be well manipulated just by three physical quantities, which are easily controlled in the experiments. For instance, the radial distributions of the NPs can be precisely controlled by changing the grafted hydrophobic chain length and the tethered arm number affects the dispersity of the NPs in the angular direction of the vesicle walls. The results provide the experimentalists with a way to design carrier-assistant drug delivery systems, which can improve the encapsulation efficiency, realize the specific targeting, and control the release of drug.

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hydrophobic compounds simultaneously.1,9−11 Incorporating various NPs (e.g., gold NPs, magnetic NPs, quantum dots, and upconversion NPs) into organic vesicular membranes can also impart the system with optical, electronic, and magnetic properties, which may lead to promising applications in cancerrelated diagnosis and treatment. One commonly used strategy for the fabrication of NP-embedded nanovesicles is to coassemble polymer-coated NPs, namely, “hairy” nanoparticles (HNPs) with amphiphilic block copolymers (BCPs).12−15 For example, Yang et al.16 recently developed a new class of magneto-vesicles with tunable layers of densely packed superparamagnetic iron oxide nanoparticles (SPIONs) in the polymeric membrane for tumor-targeted imaging and delivery. Liu et al.17 obtained unique hybrid Janus-like vesicles with different shapes, patchy vesicles, and heterogeneous vesicles in selective solvents. This group extended the coassembly strategy to the fabrication of multifunctional hybrid vesicles with controlled distribution of multiple types of NPs in the vesicular membrane.18 Moreover, Mai and Eisenberg19 reported a general approach for controllable incorporation of performed NPs into only the central portion of vesicle walls.

INTRODUCTION Carrier-assistant drug delivery systems (DDSs) have received tremendous attention, especially in the field of nanomedicine. Owing to impressive progress in pharmaceutics and materials science, a large number of nanocarriers with diverse sizes, architectures, and surface properties, such as liposomes,1 polymers,2 inorganic nanoparticles (NPs),3,4 and metal− organic frameworks5 have been developed for DDSs. Due to the specific properties of nanoscale particulates, a nanodrug system can offer several pharmacokinetic advantages, such as specific drug delivery, high metabolic stability, high membrane permeability, long duration of action, and improved bioavailability.6 Moreover, an abundance of stimuli-responsive features are introduced to nanocarriers, which can be applied to controllable release, such as pH, redox, radiation, enzyme, etc.7 Nevertheless, in spite of a few promising results, most of carrier-assistant DDSs have limitations, such as carrier-induced toxicity and immunogenicity, complex synthesis manipulation, low drug-loading capacity, and inefficient drug release at the lesion site,8 which has hampered their further translation to the clinic and eventually to the market. To make the carrier-assistant DDSs into practice, nanosized vesicles (e.g., polymersomes or liposomes) are one of the most widely used nanocarriers for drug delivery, because of their unique ability to encapsulate and deliver hydrophilic and © XXXX American Chemical Society

Received: June 3, 2018 Revised: August 8, 2018

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DOI: 10.1021/acs.macromol.8b01172 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

Figure 1. Morphologies of the aggregates formed by P(BnA2)m and B10A2. (a) MCV-like vesicles; (b) multicavity vesicles; (c) bilayers; and (d,e) vesicles. The arrows point to the cross sections of the aggregates. The green, red, and blue beads represent block A, block B, and nanoparticle P, respectively. − rij/rc for rij ≤ rc and ω(rij) = 0 for rij > rc. The dissipative force is a friction force that acts on the relative velocities of particles, and it is defined by F⃗ Dij = −γω2(rij)(r̂ij × v⃗ij)r̂ij, where γ is the friction coefficient governing the magnitude of the dissipative force and v⃗ij = v⃗i − v⃗j. The random force that compensates for the loss of kinetic energy is defined by F⃗ Rij = σω(rij)θijr̂ij, where θij is a randomly fluctuating variable with Gaussian statistics and σ2 = 2γkBT. In our simulation systems, there are four different types of DPD particles, including hydrophilic beads (A), hydrophobic beads (B), nanoparticle beads (P), and solvent beads (S). The vesicles in our systems are self-assembled from B10A2 type diblock copolymers. The nanoparticles are modified by linear amphiphilic diblock copolymer chains, i.e., P(BnA2)m, where nB is the number of hydrophobic block beads, and marm represents the tethered arm number, as shown in Figure S1 of the Supporting Information (SI). We employed the finitely extensible nonlinear elastic (FENE) potential between the 1 consecutive beads:29 VFENE(rij) = − 2 kR 02 ln[1 − (rij/R 0)2 ] for rij < R0 and VFENE(rij) = ∞ for rij ≥ R0. Here, we set k = 50 and R0 = 1.5rc. The value of FENE spring k is strong enough to make bond crossings energetically infeasible. There is no extra angle force between the copolymer arms. We performed the simulation in a cubic box (303) under the periodic boundary conditions with the number density of 3. The B10A2 free copolymer concentration is fixed at 0.10 (i.e., 675 B10A2 free copolymers in total). The number of P(BnA2)m, i.e., NP, varies from 0 to 150. The radius of a nanoparticle bead is twice as large as that of a copolymer bead or solvent bead.30,31 In the present simulations, all the polymer and solvent beads are of the same mass as m = 1. The interaction cutoff radius for block copolymer and solvent particles is set to rc = 1 as the unit of length, and the energy scale kBT = 1. Here, kB is the Boltzmann constant, and T is the temperature.

The assembly of BCP-tethered NPs has provided an effective route to the fabrication of hybrid vesicles with high density and broad size range of NPs in the membrane.17,20−22 These hybrid vesicles have been demonstrated for drug delivery,16 photoacoustic imaging,23 enhancing MRI,16,18 and photothermal/photodynamic therapy24 due to their collective properties of assembled NPs. However, the efficacy of carrierassistant DDSs is strongly dependent on the content and organization of NPs in individual ensembles. There thus remains challenging in the precisely controlled incorporation of NPs into different portions of vesicle walls. Herein, we report the coassembly of free amphiphilic BCPs and HNPs, which are stabilized with amphiphilic copolymers of the same composition as that of the free BCPs. The morphological structures of the aggregates are studied, and the phase diagrams are presented. Very importantly, a quantitative model is used to evaluate both the angular and radial distributions of the NPs within the vesicle walls simultaneously. We mainly explore the effects of three physical quantities, i.e., the HNP number NP, the tethered arm number marm, and the grafted hydrophobic chain length nB, and find the properties of the synthetic vesicles can be precisely controlled just by manipulating these three physical quantities. We suppose this work could inspire the researchers both in theoretical simulation and experimental areas. Theoretical followers can take advantage of the quantitative model to further study the behaviors of aggregates for many systems. The results from this study could lead experimental researchers to design carrier-assistant DDSs, which may potentially improve the encapsulation efficiency, realize the specific targeting, and control the release of drug.

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The time unit τ is defined as τ = mrc2/kBT . The time integration of Newton’s equation of motion was accomplished using the modified velocity-Verlet algorithm with λ = 0.65 and Δt = 0.03.28 The amplitude of random noise was set as σ = 3.0. A typical DPD simulation requires only about 105 steps to equilibrate.28,32 In our simulations, each simulation took at least 2.0 × 106 steps and the last 2.0 × 105 steps were for statistics. In order to confirm the bilayer structure, we carried out 1.0 × 107 steps in these cases. Simulations with different initial random configurations and for various box sizes have been implemented. The simulation results show that the morphology of aggregates at equilibrium is independent of the initial conditions. The different sizes of boxes do not affect the formation of aggregates except the number of aggregates in the boxes after equilibrium.32 The interaction parameter aij is determined by the characteristic of the beads (either hydrophilic or hydrophobic). Typically, the pairwise repulsive interaction parameter between the same type of DPD particles is set as aii = 25, i.e., aAA = aBB = aPP = aSS = 25. According to our previous work,33 we specifically set aAB = 85, aBS = 130, aAP = 100, and aSP = 150 to describe the incompatibility between these corresponding beads, and fixed the interaction

METHODS AND MODELS

DPD method is a suitable and efficient method for simulating the selfassembly of BCPs and HNPs.17,21,25 It is a particle-based, mesoscopic simulation technique, which is introduced by Hoogerbrugge and Koelman.26,27 Similar to molecular dynamics (MD) simulations, DPD captures the time evolution of a many-body system by solving Newton’s equation of motion:28 midv⃗i/dt = fi⃗ . The nonbonded force acting on a particle is a pairwise additive force that contains three C D R parts, f ⃗ = ∑ (Fij⃗ + Fij⃗ + Fij⃗ ), where the sum runs over all i

j≠i

particles j within a certain cutoff radius rc. The conservative force is a soft repulsion taking the form of F⃗ Cij = aijω(rij)r̂ij, where aij is the repulsive interaction parameter between particle i and j, r⃗ij = r⃗i − r⃗j, rij = |r⃗ij|, r̂ij = r⃗ij/rij. The weight function ω(rij) provides the range of interaction for DPD particles with a commonly used choice: ω(rij) = 1 B

DOI: 10.1021/acs.macromol.8b01172 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules parameter aAS = 25 and aBP = 25 to correctly describe the compatibility between the solvophilic block A and the solvent S, and the solvophobic block B and the nanoparticle P.

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RESULTS AND DISCUSSION Morphological Diagram of the Aggregates Formed by BCPs and HNPs. Typical assembled aggregates including Momordica charantia L. Var. abbreviata Ser. (MCV)-like vesicles with branched nanoparticle strips on the surfaces, multicavity vesicles, vesicles and bilayers are obtained by changing marm, nB, and NP (Figure 1). Figure 2 shows the

Figure 2. Morphological phase diagram of the aggregates formed by P(BnA2)m and B10A2 in terms of the tethered arm number marm and the grafted hydrophobic chain length nB with fixed NP = 100.

morphological phase diagram of the aggregates formed by HNPs and BCPs in terms of marm and nB with fixed NP = 100. With the increase of marm, the NPs change from aggregation (Figure 1d) to dispersion (Figure 1e). When nB = 2, the NPs are distributed on the vesicle surfaces. MCV-like vesicles are observed in the case of marm > 3. In general, the aggregation morphologies change from multicavity vesicles to vesicles and further to bilayers with the increase of nB, seeing the upper part (marm > 2) of the phase diagram. To explain the phase transitions, we draw several representative phase diagrams of the aggregates formed by P(BnA2)m (nB = 2, 4, 10) and B10A2 as a function of marm and NP. Figure 3a shows the morphological phase diagram of the aggregates formed by P(B2A2)m and B10A2. When NP < 80, vesicles are formed. It is believed that the uniform dispersion of NPs in polymer aggregates is difficult for a variety of reasons, including their affinity toward aggregation owing to attractive van der Waals and polymer mediated depletion attraction forces.34 A facile approach to mitigate the nanoparticle aggregation is through steric stabilization, wherein polymers are absorbed or grafted onto the particle surface, allowing stable dispersions of NPs in versatile media ranging from simple liquids to elastic polymers.34,35 Therefore, the BCP tethers can tailor the interactions between the NPs via steric stabilization. The distribution functions of the NPs are given in Figure S2, which indicates the dispersion of the NPs due to the steric effect of the tethered arms. Therefore, the NPs are evenly distributed when marm = 3−7. MCV-like vesicles exist in the upper right part (more polymer arms and moderate number of

Figure 3. Morphological phase diagrams of the aggregates formed by (a) P(B2A2)m, (b) P(B4A2)m, and (c) P(B10A2)m and B10A2 as a function of the tethered arm number marm and the HNP number NP.

HNPs) of the phase diagram. When NP > 100, new membranes are formed by the HNPs on the vesicle surfaces and turn one-cavity vesicles into multicavity vesicles. When it comes to the coassembly of P(B4A2)m and B10A2, the major aggregation morphologies are vesicles and multicavity vesicles (Figure 3b). In these cases, the NPs are no longer distributed on the vesicle surfaces like the coassembly of C

DOI: 10.1021/acs.macromol.8b01172 Macromolecules XXXX, XXX, XXX−XXX

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Figure 4. Cumulative percentage pc and radial density distributions ΦX (X = A, B, P) as a function of the increasing radial distance d from the outer edge toward the center of the vesicle formed by (a) P(B10A2)3, (b) P(B10A2)6 and B10A2 with fixed NP = 50. Note that normalizations have been R chosen such that 4π∫ 0 outΦX (d)d2d(d) = 1.

improved model based on Mai and Eisenberg’s19 to characterize the angular and radial distributions of the NPs within the vesicle walls simultaneously, which is shown in Figure S6. Mai and Eisenberg found from the TEM micrograph that the NPs are randomly distributed in a thin spherical layer or shell going through the middle of the vesicle wall. On the basis of this point, they proposed a model to analyze their measured data. Their model was constructed by assuming (i) the NPs are located in a thin spherical shell and (ii) the NPs are “randomly distributed”. As we know, the location of a NP in the vesicle can be expressed in the spherical coordinate (r,ϕ,ψ), where the origin is set to be the geometric center of the vesicle. In the simulations, we also find that the NPs are uniformly distributed in the ϕ and ψ directions (or “randomly distributed” as claimed by Mai and Eisenberg), in the case of marm = 3−7. This feature shows an excellent agreement with the experimental results of Mai and Eisenberg. However, in the r direction, the NPs together with the amphiphiles present some regular distributions but are not just limited within a “shell”. Mai and Eisenberg’s model provides us with a good way to characterize the uniform distribution in the ϕ and ψ directions, but how the NPs are distributed in the r direction is still not fully described. Therefore, we attempt to combine their original model and arithmetic with radial functions, aiming at describing a fulldimensional characterization of the distribution of the NPs. On the one hand, the radial density distribution function ΦX , which essentially sums all the information over the angular directions ϕ and ψ, can completely represent features in the r direction. The hydrophilic beads present a double peak, which are corresponding to the inner and outer coronas of the vesicle. The hydrophobic beads appear a uniform radial distribution within the vesicle wall, while the NPs aggregate at a narrow interval (see the lower panels in Figure 4 for an example). On the other hand, in order to show the uniform distribution in the ϕ and ψ directions (so-called “angular distribution”), we followed Mai and Eisenberg’s original model, in which the cumulative percentage of the NPs (i.e., the “theoretical curve”, pc) as a function of the increasing radial

P(B2A2)m and B10A2. Instead, they are incorporated into the vesicle walls owing to the longer grafted hydrophobic chain length. When the steric effect of the tethered arms is strong enough to diminish the van der Waals force between the NPs (marm = 3−7), the aggregation morphologies change from vesicles to multicavity vesicles with the increase of NP. However, the phase transition mechanism is different from that of the coassembly of P(B2A2)m and B10A2. Unlike forming new membranes onto the vesicle surfaces by P(B2A2)m, the P(B4A2)m type HNPs can get into the cavities and connect the inner hydrophilic coronas, on account of the longer grafted hydrophobic chain length (Figure S3). We then analyze the morphological phase diagram of the aggregates formed by P(B10A2)m and B10A2, which is presented in Figure 3c. A new aggregation morphology bilayer appears with larger marm and NP. The wall thicknesses of the vesicles and the thicknesses of the bilayers are comparable. When NP is large enough, it seems that the small amount of the BCPs can be neglected. In order to consider this extreme situation, we draw a morphological phase diagram of the aggregates formed by P(B10A2)m and B10A2 with fixed B10A2 type polymer, including the BCP tethers and the free BCPs, which is presented in Figure S4. The aggregates in the lower and left part of the phase diagram are similar to Figure 3c, but the aggregates are disk-like vesicles rather than bilayers when the quantity of the HNPs is significantly larger than that of the BCPs and the NPs are grafted with more polymer arms. It is in agreement with our previous work for amphiphilic diblock copolymer tethered NPs.25 There is a mixed phase between the vesicle and the bilayer phase regions. So we suppose the bilayers are probably the metastable structures during the process of forming vesicles. Angular and Radial Distributions of NPs within Vesicle Walls. We further analyze the incorporation of particles into vesicle walls. As mentioned earlier, the tethered arm number affects the dispersity of the NPs within the vesicle walls. We focus on the uniform distributions of the NPs in the case of marm = 3−7 (Figure S5). In this section, we use an D

DOI: 10.1021/acs.macromol.8b01172 Macromolecules XXXX, XXX, XXX−XXX

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are distributed within the vesicle walls, where l is the averaged thickness of the nanoparticle layer. The depth percentage and width percentage as a function of various NP for the coassembly of P(B10A2)3/P(B10A2)6 and B10A2 are shown in Figure 5. The depth percentage is around 55%, i.e., the NPs are

distance d from the outer edge toward the center of the vesicle can be evaluated by the following:19 pc (d) =

(R out − a)2 − (R out − d)2 R out − a

× 100%

(1)

where Rout is the radius of the vesicle and a is the empty distance (a ≤ d ≤ Rout). Regardless of the width of the radial distribution of the NPs, here they are assumed to be distributed on a spherical shell surface, whose radius is the average value of the distances away from the geometric center, as displayed in Figure S6. This is quite reasonable, since only angular distribution are concerned. Therefore, the theoretical curves can be regarded as the criteria and the corresponding simulated curves that deviate from them indicate the nonuniform angular distributions of the NPs within the vesicle walls. Note that the angular distributions are here characterized by using a radial-dependent function instead of a direct ϕ- or ψ-dependent one. We now analyze the incorporation of P(B10A2)m into the vesicles walls formed by B10A2 (marm = 3−7), in which the NPs are localized in the central portion of the vesicle walls. Figure 4 shows the theoretical and simulated curve as well as the radial density distribution function for marm = 3 and 6, respectively. Here we discuss the marm = 6 case (panel b) in detail. With sufficient theoretical simulation results, a statistical radius of the vesicle is calculated to be Rout = 9.37. Now the origin is set at the outer hydrophilic corona, which is corresponding to the abscissa value of the first peak in the radial density function (lower panel). Then the NPs empty distance (i.e., parameter a) can be determined to be the abscissa value of the peak of ΦP(d). In the theoretical curve of pc, we can see a clear threshold at d = a = 2.82, which represents a void region of NPs at 0 < d < a. At d = Rout, all the NPs are taken into account and pc equals to 100%, which shows the normalization. However, the simulated result displays a threshold at d = 2.0, which is identical to the threshold behavior in the radial density function ΦP(d). It also indicates that the NPs are distributed in a range of interval rather than on a “thin shell surface”, and the width of the distribution will be discussed below. Except for the threshold value, the simulated result is in excellent agreement with the theoretic model, and these two curves are similar to what Mai and Eisenberg have done. Since the vesicle wall (w) is 5.28 thick and the empty distance exists on both internal and external interfaces of the wall, it appears that the NPs are located within a spherical layer of 1.28 (calculated by 5.28−2 × 2.0), i.e., central 20% of the wall. We can see that the radial density distribution of the NPs is between the inner and the outer hydrophilic coronas, which support the same conclusion that the NPs are incorporated into only the central portion of the vesicle wall. The cumulative percentage curve and the radial density function can support and consist with each other. Hence, the distributional behaviors can be described completely and clearly by this angular-radial-combined model, and it is supposed to be applied to other bulbiform distribution systems. Since the NPs are distributed uniformly in the angular direction in all cases, we next quantitatively evaluate the radial distributions of the NPs within the vesicle walls, using the depth percentage pd = a/w × 100% to measure the depth the NPs are located below the vesicle surfaces, and the width percentage pw = l/w × 100% to determine the range that they

Figure 5. Depth percentage pd (solid line) and width percentage pw (dashed line) as a function of various NP for the coassembly of P(B10A2)3 (blue circle), P(B10A2)6 (red square), and B10A2.

localized in the central portion of the vesicle walls. The width percentage is around 20%, i.e., the range that the NPs are distributed is 20%. Under these circumstances, NP does not appear to have a significant effect on the radial distributions of the NPs within the vesicle walls. The relationships between the averaged vesicular radius and various NP for the coassembly of P(B10A2)3/P(B10A2)6 and B10A2 are given in Figure S7. It is pretty obvious that the cavity sizes, the vesicle sizes, and the corresponding wall thicknesses increase with the increase of NP. In summary, the NPs are evenly distributed within the vesicle walls in the angular direction while they are incorporated into only the central portion of the vesicle walls in the radial direction for the coassembly of P(B10A2)m and B10A2 (marm = 3−7). We further analyze how nB affects the localization of the NPs within the vesicle walls. Figure 6 presents the relationships between pd and nB for the coassembly of P(BnA2)m and B10A2, which are irrelevant to the tethered arm number (marm = 3−7). We can see pd increases with nB in the case of 2 ≤ nB ≤ 12. As mentioned above, the NPs tend to be localized on the vesicle surfaces when nB = 2. Therefore, the depth percentage is ca. 0, i.e., on the vesicle surfaces under these circumstances. With the increase of nB, the NPs gradually move to the center of the vesicles, i.e., they are gradually located deeper below the vesicle surfaces. The solid line is linear least-squares fit to the simulation data points in the case of 2 ≤ nB ≤ 9, and its slope yields the relative speed of the movement of the NPs from the vesicle surfaces to the center of the vesicles. When 9 < nB ≤ 12, the NPs are just incorporated into the central portion of the vesicle walls and will not move deeper. On the basis of the fitting formula, the radial distributions of the NPs within the vesicle walls can be precisely controlled by changing nB from 2 to 9 under such circumstances. As a contrast, the coassembly of P(Bn)m and B10A2 is also investigated. It is proven that the terminal hydrophilic tethers have a significant impact on the controlled localization of the NPs within the vesicle walls E

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P(B10A2)6 and B10A2. We find these two percentages (70% and 60%) are both bigger than 50%. We now analyze how nB affects the stretch mode of the tethered arms within the vesicle walls. It should be remembered that, the NPs are distributed on the outer surfaces of the vesicles when nB is small. So the tethered arms all point to the outside interfaces, i.e., the stretch mode is (0, 5), (Figure 8a). As we know, the Gibbs free energy increases when the surface area of the system increases. Therefore, adsorbing the HNPs with short arms onto the outer surfaces of the vesicles will increase smaller surface areas and thus increase less energy. In addition, the steric hindrance of the tethered arms is smaller when they are located at the outer surfaces of the vesicles so that the energy is smaller as well. It is a result of thermal equilibrium that the NPs tend to stay on the outer surfaces of the vesicles when nB is small. We also calculate the total mode percentages in the case of nout > nin, as shown in Figure 8b. pm(nout > nin) decreases from 100% to 75% with the increase of nB. As nB increases, the NPs move from the vesicle surfaces to the center of the vesicles so that the tethered arms can be extended to both the inside and the outside interfaces. Remarkably, pm(nout > nin) sustains above 50%, i.e., the tethered arms are more likely to extend to the outside interfaces than that to the inside interfaces, for the steric reason, which is consistent with Figure 7. In addition, we calculate the radius of gyration of BnA2, [⟨Rg2⟩/⟨Rg02⟩]1/2, as shown in Figure 8c. We notice that all of the values are bigger than 1, which means the tethered arms are stretched compared to the ones without disturbance. Obviously, the steric hindrance of the tethered arms is larger in the case of shorter nB, because they all tend to point to the outside interfaces. Moreover, the longer flexible arms can reduce the steric hindrance effect by folding themselves. On the basis of these two factors, it appears reasonable that the value of [⟨Rg2⟩/ ⟨Rg02⟩]1/2 decreases with the increase of nB. The incorporation of other P(BnA2)m with various marm (marm = 3, 4, 6, 7) into vesicle walls are similar to what we have just discussed (Figures S9 and S10). These results may provide valuable microscopic insights and have potential application for carrier-assistant DDSs, such as improving the encapsulation efficiency, realizing the specific targeting and controlling the release of drug. For example, the NPs can be used for small molecular weight drugs. Combined with stimuli-responsive nanocarriers, the

Figure 6. Depth percentage pd as a function of the grafted hydrophobic chain length nB for the coassembly of P(BnA2)m (marm = 3−7) and B10A2 with fixed NP = 50. The solid line is linear leastsquares fit to the data points in the case of 2 ≤ nB ≤ 9.

because they can be localized in the inner or the outer hydrophilic coronas of the vesicle walls (Figure S8). Stretch Modes of the Tethered Arms within Vesicle Walls. As previous work19 discussed, the tethered arms can be extended to either the inside or the outside interfaces of the vesicles. A notation including two numbers, (nin, nout), is used to label a stretch mode that the tethered arms extend. It indicates the numbers of the tethered arms which are extended to the inside (i.e., nin) and the outside (i.e., nout) interfaces. The mode percentage pm is defined as the ratio of the number of the HNPs in a specific mode to the total number of the HNPs. Figure 7a,b show pm for the incorporation of P(B10A2)3 and P(B10A2)6 into the vesicle walls with various NP, respectively. From the figure, we can know the stretch mode of (1, 2) is the most remarkable one for the coassembly of P(B10A2)3 and B10A2 while (1, 5), (2, 4), and (3, 3) for P(B10A2)6 and B10A2. Under these circumstances, NP does not appear to have a significant effect on the distributions of the various stretch modes. We further calculate the total mode percentages in the case of nout > nin, i.e., (0, 3) and (1, 2) for the coassembly of P(B10A2)3 and B10A2, and (0, 6), (1, 5), and (2, 4) for

Figure 7. Mode percentage pm for the coassembly of (a) P(B10A2)3, (b) P(B10A2)6, and B10A2 with various NP. The two-number-labeled notation (nin, nout) means the numbers of the tethered arms which are extended to the inside (i.e., nin) and the outside (i.e., nout) interfaces. F

DOI: 10.1021/acs.macromol.8b01172 Macromolecules XXXX, XXX, XXX−XXX

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describing the behaviors of NPs that are distributed within vesicle walls. The tethered arm number marm affects the dispersity of the NPs in the angular direction of the vesicle walls. The grafted hydrophobic chain length nB precisely determines the localization of the NPs in the radial direction of the vesicle walls. Therefore, the properties of the synthetic vesicles can be precisely controlled just by manipulating NP, marm, and nB. In addition, we observe the tethered arms tend to point to the outside interfaces rather than the inside interfaces of the vesicles, for the steric reason. We suppose this work could help researchers design carrier-assistant DDSs, which may potentially improve the encapsulation efficiency, and realize the specific targeting and control the release of drug.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b01172. The model for determining the distribution of the NPs in the angular or radial direction of the vesicle wall; the model of the HNP and free BCP; one figure of the snapshots of the incorporation of HNPs into vesicle wall; one figure of the distribution functions g(rPP) of the NPs within the vesicles; one figure of the snapshots of two formation pathways of the multicavity vesicles; two figures of the morphological phase diagrams of the aggregates formed by P(BnA2)m and B10A2 under different conditions; one figure showing the relationships between the averaged vesicular radius and various nanoparticle number; one figure of the mode percentages for the coassembly of P(BnA2)m and B10A2; and one figure of the total mode percentages and the radiuses of gyration of the tethered arms for the coassembly of P(BnA2)m and B10A2 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID Figure 8. (a) Mode percentage pm for the coassembly of P(BnA2)5 and B10A2 with fixed NP = 50. (b) Total mode percentage in the case of nout > nin for the coassembly of P(BnA2)5 and B10A2 with fixed NP = 50. (c) Radius of gyration of the tethered arms BnA2 of P(BnA2)5.

Rong Wang: 0000-0001-7525-1400 Daiqian Xie: 0000-0001-7185-7085 Notes

The authors declare no competing financial interest.

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NPs localized in different portions of vesicle walls may have different efficiencies of drug release and then achieve targeting goals.

ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (grant Nos. 21474051, 21674047, 21590802, 21734005, and 21733006), and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT).

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CONCLUSIONS This paper describes the self-assembly and aggregation behaviors of HNPs in hybrid assemblies formed by BCPs in a dilute solution. By systematically varying the HNP number NP, the tethered arm number marm and the grafted hydrophobic chain length nB, four different aggregates are obtained, including MCV-like vesicles, multicavity vesicles, bilayers, and vesicles. We use an improved quantitative model to characterize the angular and radial distributions of the NPs within the vesicle walls simultaneously. This angular-radial-combined model is believed to be applied as a general model for

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DOI: 10.1021/acs.macromol.8b01172 Macromolecules XXXX, XXX, XXX−XXX