Controlling Vesicular Size via Topological Engineering of Amphiphilic

Dec 5, 2017 - †Key Lab of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, ‡Key Lab of Bioorga...
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Article Cite This: Macromolecules XXXX, XXX, XXX−XXX

Controlling Vesicular Size via Topological Engineering of Amphiphilic Polymer in Polymerization-Induced Self-Assembly Meng Huo,†,‡ Ziyang Xu,§ Min Zeng,† Pengyu Chen,§ Lei Liu,† Li-Tang Yan,*,§ Yen Wei,*,‡ and Jinying Yuan*,† †

Key Lab of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, ‡Key Lab of Bioorganic Phosphorus Chemistry & Chemical Biology of Ministry of Education, Department of Chemistry, and §Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering, Tsinghua University, Beijing 100084, P. R. China S Supporting Information *

ABSTRACT: The significance of polymer topology to the size and morphology of polymeric assemblies was less studied. Herein we report the preparation of polymersomes with tunable sizes via topological engineering of the solvophobic block of the amphiphilic copolymer in polymerization-induced self-assembly (PISA). The topology of the solvophobic block could be facilely regulated by reversible addition−fragmentation chain transfer (RAFT) dispersion copolymerization of two kinds of monomers with distinctive molecular geometries at variable feed ratios. As a proof-of-concept study, RAFT dispersion copolymerization of benzyl methacrylate (BzMA) and stearyl methacrylate (SMA) produced polymersomes with size ranging from 200 to 1500 nm depending on the ratio of BzMA/SMA. Besides vesicles, assemblies with complex internal structures were obtained by varying the ratio of BzMA/SMA, suggesting the robustness of this strategy. The mechanism was revealed by a series of coarse-grained molecular simulations, which elucidated the dependence of the packing parameter on the composition of the solvophobic block. The generality and modularity for regulating vesicular size by topological engineering of solvophobic block were further established by RAFT dispersion copolymerization of BzMA and 2(perfluorooctyl)ethyl methacrylate, which also generated polymersomes with tunable sizes. The topological engineering of copolymer by RAFT dispersion copolymerization thus serves as a versatile and modular approach to controlling the size and morphology of polymer assemblies.

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solvophobic block.20−27 As the solvophobic block grows, the amphiphilic block copolymers associate into assemblies in situ, which further reorganize to other morphologies, such as wormlike micelles and vesicles.28−42 Given its unique mechanism, PISA allows to target polymer assemblies at high solids content (as high as 50 wt %) by simple regulation of the polymerization formulation.43−54 Nevertheless, the regulation capacity of PISA over the nanostructure of polymer assemblies is still limited. For example, the mechanistic study revealed that the vesicular wall thickness increases while the vesicular size remains almost constant during PISA,55,56 which suggests that the size of the polymersomes could not be tuned by just changing the degree of polymerization (DP) of the solvophobic block, despite the fact that size of polymersomes is significant for their applications in drug delivery, bioimaging, and miniaturized optoelectronic devices.57−60 For instance, the size of polymersomes is an important factor influencing their biodistribution, in vivo circulation time, and their interaction with the cells.59,61 Besides, the nanostructure of polymersomes

INTRODUCTION Polymersomes are a class of self-assembled bilayered membranes that are composed of amphiphilic copolymers.1−3 As they have similar structural feature with the cell membrane, polymersomes have attracted profound interest since their emergence. Compared with their small molecular counterparts, the liposomes, polymersomes have superior stability against extreme dilution, which makes them attractive candidates for the medical and pharmaceutical applications.4−6 Moreover, the size, permeability, and surface properties of polymersomes can be tailored to fulfill the in vivo requirements.7−9 As a result, polymersomes have shown intriguing potential as drug and gene carriers,5,10,11 nanoreactors,12,13 artificial organelles,14−16 etc. Typically, polymersomes are prepared by self-assembly of the amphiphilic copolymers through nanoprecipitation or filmrehydration techniques,17,18 which have been suffering from imperfections such as low solids content (usually lower than 1 wt %) and sophisticated kinetically constrained morphologies.8,19 Recently, a novel method termed as “polymerizationinduced self-assembly (PISA)” emerged as a revolutionary strategy for fabrication of polymer assemblies by chain extension of a soluble polymeric stabilizing chain with a © XXXX American Chemical Society

Received: September 20, 2017 Revised: November 13, 2017

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Scheme 1. Regulating Vesicular Size by RAFT Dispersion Copolymerization of BzMA and SMA at Tunable Feed Ratios

is related to the vesicular size, by which their functionality could also be tuned.52,58,60,62,63 In spite of the significance of vesicular size, only a few examples were reported concerning the size regulation of polymersomes by PISA.64−66 For instance, Armes et al. designed a system in which reversible addition−fragmentation chain transfer (RAFT) dispersion polymerization of benzyl methacrylate (BzMA) was mediated by a binary mixture of two poly(methacrylic acid) macro-chain-transfer agents (macroCTAs) with distinctly different molecular weights.64 By adjusting the relative molar ratio of the two macro-CTAs, polymersomes with diameter ranging from 200 to 500 nm could be prepared with low polydispersity. D’Agosto et al. studied the effect of the hydrophile topology on the morphology of the assemblies.65 Poly(ethylene glycol) acrylate units were incorporated to different locations of the poly(Nacryloylmopholine) backbone to construct macro-CTAs with different topologies, which were used to mediate the PISA of styrene in aqueous medium, with the morphology of the resulting assemblies related to the chain topology of the macroCTAs. This seminal study suggests the significance of polymer topology to the size and morphology of polymeric assemblies, whereas it is restrained by the laborious synthesis and indistinct mechanism. Therefore, there is still urgent needs to explore a modular strategy with general applicability and robust regulation capacity over the vesicular nanostructure, especially over the size of polymersomes. We envision that each monomer has specific molecular volume and shape so that copolymers with distinct molecular topologies could be facilely prepared by RAFT copolymerization of two kinds of monomers at different feed ratios. The difference in molecular topologies may result in assemblies with variable chain packing densities and tunable nanostructures. Herein we report a general and modular strategy for regulating

vesicular size by topological engineering of the solvophobic block (Scheme 1). As a proof-of-concept study, RAFT dispersion copolymerization of BzMA and stearyl methacrylate (SMA) is performed in ethanol with poly(N,N-dimethylaminoethyl methacrylate) (PDMA) as the macro-CTA. The size of the corresponding polymersomes is regulated by the feed ratio of BzMA/SMA. The underlying mechanism is studied by coarse-grained molecular simulations. Furthermore, the generality and modularity of this strategy are established by RAFT dispersion copolymerization of BzMA and 2(perfluorooctyl)ethyl methacrylate (FMA).

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EXPERIMENTAL SECTION

Materials and Instrumentation. N,N-Dimethylaminoethyl methacrylate (DMA) (99%) and 2,2′-azobis(2-methylpropionitrile) (AIBN) (99%) were purchased from J&K Co. Benzyl methacrylate (BzMA) (98%) and stearyl methacrylate (SMA) (97%) were purchased from TCI (Shanghai). DMA and BzMA were passed through a short alumina column to remove the inhibitors. SMA was heated to above its melting point and passed through an alumina column rapidly. AIBN was recrystallized from ethanol and kept at −20 °C before use. 4-(4-Cyanopentanoic acid) dithiobenzoate (CPADB) was synthesized according to the reported literature.67 All the other regents were used as received. 1 H NMR spectra of the polymers were recorded by a 400 MHz JEOL JNM-ECA 400 spectrometer at ambient temperature. The molecular weights and dispersities (Đ) of these polymers were characterized by a Waters GPC system containing a Waters isocratic HPLC pump, a refractive index detector, and three styragel columns. The eluent was THF (containing 2% triethylamine), and the flow rate was kept as 1 mL min−1. The GPC system was calibrated with a series of near-monodisperse polystyrene standards. The hydrodynamic sizes of the block copolymeric assemblies were measured with a Marven Zetasizer Nano ZS90. A 633 nm He−Ne laser was equipped as the laser source, and the scattering light at 90° angle was detected by an avalanche photodiode detector. The sizes and morphologies of the assemblies at dry state were recorded by a Hitachi H-7650B B

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Table 1. Molecular Characteristics of PDMA-b-P(BzMA-co-SMA)-42k-x (x = 0, 10, 20, 30, 50, 70, 90, 100) Copolymers entry

target DPBzMA

target DPSMA

DPBzMAa

DPSMAa

SMA (wt %)b

Mn(NMR) (kDa)c

Mn(SEC) (kDa)d

Đe

S-42k-0 S-42k-10 S-42k-20 S-42k-30 S-42k-50 S-42k-70 S-42k-90 S-42k-100

240 216 192 168 120 72 24 0

0 12 24 37 62 87 112 124

232 206 190 154 109 58 14 0

0 13 25 35 58 81 112 116

0 10.8 20.1 30.3 50.5 72.9 93.8 100

47.4 47.3 48.4 45.5 45.4 44.2 46.9 45.8

44.9 53.2 45.6 43.4 48.5 42.7 48.1 49.2

1.18 1.22 1.21 1.22 1.35 1.22 1.26 1.19

Determined by 1H NMR. bSMA wt % = 338DPSMA/(338DPSMA + 176DPBzMA) × 100. cMn of the copolymers calculated according to the 1H NMR spectra. Mn(NMR) = 338DPSMA + 176DPBzMA + 6600. dObtained from SEC. eĐ = Mw/Mn. a

transmission electron microscope at 80 kV. For transmission electron microscopy (TEM) sampling, a drop of assemblies was dripped onto a carbon-coated copper grid and was adsorbed for 1 min before being blotted up by filter paper. After repeating this operation for three times, the copper grid was dried at room temperature for TEM observation. For all the PDMA-b-P(BzMA-co-SMA) copolymeric assemblies, the TEM samples were stained with phosphotungstic acid to enhance the contrast of the TEM images. Scanning electron microscopy (SEM) images were recorded on a Hitachi SU-8010 field emission scanning electron microscope at 15 kV. Preparation of PDMA Macro-CTA. PDMA macro-CTA was prepared by RAFT polymerization of DMA according to the formulation published before.52 The polymerization was stopped after 6 h, and the conversion was 87%. 1H NMR and SEC were used to characterize the molecular characteristics of the polymers (Figure S1a). The DP was calculated to be 42, Mn(NMR) = 6.6 kg mol−1, Mn(SEC) = 5.0 kg mol−1, and Đ = 1.18. Preparation of PDMA-b-P(BzMA-co-SMA)-42k-x (x Represents the Mass Ratio of SMA within the Solvophobic Block, x = 0, 10, 20, 30, 50, 70, 90, 100) Vesicles. PDMA-b-P(BzMA-coSMA)-42k-x vesicles were prepared via PISA using RAFT dispersion copolymerization of BzMA and SMA in ethanol at 15 wt % solids content. For all the PDMA-b-P(BzMA-co-SMA)-42k-x samples, the molecular weight of the solvophobic block P(BzMA-co-SMA) was kept as 42 kDa, while the weight percentage of SMA within the P(BzMAco-SMA) block (SMA wt %) was systematically varied from 0 to 100. The detailed feed ratios of BzMA and SMA are listed in Table 1. In a typical formulation targeting PDMA-b-P(BzMA-co-SMA)-42k-50 vesicles (entry S-42k-50 in Table 1), AIBN (7 μmol, 1.2 mg), PDMA (0.02 mmol, 132 mg), BzMA (2.4 mmol, 422 mg, 406 μL), and SMA (1.24 mmol, 422 mg) were dissolved into 7.0 mL of ethanol, and the mixture was bubbled by N2 for 20 min. Then the Schlenk tube was heated in an oil bath at 70 °C for 24 h, after which a small portion was extracted for monomer conversion measurement. The remaining colloid was dialyzed against ethanol to remove the residual monomers. For other samples targeting different SMA wt %, the feed ratios of BzMA and SMA were differed accordingly. Preparation of PDMA-b-P(BzMA-co-SMA)-63k-x (x = 0, 15, 30, 50, 70, 85, 100) Vesicles and PDMA-b-P(BzMA-co-SMA)88k-x (x = 0, 20, 40, 60, 80, 100) Assemblies. PDMA-b-P(BzMAco-SMA)-63k-x and PDMA-b-P(BzMA-co-SMA)-88k-x assemblies were prepared by PISA using similar formulas to those of the PDMA-b-P(BzMA-co-SMA)-42k-x vesicles. Preparation of PDMA-b-P(BzMA-co-FMA)-42k-x (x = 0, 10, 20, 25, 30) Vesicles. PDMA-b-P(BzMA-co-FMA)-42k-x vesicles were prepared using RAFT dispersion copolymerization of BzMA and FMA in ethanol at 15 wt % solids content. For all the PDMA-bP(BzMA-co-FMA)-42k-x samples, the mass percentage of FMA in the hydrophobic block was systematically varied, while the target molecular weight of the whole hydrophobic P(BzMA-co-FMA) block was kept as 42 kDa. Taking PDMA-b-P(BzMA-co-FMA)-42k-25 vesicles as the example, AIBN (4 μmol, 0.66 mg), PDMA (0.02 mmol, 132 mg), BzMA (3.6 mmol, 634 mg, 609 μL), FMA (0.4 mmol, 211 mg, 132 μL), and ethanol (7.0 mL) were sealed in a Schlenk tube, purged for 20 min, and polymerized in a 70 °C oil bath for 24 h. The

resulting mixture was dialyzed against ethanol to remove the residual monomers, and the colloidal dispersion was diluted and stored for further use. Coarse-Grained Molecular Simulations. In this work, we employ the dissipative particle dynamics (DPD) technique, a method that samples the NVT ensemble, to conduct the coarse-grained molecular simulations.68 For the complicated problems considered here, DPD offers an approach that can be used for modeling physical phenomena occurring at larger time and spatial scales than molecular dynamics (MD). In DPD, each bead represents a cluster of atoms, and experiences a force with the components of conservative interaction force F C , dissipative force F D , and random force F R , i.e., fi = ∑i ≠ j (FCij + FijD + FijR ), where the sum runs over all beads j. The interaction forces are treated as pairwise additive and are truncated at a certain cutoff distance rc. The conservative force is a soft, repulsive force given by FCij = aij(1 − rij)r̂ij, where aij is the maximum repulsion between beads i and j, rij = |ri − rj|/rc, and r̂ij = rij/|rij|. aij has a linear relationship with Flory−Huggins χij parameter: χij ≈ (aij − aii)/3.27, where aii = 25 is the repulsion parameter between like species (i.e., χii = 0), and a larger aij corresponds to a stronger bead− bead repulsion. Here, for interactions between unlike beads, aPBa = aPSa = aBaBb = aBaSb = aSaBb = aSaSb = 20, aPW = aBaW = aSaW = 20, aBaSa = aBbSb = 25, and aBbW = aSbW = 100, where the subscript P represents PDMA, Ba and Sa are the monomers of BzMA and SMA, Bb and Sb are BzMA and SMA after reaction, and W is solvent. The repulsion between solvent and BzMA (SMA), i.e., aBbW (aSbW), is chosen to 100, causing the solvophobic property of the block formed through polymerization. The drag force is FDij = −γωD(rij)(r̂ij·vij)r̂ij, where γ is a simulation parameter related to viscosity (γ = 4.5), ωD is a weight function that goes to zero at rc, and the relative velocity is vij = vi − vj. The random force is FRij = σ̃ωR(rij)ξijr̂ij, where ξij is a zero-mean Gaussian random variable of unit variance and σ̃2 = 2γkBT. Here, kB is the Boltzmann constant and T is the temperature of the system. We select weight functions to take the following form: ωD(rij) = ωR(rij)2 = (1 − rij)2 for rij < rc. Each solvophilic block of PDMA is modeled as four beads encompassing initiator site that can induce the RAFT polymerization of BzMA and SMA monomers modeled respectively by one and two connected beads due to their different molecular shapes (Figures S5 and S6). The polymerization leads to the formation of the second solvophobic block, which in turn causes the self-assembly of newly produced amphiphilic block copolymers (Figure S7). All simulations are carried out in the canonical ensembles using a modified velocityVerlet integration algorithm with a time step Δt = 0.01τ, where τ is the time unit of DPD. Such a small time step ensures the accurate temperature control over the simulation system.69 The simulation box is (30rc)3 in size and with periodic boundary condition in all directions, which is large enough to avoid the finite size effect. Each structure is determined over three independent runs, and each run is equilibrated with more than 2 million time steps to ensure equilibrium after the polymerization reaction as stated below. Our simulation work is calculated on a 4 GHz Intel(R) Core(TM) i7-4790K processor over 1000 h CPU time. C

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Figure 1. TEM and DLS characterizations for PDMA-b-P(BzMA-co-SMA)-42k-x (x = 0, 10, 20, 30, 50, 70, 90, 100) vesicles. (a−h) TEM images of PDMA-b-P(BzMA-co-SMA)-42k-x vesicles: (a) x = 0, (b) x = 10, (c) x = 20, (d) x = 30, (e) x = 50, (f) x = 70, (g) x = 90, (h) x = 100. (i) Size statistics of the PDMA-b-P(BzMA-co-SMA)-42k-x vesicles vs the SMA wt %. (j) DLS profiles and (k) number-averaged diameters of the PDMA-bP(BzMA-co-SMA)-42k-x vesicles. Scale bars: 500 nm. Reaction Scheme of “Living”/Controlled Polymerization. For a “living”/controlled polymerization process such as RAFT, the chains with active ends continue to grow because of the low probability of termination. Thus, we only consider the elemental reactions of initiation and propagation in the modeling. The detailed model of the polymerization process in the present work is similar to a DPD-based living copolymerization reaction scheme where the reactive components within the system, including the initiators and monomers, are modeled as DPD beads.70,71 In particular, during each reaction step for each reactive bead, we randomly select another bead within the interaction radius, Rr, of the given bead. Subsequently, a polymerization probability P is generated to decide whether the reacting pair of beads will form a bond.72 In the simulations, the reaction rate constants can be controlled by modifying the probabilities of initiation, Pi, and propagation, Pp, which should be sufficiently small to ensure controlled polymerization growth in the kinetically controlled reaction regime. Therefore, we take Pi = 0.0025 and Pp = 0.0005 for the reactions of all the monomers in the present work. A successful reaction can lead to irreversible bond formation, with the energy of the harmonic spring potential given by Ubond = Kb[(r − b)/rc]2, where Kb = 64kBT and b = 0.5rc are the bond constant and the equilibrium bond length, respectively. Chain length, L, is expressed in total number of DPD beads connecting together in a chain (Figure S6b). The reactions are performed every 10 time steps (0.1τ) as the reaction interval. The monomers are randomly added to the system at the initial stage. During the simulations, we systematically vary the concentration of SMA, CS, that is equal to the weight percentage of SMA within the solvophobic block, i.e., SMA wt %, to tailor the molecular topology of

the newly formed block and thereby to realize the PISA of the block copolymers.

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RESULTS AND DISCUSSION As a proof-of-concept study, we first synthesized PDMA as the macro-CTA for mediating the dispersion copolymerization of BzMA and SMA. BzMA and SMA are chosen as they both are typical monomers used in alcoholic PISA, producing PDMA-bPBzMA and PDMA-b-PSMA vesicles of ca. 200 and 180 nm, respectively.55,73 According to previously reported work,55,56 sizes of these vesicles remained almost unchanged as the length of the solvophobic chain grew. Since BzMA has distinctly different molecular geometry from SMA, which has a long stearyl side chain, the chain packing density within the poly(N,N-dimethylaminoethyl methacrylate)-b-poly(benzyl methacrylate-co-stearyl methacrylate) [PDMA-b-P(BzMA-coSMA)] vesicles should vary with the feed ratio of BzMA/ SMA in the PISA formulation. Thus, polymersomes with tunable sizes are anticipated with PISA. To regulate the topology of the solvophobic block, the molecular weight of the solvophobic P(BzMA-co-SMA) block was set as 42 kDa, while the weight percentage of SMA in P(BzMA-co-SMA) block (denoted as SMA wt %) was adjusted from 0 to 100. Accordingly, the molar feed ratio of BzMA decreased from 240 to 0, while that of SMA increased from 0 to 124. The corresponding copolymers were denoted as PDMA-b-P(BzMAD

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statistical monomer distribution in the P(BzMA-co-SMA) block. Besides, according to the corresponding semilogarithmic plots of BzMA and SMA in Figure S2, the polymerization rate of SMA increased obviously after 4 h of polymerization, while that of BzMA remained constant. According to the monomer conversions after 4 h of polymerization, the theoretical composition of the copolymer was PDMA-b-P(BzMA60-coSMA37) (the subscripts represent the DPs). Hence, the reason for the rate increment of the polymerization of SMA could be because the DP of SMA within the assemblies were large enough to enrich more SMA monomers after 4 h of polymerization. The fact that the polymerization rate of BzMA was constant indicates that the solubilization of BzMA and SMA in the assemblies has no influence to each other. The compositional effect of the solvophobic block on the size and morphology of the assemblies was evaluated by TEM and dynamic laser scattering (DLS) (Figure 1). Based on the TEM data, for PDMA-b-P(BzMA-co-SMA)-42k-0 sample with no SMA, the assemblies are composed of vesicles and “solid vesicles” of 186 ± 37 nm. According to Armes et al., these “solid vesicles” are actually solid nanoparticles formed by the inward growth of the hollow vesicles at high DP of BzMA.55 To emphasize their relationship with the common hollow vesicles obtained from PISA of PDMA-b-PBzMA at lower DP of PBzMA, we use the term “solid vesicles” to describe them. As the SMA wt % increases from 0 to 50, the “solid vesicles” disappear, and the size of the vesicles increases successively to 528 ± 129 nm, whereas the size decreases when the SMA wt % further increases from 50 to 100. Eventually, the size decreases to 215 ± 36 nm and both hollow and solid vesicles could be observed for PDMA-b-P(BzMA-co-SMA)-42k-100 with no BzMA moiety, which is similar to the results of Armes et al.73 Subsequently, the hydrodynamic sizes of these assemblies were monitored by DLS, which shows considerably narrow size distribution (PDI < 0.30) for all of the samples. The numberaveraged size of these assemblies increases from 227 ± 68 to 466 ± 138 nm as SMA wt % increases from 0 to 50 while decreases to 195 ± 72 nm as SMA wt % further increases to 100, which coincides with the trend of the size variation obtained from TEM particle statistics. Both the TEM and DLS results verify our assumption that RAFT dispersion copolymerization of BzMA and SMA enables to produce PDMA-bP(BzMA-co-SMA) vesicles whose size could be facilely tuned by the feed ratio of BzMA/SMA. Compared with the topological engineering of the hydrophile which realized the morphological regulation by emulsion polymerization,65 our results indicates that the topology of the hydrophobic block could be readily engineered via RAFT dispersion copolymerization, which would thus serve as a new approach to regulate the vesicular size. The above trend is valid for PDMA-b-P(BzMA-co-SMA) copolymers with different molecular weights of solvophobic block. Besides the polymersomes constituted of PDMA-bP(BzMA-co-SMA)-42k, polymersomes were also fabricated via PISA of PDMA-b-P(BzMA-co-SMA)-63k and PDMA-b-P(BzMA-co-SMA)-88k copolymers, the solvophobic blocks of which were separately set as 63k and 88k (Tables S1 and S2). The morphology of PDMA-b-P(BzMA-co-SMA)-63k-0 assemblies is “solid vesicles” of 171 ± 20 nm while hollow vesicles of 446 ± 107 nm are obtained for PDMA-b-P(BzMA-co-SMA)63k-15 sample (Figure S3a,b). Systematic adjustment of the SMA wt % from 15 to 50 results in the dramatic increase of the vesicular size, which even reaches to 1500 ± 499 nm for

Figure 2. DLS and TEM characterizations of PDMA-b-P(BzMA-coSMA)-88k-x (x = 0, 20, 40, 60, 80, 100) assemblies. (a) DLS profiles and (b) number-averaged diameters of the PDMA-b-P(BzMA-coSMA)-88k-x assemblies. (c−h) TEM images of PDMA-b-P(BzMA-coSMA)-88k-x assemblies: (c) x = 0, (d) x = 20, (e) x = 40, (f) x = 60, (g) x = 80, (h) x = 100.

co-SMA)-42k-x (x represents the SMA wt %, x = 0, 10, 20, 30, 50, 70, 90, 100), and their detailed molecular characteristics were characterized using 1H NMR and size exclusion chromatography (SEC) (Table 1 and Figure S1). Both the DPs of BzMA and SMA reach their theoretical feed ratios for all the copolymers in Table 1. Moreover, their molecular weights are close to each other, and their dispersities are all very low, suggesting successful RAFT copolymerizations. To understand their copolymerization behaviors, polymerization kinetics of PDMA-b-P(BzMA-co-SMA)-42k-50 sample was monitored (Figure S2). We found that both BzMA and SMA achieved monomer conversion of >90% after 12 h, though the polymerization rate of SMA is slightly faster than that of BzMA. According to the Alfrey−Price’s Q−e values of BzMA74 and SMA,75 the reactivity ratios of BzMA and SMA are calculated to be 1.09 and 0.83, respectively, indicating relatively E

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Figure 3. (a) Representative snapshots showing the simulated morphologies formed by the polymerization-induced self-assembly of block copolymers with solvophilic block of PDMA (green beads) and solvophobic block consisting of BzMA (blue beads) and SMA (pink beads), where the concentration of SMA: CS = 0 (top), 0.5 (middle), and 1.0 (bottom). Solvent beads are not shown for clarity. (b) The averaged radius of polymersomes, R, as a function of CS. (c) The averaged values of volume of an individual block polymer, V, effective area of solvophilic block segments, ah, and length of fully extended solvophobic segments, lc, as a function of CS. Geometric packing parameters calculated by assuming a truncated cone, as illustrated by the schematic diagram inserted in the top panel. (d) The dependence of geometric packing parameter, P, on CS.

Scheme 2. RAFT Dispersion Copolymerization of BzMA and FMA in Ethanol with PDMA as the Macro-CTA

Table 2. Molecular Characteristics of PDMA-b-P(BzMA-co-FMA)-42k-x (x = 0, 10, 20, 25, 30) Copolymers entry

target DPBzMA

target DPFMA

DPBzMAa

DPFMAa

FMA (wt %)b

Mn(NMR) (kDa)c

Mn(SEC) (kDa)d

Đe

F-42k-0 F-42k-10 F-42k-20 F-42k-25 F-42k-30

240 216 192 180 168

0 8 16 20 24

232 200 180 146 138

0 3 9 9 14

0 4.3 13.2 15.7 23.3

47.4 43.4 43.1 37.1 38.3

44.9 47.6 44.9 39.8 37.4

1.18 1.16 1.18 1.18 1.20

Determined by 1H NMR. bFMA wt % = 532DPFMA/(532DPFMA + 176DPBzMA) × 100. cMn of the copolymers calculated according to the 1H NMR spectra. Mn(NMR) = 532DPFMA + 176DPBzMA + 6600. dObtained from SEC. eĐ = Mw/Mn. a

593 nm and then decreases to 235 ± 85 nm with the increment of the SMA wt % (Figure S3i,j). DLS characterizations reveal similar bell-shaped curve for the size of PDMA-b-P(BzMA-co-SMA)-88k-x (x = 0, 20, 40, 60, 80, 100) assemblies vs SMA wt % (Figure 2a,b). However, TEM and SEM observations indicate that large compound micelles (LCMs) and large compound vesicles (LCVs) of several micrometers were obtained for PDMA-b-P(BzMA-co-SMA)-

PDMA-b-P(BzMA-co-SMA)-63k-50, indicating the powerful regulation capacity of polymer topology over the size of the polymersomes (Figure S3b−d). Upon further increasing the SMA wt % to 85, the vesicular size significantly reduces to 274 ± 57 nm (Figure S3e,f). For PDMA-b-P(BzMA-co-SMA)-63k100 formulation, “solid vesicles” of 205 ± 28 nm are observed (Figure S3g). These observations are consistent with the DLS measurements, which first increases from 179 ± 53 to 3000 ± F

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polymerization leads to the formation of the second hydrophobic block, which in turn causes the self-assembly of newly produced amphiphilic block copolymers (Figures S6 and S7). Figure 3a displays some typical snapshots showing the selfassembled morphologies of these block copolymers in response to varying CS. It can be found that the block copolymers without SMA and that with pure SMA tend to aggregate into solid vesicles with small size while the hollow vesicle with large size forms when C S approaches 0.5, resembling the experimental observation of the morphologies as shown in Figure 1. In Figure 3b, we present the averaged radius of the polymersomes, R, at different CS. Clearly, R increases when CS increases from 0 to about 0.5 and then turns to decrease for a further increase of CS from 0.5 to 1.0, in good agreement with the experimental results as demonstrated in Figures 1i and 1k. On the basis of the results above, we try to rationalize the vesicular size variation during PISA by the packing parameter P17 (Scheme 1). According to the theoretical study of block copolymers, the size of the polymersomes is dictated by P, where

P = V /ahlc in which V represents the volume of the solvophobic chains, ah represents the interfacial area of the solvophilic chain, and lc is the length of the solvophobic chain. For assemblies with 1/2 ≤ P ≤ 1, vesicles are formed, whose size increases with P. Computer simulations allow for the direct calculation of the three variables governing the packing parameter: the estimated V can be acquired from the approximation of the averaged volume occupied by the hydrophobic block of each polymer chain in the vesicle; ah is obtained by the perimeter area of the vesicle divided by the total number of polymer chains that make up the vesicle; lc is quantified based on the numberaverage length of hydrophobic segments (for example, see Figure S6b). Figure 3c summarizes V, ah, and lc at various CS, highlighting the significant dependence of these variables on the SMA concentration. In Figure 3d, we plot the packing parameter P against CS. By comparing Figure 3d to Figure 3b, it is interesting to notice that the P−CS relation presents a strong correlation with that of R−CS. That is, P is smaller than 1/3 for the block copolymers without SMA and with pure SMA, corresponding to the solid spherical vesicle with small size. The larger the P value, the less curvature and larger size one would expect from the resulting morphologies. Indeed, P reaches the peak value at around CS = 0.5 where the hollow vesicles with the largest size occur as P > 1/2. This corroborates the assumption that regulation over the vesicular size can be ascribed to the variable geometric packing of the copolymers tailored by the topology of the solvophobic block. Ideally, the topological engineering of the solvophobic block should be applicable to any two kinds of monomers that each is suitable for PISA in the same solvent, such as BzMA/2(perfluorooctyl) ethyl methacrylate (FMA), BzMA/methy methacrylate, and N,N′-diethylacrylamide/diacetone acrylamide.23,24 Among these monomers, FMA is a representative of the semifluorinated (meth)acrylates which are soluble in ethanol while corresponding polymers are not. Besides, FMA has a long alkyl fluoroalkyl side chain, which endows the corresponding PFMA with many superior properties, including liquid crystallinity and antifouling properties.77,78 As a result, RAFT dispersion copolymerization of BzMA and FMA was investigated to examine the generality of our finding that polymer topology plays significant role in controlling the size

Figure 4. TEM and DLS characterizations for PDMA-b-P(BzMA-coFMA)-42k-x (x = 0, 10, 20, 25, 30) vesicles. (a−e) TEM images of PDMA-b-P(BzMA-co-FMA)-42k-x vesicles: (a) x = 0, (b) x = 10, (c) x = 20, (d) x = 25, (e) x = 30. (f) Size statistics of the PDMA-bP(BzMA-co-FMA)-42k-x vesicles vs FMA wt %. (g) DLS profiles and (h) number-averaged diameters of the PDMA-b-P(BzMA-co-FMA)42k-x vesicles. No staining agent was used. Scale bars: 500 nm.

88k-40 and PDMA-b-P(BzMA-co-SMA)-88k-60 samples, respectively (Figure 2e,f and Figure S4). It is noteworthy that both LCMs and LCVs are inverted microstructures formed by self-assembly of block copolymers with the packing parameter P > 1,76 which highlights the broad regulation capacity of polymer topology over the chain packing of the copolymers. To pinpoint the underlying mechanism of the experimentally observed regulation of polymer topology over the vesicular size, we performed systematic computer simulations for the PISA of PDMA-b-P(BzMA-co-SMA). Full technical details on the simulation method and the models of different entities used in the simulations are described in the experimental part. During the simulations, the concentration of SMA (CS, equals to SMA wt % in the experiments) was varied while the total beads in each hydrophobic block remained almost invariable to reproduce the PISA formulations in the experiments. The G

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Macromolecules Author Contributions

and morphology of polymer assemblies (Scheme 2 and Figure S8). The molecular weights of the solvophobic block of PDMAb-P(BzMA-co-FMA) were set as 42 kDa, and the FMA wt % within the solvophobic block was varied from 0 to 30. The detailed structural characterizations for the PDMA-b-P(BzMAco-FMA)-42k-x (x represents the weight percentage of FMA, x = 0, 10, 20, 25, 30) copolymers are summarized in Table 2. As with the PISA of BzMA and SMA, TEM reveals dramatic regulative capacity of the hydrophobe topology over the vesicular size, which increases to 575 ± 148 nm as the FMA wt % increases to 30 (Figure 4a−f). Likewise, the Dh of these samples increases from 227 ± 68 to 766 ± 210 nm (Figure 4g,h), thus proving the generality of the role of polymer topology in controlling the size and morphology of polymer assemblies.

M.H. and Z.X. contributed equally. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The National Natural Science Foundation of China (Grant Nos. 21422403, 51633003, 21374053, and 51573086) is acknowledged for financial support. L. Yan acknowledges financial support from Ministry of Science and Technology of China (Grant No. 2016YFA0202500). We acknowledge H. Che (Eindhoven University of Technology) and Z. Chen (Stanford University) for their helpful discussions.

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CONCLUSION We have demonstrated the significance of polymer topology to the nanostructure of assemblies. By RAFT-mediated dispersion copolymerization of BzMA and SMA at varying feed ratios, the topology of the PDMA-b-P(BzMA-co-SMA) copolymer was systematically regulated, leading to polymersomes with size ranging from 200 to 1500 nm. Furthermore, polymer assemblies with high-order nanostructures, including LCMs and LCVs, could also be achieved for PDMA-b-P(BzMA-coSMA) copolymers with proper solvophobe topologies, indicating the broad regulation capacity. The regulation capacity of polymer topology over the vesicular size was rationalized by different chain packing parameters for copolymers with different topologies, which was verified by coarse-grained molecular simulations. The above findings were further generalized by RAFT dispersion copolymerization of BzMA and FMA, which also generated polymersomes with controlled sizes. In view of the growing monomer toolkit of PISA, we anticipate that our finding would play increasingly significant role in the preparation of drug carriers, imaging agents, and nanoreactors.

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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.7b02039. 1 H NMR spectra of the polymers, conversions of BzMA and SMA vs time, molecular characteristics of PDMA-bP(BzMA-co-SMA)-63k-x and PDMA-b-P(BzMA-coSMA)-88k-x copolymers, TEM and DLS characterizations for PDMA-b-P(BzMA-co-SMA)-63k-x assemblies, SEM images of P(BzMA-co-SMA)-88k-40 and P(BzMA-co-SMA)-88k-60, molecular simulations of the PISA process (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (L.Y.). *E-mail: [email protected] (Y.W.). *E-mail: [email protected] (J.Y.). ORCID

Li-Tang Yan: 0000-0002-6090-3039 Jinying Yuan: 0000-0002-1667-9252 H

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