Article Cite This: Macromolecules XXXX, XXX, XXX−XXX
Nanoparticles from Amphiphilic Heterografted Macromolecular Brushes with Short Backbones Teresa Palacios-Hernandez, Hanying Luo, Elena Alexandra Garcia, Lazaro A. Pacheco, and Margarita Herrera-Alonso* Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States S Supporting Information *
ABSTRACT: Heterografted macromolecular brushes are highly grafted macromolecules with two different side chains attached to a backbone. When endowed with an amphiphilic character, these can serve as unique stabilizers of biphasic systems and solute carriers and yield interesting self-assembled structures. Herein, we report on the solution structure of amphiphilic double-brush copolymers with short backbonesi.e., comparable to the length of the side-chainsin a selective solvent for one of the grafted blocks. As determined by small-angle neutron scattering measurements, poly(ethylene glycol)/poly(D,Llactide) double brushes adopt a cylindrical structure with highly extended backbones in DMSO. In contrast, brushes undergo intermolecular self-assembly into spherical nanoparticles in water, with aggregation numbers that vary inversely with backbone degree of polymerization. While considerably less susceptible to intermolecular association than linear diblocks of similar hydrophobic and hydrophilic block lengths, the inability of the PEG component to maintain their unimolecular form results in well-defined spherical nanoparticles with very low aggregation numbers (3 < Nagg < 10) which could potentially lead to interesting compartmentalized nanomaterials.
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INTRODUCTION Macromolecular brushes are a special class of polymers consisting of a linear backbone densely grafted with polymeric side-chains. Backbone degree of polymerization, side-chain length, and degree of branching are all used to control the dimensions of these macromolecules which generally exhibit a cylindrical structure due to excluded volume interactions among side-chains. Precision tuning of these molecular parameters has been largely achievable through the advancement of controlled radical polymerization techniques combined with highly efficient conjugation strategies by “graf ting to”, “graf ting f rom”, and “graf ting through” methods. The versatility of these approaches has also been exploited to produce macromolecular brushes with two or more side-chain components (heterografted), whose placement along the backbone and relative to one another has led to a variety of uni- or multimolecular constructs with distinct properties from those accessible though the use of linear analogues. The most widely studied category of heterografted macromolecular brushes are those with block-like side-chains since their core−shell (double cylinder) structure can conveniently serve as single-molecule templates for the formation of hybrid structures and as nanochannels or hollow containers for small molecules.1−15 Other classes of heterografted macromolecular brushes include the statistical heterografted ones and the lesser known double-brush ones wherein two different side-chains are attached at a block junction in a double-brush architecture.16−21 The combined effects of backbone and side-chain lengths, comonomer incompatibility, and side-chain responsiveness of © XXXX American Chemical Society
double-brush copolymers have been examined to explain their self-assembled structures,19,22−24 efficiency as stabilizers of biphasic systems,25 intramolecular phase separation,25−29 ability to act as carriers of small-molecule solutes,30 and triggered shape change.30,31 Compared with linear diblock copolymers of the same comonomers, heterografted brush copolymers have been shown to be less susceptible to intermolecular association, which may explain their enhanced efficiency toward interfacial stabilization.25,32 This effect, however, was suggested to be dependent on backbone degree of polymerization or the transition from brush- to star-like surfactants.32 Herein we examine the effect of backbone length on self-assemblies from short amphiphilic double-brush copolymers by showing that intermolecular association can occur in a selective solvent to form well-defined spherical nanoparticles, and aggregation numbers vary inversely with backbone length. Similar to amphiphilic copolymerswhich are able to generate uni- or multimolecular particles thorough hydrophobic or hydrogenbonding interactions with great precision and tunability33−37 the self-assembly of short amphiphilic double-brush copolymers into spherical nanoparticles with small aggregation numbers may provide an interesting route toward nanoparticle compartmentalization. Received: February 7, 2018 Revised: March 13, 2018
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DOI: 10.1021/acs.macromol.8b00300 Macromolecules XXXX, XXX, XXX−XXX
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Figure 1. (A) Synthesis route of amphiphilic double-brush copolymers: (i) azobis(isobutyronitrile), 2-cyano-2-propyl 4-cyanobenzodithioate; (ii) sodium azide, ammonium chloride; (iii) D,L-lactide, 1,8-diazabicyclo[5.4.0]undec-7-ene; (iv) alkynylpoly(ethylene glycol), CuSO4·5H2O), ascorbic acid. (B) Gel permeation chromatograms of PGMA(50)-g-[PLA(15)/PEG(45)] at different stages of the synthesis, as indicated.
Table 1. Amphiphilic Double-Brush Copolymers PGMA(n)-g-[PLA(16)/PEG(45)] in Good and Selective Solventsa in D2O PGMA (n)
Mnb (× 105 Da)
40 50 72 114
1.79 2.23 3.27 5.10
Mwc (× 105 Da)
CCMCd (mg/L)
± ± ± ±
3.76 3.61 2.79 2.32
2.09 2.39 3.50 9.20
0.02 0.01 0.05 0.11
Re (nm) 7.1 8.7 7.5 9.7
± ± ± ±
0.9 0.8 1.3 1.0
Rhf (nm)
PDf
± ± ± ±
0.14 0.09 0.13 0.06
10.8 11.2 11.6 12.8
0.8 0.6 0.1 0.2
Mw,NPg (× 105 Da)
Naggh
± ± ± ±
9.6 8.2 4.6 3.1
19.99 19.50 16.00 29.03
4.52 0.25 0.22 2.97
a Numbers in parentheses refer to repeat units. bEstimated from 1H NMR. cMeasured by static light scattering. dMeasured by fluorescence of pyrene encapsulation. eEstimated from transmission electron micrographs. fMeasured by dynamic light scattering. gMeasured by static light. hCalculated as H2O /MDMSO the ratio of molecular weights (from SLS) of the polymers in water and in DMSO as Nagg = Mw,SLS w,SLS .
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EXPERIMENTAL SECTION
provided by NIST. Heterografted double-brush copolymers were examined in DMSO-d6 and in D2O. As shown in Figure 2,
Details regarding synthesis and characterization are provided in the Supporting Information.
RESULTS AND DISCUSSION Amphiphilic double-brush copolymers were synthesized from a bifunctional derivative of poly(glycidyl methacrylate) [PGMA] through a combination of “graf ting from” and “graf ting to” reactions, as previously reported.22,38 PGMA length was controlled according to the monomer:initiator:CTA ratio, targeting between 40 and 120 backbone repeat units. The number of backbone repeats was estimated based on monomer conversion. Hydroxyl groups of azidolyzed PGMA were used as initiating sites for the ring-opening polymerization of D,Llactide. Poly(D,L-lactide) [PLA] degree of polymerization was estimated by 1H NMR based on the ratio of chain- vs terminalmethine signals (5.2 and 4.3 ppm, respectively, Figure S1). Representative chromatograms of different stages of the polymerization are included in Figure 1 for the heterografted brush with 50 PGMA backbone units or PGMA(50). As shown for PGMA(50)-g-[PLA(15)/PEG(45)] in Figure 1, the majority of samples appear to have narrow molecular size distributions and a minimum content of unreacted PEG. Number- and weight-average molecular weights of PGMA(n)g-[PLA(16)/PEG(45)] double-brush copolymers were measured by 1H NMR and static light scattering, as shown in Table 1. Structures of double-brush copolymers in different solvents were examined by small-angle neutron scattering on the NG-7 30 m SANS instrument at the National Institute of Standards and Technology, Center for Neutron Research. An incident wavelength of 6.0 Å was used with sample−detector distances of 1, 4, and 13 m to cover a q-range from 0.003 to 0.55 Å−1. All measurements were performed at ambient temperature. Raw data were reduced and analyzed with IGOR Pro (WaveMetrics), using the SANS reduction and analysis packages
Figure 2. Small-angle neutron scattering intensity for amphiphilic double-brush copolymers with varying backbone lengths in DMSO-d6.
scattering curves of all copolymers in DMSO-d6 overlap in the intermediate and high-q regions, indicating they exhibit similar cross-sectional areas, internal density, and radial density profiles.39 The increasing slope with backbone length is suggestive of elongation. SANS data were initially fit to an empirical Guinier−Porod model to provide quantitative information regarding the scatterers’ conformation in solution. This model, which is particularly useful for nonspherical objects, yields a dimension parameter (s) and a radius of gyration (Rg) of the scatterer: three-dimensional globular objects are characterized by s = 0, whereas s = 1 is indicative of rod-like scatterers.40 A summary of the fits is provided in Table 2 (see Supporting Information for fits to experimental data). As shown in Table 2, the dimension parameter increases from 0.13 B
DOI: 10.1021/acs.macromol.8b00300 Macromolecules XXXX, XXX, XXX−XXX
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Table 2. Summary of Small-Angle Neutron Scattering Analysis for Double-Brush Copolymers of PGMA(n)-g-[PLA(16)/ PEG(45)] in Good and Selective Solvents Guinier−Porod model
cylinder polydisperse radius model
PGMA (n)
solvent
dimension variable, s
radius of gyration, Rg (nm)
length, L (nm)
radius, R (nm)
PDa
40 50 72 114 50 72
DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 D2O D2O
0.13 0.18 0.39 0.59 0.04 0.08
5.3 5.5 5.3 5.3 6.8 7.1
17.2 19 28.5 39.4
4.3 4.5 4.3 4.1
0.2 0.21 0.28 0.33
polycore−shell sphere model core radius (nm)
PDa
shell thickness (nm)
lbb nm) 0.21 0.2 0.27 0.27
4.6 4.7
0.34 0.36
2.2 2.4
a Radius polydispersity. bContribution per backbone repeat unit estimated according to L = lbNb + 2R, where L and R are provided by a cylinder polydisperse radius model fit of SANS data and Nb is the number of backbone repeat units (n in column 1).
Figure 3. (A) Results from the cylinder polydisperse radius fits as functions of the degree of polymerization of PGMA for PGMA(n)-g-[PLA(16)/ PEG(45)] brushes. (B) Schematic representation of a PGMA-g-[PLA/PEG] double-brush copolymer in solution. Brush lengths (L) and radii (R) were used to determine the contribution per repeat unit of the backbone according to L = lbNb + 2R. PEG blocks are shown in blue, PLA blocks in yellow, and the PGMA backbone in red. (C) Brush dimensions as functions of backbone degree of polymerization (n) in DMSO-d6. Structures are drawn to scale from fits to a cylinder polyradius model.
to 0.59 with backbone length, indicative of increasing brush elongation. Brush gyration radii, on the other hand, were generally invariant to backbone length. The general trend of increasing elongation with backbone length was previously reported by Verduzco et al., who examined the solution conformation of brush copolymers consisting of a poly(oxanorbornene) backbone (PNb) grafted with polystyrene (PS) side-chains [PNb(PS)] by SANS.41 The authors studied the effects of backbone and side-chain length on polymer structure in solution and reported a conformational sphere-to-cylinder transition in brush structure occurring at ∼120 backbone repeat units, noting that this critical point may vary according to side-chain grafting density, flexibility, and length. Interestingly, instead of a transition point, we observe a rather constant increase of the dimension parameter with backbone length which suggests that PEG/PLA double-brush copolymers exhibit a cylinder-like structure in DMSO even at short backbone lengths. We attribute the difference between PNb(PS) brushes and those examined herein to two structural factors. First is the double-brush architecture of PGMA(n)-g[PLA(16)/PEG(45)] copolymers, as each backbone repeat unit is presumed to have two rather than one side-chain as in the case for PNb(PS), thus enhancing excluded volume effects of the side-chains along the length of the brush, which would in turn affect backbone conformation. The second factor that may explain the observed elongation for short brushes is side-chain spacing, which is shorter in the case of a methacrylate backbone compared to a poly(oxynorbornene) one. Lastly, the invariance
of radius of gyration on backbone length is explained by the fact that it corresponds to a measure of the scatterers’ crosssectional area which is expected to remain constant for PGMA(n)-g-[PLA(16)/PEG(45)] brushes since side-chain length was not varied among samples. Although Verduzco et al. conclude that the use of a cylindrical form factor to model SANS data of short bottlebrushes would be inappropriate,41 the observed structural differences between PNb(PS) and PGMA-g-PLA/PEG brushes would suggest otherwise. Hence, following their and others’ approach, we fit our data to rigid- and flexible-cylinder form factors, which approximate an individual bottlebrush macromolecule to either a rigid cylinder with a constant radius or a flexible cylinder with a constant radius and a characteristic Kuhn step length, respectively.39,41 While the rigid cylinder model yielded better results than did the flexible one, the best fit was instead achieved when the form factor of a rigid cylinder with a polydisperse radius was used. This model provides cylinder length (L), cylinder radius (R), and a Schulz polydispersity of the radius; a summary of the results from this fit is presented in Table 2. Unlike the previous examples, it is possible that our data are better fit by a model that accounts for radius (i.e., side-chain) polydispersity since our protocol uses “graf ting f rom” followed by “graf ting to” methods, both of which may be affected by steric congestion and would therefore result in structures with a larger radial dispersity compared to the “graf ting through” polymerization used by Verduzco et al. Consistent with the Guinier−Porod analysis, cylinder radii C
DOI: 10.1021/acs.macromol.8b00300 Macromolecules XXXX, XXX, XXX−XXX
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Figure 4. (A−D) Transmission electron micrographs of PGMA(n)-g-[PLA(16)/PEG(45)] double-brush copolymers: (A) n = 40, (B) n = 50, (C) n = 72, and (D) n = 114. (E) Particle size distributions (intensity) of PGMA(n)-g-[PLA(16)/PEG(45)] double-brush copolymers in water as functions of the number of backbone repeats measured by dynamic light scattering.
hydrophobic ratio is constant for all copolymers, the small decrease observed may result from a smaller entropic loss upon micellization, as previously observed for oligomeric surfactants.45,46 Transmission electron micrographs (TEM) of the resulting particles are provided in Figure 4 along with their particle size distributions (intensity) measured by dynamic light scattering (DLS). Summaries of the results from both methods are included in Table 1, and statistical analysis of TEM micrographs is included in the Supporting Information (Figure S9). From the images it would appear that PGMA(n)-g-[PLA(16)/ PEG(45)] brushes in water exhibit a well-defined spherical morphology of relatively uniform size with limited aggregation. Statistical analysis of the micrographs revealed particle radii ranged from 7 to 10 nm with no clear trend regarding backbone length. DLS analysis of brushes in water revealed z-average particle radii ranging between 11 and 13 nmlarger than those estimated by TEMwith narrow size distributions (Figure 4 and Table 1) and a small increase in average particle size with backbone length. The difference of brush dimensions between DLS and TEM may be partially attributed to the type of average used (number for TEM vs z for DLS) but may also be caused by undersizing in TEM. Furthermore, particle dimensions appear to be insensitive to polymer concentration within the range examined as a decrease of the initial polymer concentration from 10 to 5 mg/mL produced no appreciable change in average particle size and size distribution (Figure S10). SANS curves of brushes PGMA(50)-g-[PLA(16)/PEG(45)] and PGMA(72)-g-[PLA(16)/PEG(45)] in D2O are provided in Figure S11, and a summary of their analysis is shown in Table 2. As previously observed for the polymer in DMSO, scattering curves of both copolymers in D2O overlap in the intermediate q-region; however, the most important result from the Guinier−Porod analysis (Figure S12) is that their dimension variables are considerably smaller than in the organic solvent and clearly indicative of spherical particles (s < 0.1), as also confirmed by TEM. Gyration radii in D2O, which now correspond to those of spherical particles, are larger than those in DMSO. In a recent report on the structural characterization of assemblies from amphiphilic linear and brush copolymers by SAXS, the radius of gyration of
provided by the model were relatively constant whereas cylinder length increased with backbone degree of polymerization (Figure 3). Furthermore, the values provided by the model for brush radii (4.1−4.5 nm) would indicate that PLA and PEG side-chains are stretched in the radial direction. A schematic representation of brush structure provided by the model is given in Figure 3 for the different copolymers. The length provided by the cylindrical form factor is expected to take into account both the length of the backbone and side-chain contributions at the ends of the backbone, which are particularly important in the case of short brushes.42 It is assumed that the chains closest to the ends can rotate more freely than those along the length of the brush and form spherical caps.41 If side-chain contribution is accounted for by considering that their extension at the ends of the backbone is equivalent to that along its length then,43 L = lbNb + 2R, where lb and Nb are the contribution per repeat unit of the backbone and the number of backbone repeats, respectively. lb was estimated according to this equation with the values provided by the cylinder polydisperse radius model, and the results are given in Table 2. The data indicate that the backbone is close to its fully extended conformation, which would correspond to lb = 0.25 nm. The fact that the contribution per repeat slightly exceeds the theoretical value in the case of the longest brushes may be attributed to radius polydispersity, which as shown in Table 2 is the highest for these two samples. Furthermore, sidechain extension at the ends of the brush is expected to differ from that along its length, which in turn would also affect the difference between experimental values and the theoretical prediction. Double-brush copolymers were transferred into water, a selective solvent for PEG, by a large and rapid change in solvent quality at concentrations well above their critical micelle concentration. This was achieved though the use of a fourstream vortex mixer in which micromixing occurs in the millisecond range.44 Initial polymer concentration in the organic solvent (tetrahydrofuran) was 1 wt %, and the dilution factor after mixing was 10, which increased to 12 after 24 h of dialysis to remove the organic solvent. Critical micelle concentrations were measured and provided in Table 1 (Figure S8). While the CCMC does not appear to vary strongly with backbone length, as would be expected since the hydrophilic to D
DOI: 10.1021/acs.macromol.8b00300 Macromolecules XXXX, XXX, XXX−XXX
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values of which depended only on the total hydrophobic content of the copolymer.33−37 When the latter is kept constant, aggregation number decreases with increasing backbone degree of polymerization. We also do not observe differences in aggregate molecular weights that are commensurate with the differences in molecular weights of the polymers themselves and, similarly, only a small increase in aggregate size as measured by DLS, TEM, or from SANS modeling. While the threshold degree of polymerization for single-molecule collapse cannot be directly established from the samples examined herein, it must be between 114 and 721, since we had previously shown the latter undergoes single-molecule collapse in water into cylindrical nanoparticles.30
PGMA(72)-g-[PLA(16)/PEG(45)] in water was reported to be 6.9 nm when self-assembly was triggered from polymer solutions with initial concentrations of either 0.27 or 2.0 mg/ mL. These values are consistent with Rg = 7.1 nm as obtained in this study when the initial concentration was 10 mg/mL. A core−shell model was used to fit SANS data from PGMA(50)-g-[PLA(16)/PEG(45)] and PGMA(72)-g-[PLA(16)/PEG(45)] in D2O assuming constant shell thickness and a homogeneous, yet polydisperse, core (Figure S12). In this model a PEG-enriched shell would stabilize the collapsed PLA/PGMA core. The scattering length density of the core was taken as that of PLA (1.73 × 10−6 Å−2)47 since PEG exposure studies of both copolymers revealed that the chains were highly solvated, and the PGMA backbone and grafting segments to PEG and PLA blocks represent a small fraction ( Nagg > 3), triggered by hydrophobic interactions of PLA blocks and the backbone; particle aggregation number decreases with backbone length. SAXS analysis of PGMA(72)-g-[PLA(16)/ PEG(45)] in water also confirmed the multimolecular association of this sample; the average calculated aggregation numbers in that case were similar but slightly smaller than the value measured using SLS (Nagg = 3.45 vs Nagg = 4.6). Spherical multimolecular assemblies were previously predicted by dissipative particle dynamics simulations of amphiphilic asymmetric macromolecular brushes.48 The assembly behavior of the amphiphilic double-brush copolymers shown here appears to follow that of amphiphilic random copolymers, which form highly regulated aggregates with constant molecular weights and dimensions (Rh), the
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CONCLUSIONS We investigated the solution structures of amphiphilic doublebrush copolymers of PEG/PLA in different solvents. SANS data of brushes in DMSO were best modeled by the form factor of rigid cylinders with polydisperse radii, yielding cylinder dimensions (average radius and length). This information was used to extract the conformation of the PGMA backbone in this solvent which was found to be nearly fully chain extended. In contrast, when PEG/PLA brushes were transferred into water using a rapid mixing process, they collapsed into well-defined spherical nanoparticles with little interparticle aggregation, as confirmed by SANS, DLS, and TEM. Driven by hydrophobic interactions and insufficient steric stabilization to remain as unimolecular micelles, heterografted brushes self-assembled into multimolecular constructs with aggregation numbers that decreased with backbone degree of polymerization but were still orders of magnitude smaller than linear diblock micelles of the same comonomer block segments. The controllable and small aggregation numbers of these nanoparticles could, in analogy to amphiphilic random copolymer nanoparticles, lead to interesting compartmentalization phenomena.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b00300. Experimental section including protocols for polymer synthesis and characterization as well SANS, DLS, and TEM data of nanoparticles (PDF)
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AUTHOR INFORMATION
Corresponding Author
*(M.H.-A.) E-mail:
[email protected]. ORCID
Lazaro A. Pacheco: 0000-0002-6977-0308 Margarita Herrera-Alonso: 0000-0002-6064-8699 Present Address
T.P.-H.: Division of Biology, Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD 20993. Notes
The authors declare no competing financial interest. E
DOI: 10.1021/acs.macromol.8b00300 Macromolecules XXXX, XXX, XXX−XXX
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ACKNOWLEDGMENTS Financial support was provided through NSF CMMI 1562639. We also thank Boualem Hammouda and Yimin Mao from the Center for Neutron Research at the National Institute of Standards and Technology (NIST) for their help and valuable comments.
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DOI: 10.1021/acs.macromol.8b00300 Macromolecules XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.macromol.8b00300 Macromolecules XXXX, XXX, XXX−XXX
