Molecular Bottlebrushes as Novel Materials - Biomacromolecules

Review Cite This: Biomacromolecules 2019, 20, 27−54

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Molecular Bottlebrushes as Novel Materials Guojun Xie,† Michael R. Martinez,† Mateusz Olszewski,† Sergei S. Sheiko,§ and Krzysztof Matyjaszewski*,† †

Biomacromolecules 2019.20:27-54. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/14/19. For personal use only.

Department of Chemistry, Center for Macromolecular Engineering, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, United States § Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States ABSTRACT: Molecular bottlebrushes are building blocks for the design of unique polymeric materials whose physical properties are fundamentally governed by their densely grafted structures. Recent developments in the area of reversible deactivation radical polymerization enabled facile and effective control over multiple molecular parameters. Owing to large molecular size, anisotropic conformation, and reduced chain entanglement, molecular bottlebrushes have empowered various applications that are challenging to achieve with linear polymers. In this Review, we focus on determining correlations between brushlike architectures and materials properties.

1. INTRODUCTION A molecular bottlebrush consists of a long polymeric backbone densely grafted with shorter side chains. This molecular architecture endows polymeric materials with three features which govern their unique properties: (1) high concentration of polymeric side chains, (2) stretched polymer backbone due to the steric repulsion between side chains, and (3) decreased spatial density of chain entanglement. The distinct molecular features of bottlebrush polymers have paved the way toward novel applications that were not possible with linear chain polymers. This became feasible due to the development of advanced synthetic techniques enabling precise control of different architectural parameters including side chain length and grafting density. Several reviews have presented the general synthesis and properties of molecular bottlebrushes.1−6 This Review will focus on discussing correlations between brushlike architectures and material properties.

distance between neighboring side chains may vary with each method of polymerization. For example, the number of carbon atoms between neighboring side chains is four for a molecular brush with a polynorbornene backbone (afforded by ROMP), whereas a brush with a polymethacrylate backbone has only one carbon atom between neighboring side chains. Steric hindrance among side chains and kinetic and/or thermodynamic barriers, originating from the inherently low concentration of polymerizable groups, makes synthesis of molecular brushes with a high degree of polymerization (DP) and low dispersity challenging using the grafting-through method, especially for vinyl macromonomers.10 Polymer brushes synthesized via the grafting-through method using vinyl addition may exhibit an observable equilibrium monomer concentration, where the rate of propagation is equal to the rate of depolymerization. It was recently shown that poly(oligo(ethylene glycol) methacrylate) (POEGMA) and poly(oligo(dimethylsiloxane) methacrylate) (PODMSMA) brushes synthesized via RAFT depolymerized in the absence of initiator until the macromonomer’s equilibrium monomer concentration was achieved.11 Synthesis at high pressure has improved grafting-through by decreasing equilibrium monomer concentration.10 In the grafting-to method, backbones and side chains are prepared separately. This strategy utilizes the reaction between functionalized preformed side chains and complementary functional groups along the preformed backbones.12 However,

2. SYNTHESIS OF MOLECULAR BOTTLEBRUSHES Synthetic strategies for molecular bottlebrushes can be divided into three categories (Figure 1): “grafting-through” (polymerization of macromonomers), “grafting-to” (attachment of side chains to a backbone), and “grafting-from” (polymerization of monomers from a backbone). The grafting-through method is the polymerization of macromonomers. Molecular bottlebrushes prepared via this method are also referred to as polymacromonomers. Anionic polymerization,7 ring-opening metathesis polymerization (ROMP),8 and conventional free radical polymerization (FRP)9 are used to prepare molecular bottlebrushes via the grafting-through method. Although this method guarantees that every repeat unit contains a polymeric side chain, the © 2018 American Chemical Society

Special Issue: Biomacromolecules BPC Received: August 1, 2018 Revised: September 24, 2018 Published: October 8, 2018 27

DOI: 10.1021/acs.biomac.8b01171 Biomacromolecules 2019, 20, 27−54

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Figure 1. Three main strategies for preparing molecular bottlebrushes: “grafting-through”, “grafting-to”, and “grafting-from”.

and even a small amount of coupling will result in a very high molecular weight side product in addition to the desired brush. As a result, synthesis of polymer brushes using the graftingfrom method has often been very slow to reduce the concentration of radicals and diminish bimolecular combination. Grafting-from polymerizations are often diluted with monomer or solvent and conducted with low activity catalysts to suppress small fractions of unwanted termination and transfer pathways. Radical termination of acrylates in ATRP occurred predominately through bimolecular combination with a small portion of chains undergoing either backbiting to form midchain radicals or disproportionation; some chains are terminated through catalytic radical termination (CRT) to leave behind dead, disproportionation-like products.26 The relative fraction of chains terminated through RT and CRT can be tuned by [CuI]. This method was then applied to graftingfrom ATRP to produce molecular brushes with >80% conversion overnight with no macroscopic gelation. The reactions were relatively fast but favored termination through CRT rather than RT, allowing the polymerization to run to high conversion with minimal coupling of brushes.27 Suppression of cross-linking should aid in the synthesis of polymer brushes. High-pressure ATRP has shown promise in the synthesis of nanoparticle hybrid brushes due to its ability to suppress RT28 and could be a potentially efficient method to form molecular brushes by grafting-from. When reversible addition−fragmentation chain transfer (RAFT) polymerization is chosen to prepare bottlebrushes via grafting-from, the chain transfer agent (CTA) can be incorporated to the backbone by anchoring either the reinitiating group (the R-group) or the stabilizing group (the Z-group) to the polymer backbone.29,30 The former case is similar to the grafting-from method with side chains grown from the backbone. When the Z-group is anchored to the backbone, the synthetic method is referred to as “transfer-to”. Although the distinct chain propagation mechanism of the transfer-to method helps prevent detrimental combination side reactions in the grafting-from method, the significant amount of linear impurities limits implementation of this method.

both (1) slow diffusion of preformed polymeric side chains and (2) steric interactions among already attached side chains could prevent quantitative grafting even when highly efficient “click” chemistry is employed. This could lead to two problems: (1) limited grafting density and (2) the need to remove unreacted side chain precursors. However, the coppercatalyzed azide−alkyne cycloaddition (CuAAC) was recently significantly accelerated by proximal catalysis of Cu(I)/triazole to its neighboring azido group.13 This allowed for the synthesis of molecular brushes using the “grafting-onto” method with grafting densities with statistically more than one side chain per backbone repeating monomer unit. In the grafting-from method, polymer side chains are grown from a polymer backbone (macroinitiator) with a predetermined number of initiation sites. If side chains are evenly grown from the backbone, both high grafting density and long backbones could be achieved using this method. Reversible deactivation radical polymerization (RDRP) techniques including atom transfer radical (ATRP),14,15 reversible addition−fragmentation chain transfer (RAFT),16,17 and nitroxide-mediated polymerization (NMP)18 have significantly facilitated the synthesis of molecular bottlebrushes via the grafting-from method. These methods have become the predominant methods to synthesize brushes using the grafting-from method due to their (1) excellent functional group tolerance and (2) effective control of side chain growth. Despite the success and benefits of grafting-from RDRP, there are inherent disadvantages related to the method’s inability to fully suppress radical termination. In most RDRP systems, the majority of polymer chains will be deactivated through activation/deactivation equilibria with a small fraction terminated through radical termination (RT). The relative route of termination is dependent upon the nature of the radicals. Methacrylates undergo RT through both combination and disproportionation, whereas styrenes and acrylonitrile were suggested to primarily terminate through combination.19,20 The termination pathway for acrylates is more complex and has yet to be resolved, but it is currently believed that acrylates terminate combination of bimolecular combination, disproportionation, and inter/intramolecular transfer.21−25 The small fraction of chains terminated through RT in grafting-from RDRP could have a great impact on the final architecture of a large, multifunctional polymer brush. Too much bimolecular coupling results in macroscopic gelation,

3. NOVEL PROPERTIES INDUCED BY STRUCTURAL FEATURES OF MOLECULAR BOTTLEBRUSHES 3.1. Structural Possibilities. Recent developments in polymer synthesis have provided abundant possibilities for controlling the architecture of molecular brushes. Here, on the 28


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basis of the existence of intramolecular inhomogeneity (among side chains as well as backbones) and the topology of the entire molecule, molecular bottlebrushes reported in literature could be divided into the following categories (Scheme 1): linear homopolymer brushes (ignoring the difference between backbone and side chain repeat unit due to a small mass fraction of the backbone), branched brushes, cyclic brushes, brushes with block copolymer backbones (brush-coil block copolymers), gradient brushes, brushes with random copolymer side chains, brushes with block copolymer side chains, and mikto-grafted brushes with more than one type of homopolymer side chain. Steric interactions between side chains induce two unique physical features for molecular bottlebrushes: (1) extended backbone and (2) nonoverlapping side chains. The former feature determines the cylindrical shape of the entire macromolecule, and the latter governs the unique viscoelastic properties and alignment of bottlebrushes. Additionally, the densely grafted structure enables the design of preassembled micelles in contrast to self-assembled linear block copolymers. 3.1.1. Molecular Conformations. Although densely grafted side chains repel each other within a molecular brush, their detachment is precluded by covalent bonding to the backbone, which confines side chains to a cylindrical volume. The interplay between backbone and side chains allows cylindrical brushes to exhibit an array of conformations on different length scales.31 The backbone is flexible on the scale of the distance between neighboring side chains; however, the molecules behave like semiflexible cylinders on length scales longer than the side-chain lengths. This contrasts with flexible comb-like polymers that exhibit Gaussian chain behavior for both backbone and side chains.32 The conformation of the entire cylindrical bottlebrush molecule is closely related to its structural parameters. If the length of side chain is significantly shorter than that of the backbone, the intramolecular excluded volume effect causes stretching of the backbone, forcing the entire bottlebrush to adopt an extended and cylindrical conformation. Molecular brushes adopt wormlike conformation (Figure 2) characterized by contour length L (or length per monomer (lm)), brush diameter (D), and Kuhn length λk (or persistence length (lp)). Alternatively, when molecular brushes have side chains similar or longer than a backbone,

Figure 2. Sketch of a molecular bottlebrush. Reprinted from ref 36; Copyright 2005, with the permission of AIP Publishing.

molecular brushes adapt starlike conformations with side chains extending radially.33−35 The conformation of molecular brushes on surfaces can be directly captured by visualization techniques such as atomic force microscopy (AFM) due to the nanoscale sizes that provide intermolecular resolution.37 Furthermore, using a combination of the Langmuir−Blodgett (LB) technique and AFM, molecular weight distribution of molecular bottlebrushes can be measured. This is because the LB technique provides mass density information (mass/area) and visualization of monolayers by AFM enables accurate measurements of the number of molecules per unit area (number/area).38 By assuming molecular weight is proportional to contour length, AFM images can also give the length distribution of the visualized molecules.38 The conformation of adsorbed brush molecules on surfaces is governed by the number of side chains adsorbed.1 If the fraction of adsorbed side chains (φa in Figure 3) is close to unity, a ribbonlike conformation is energetically favored as it allows for a large number of surface contacts (Figure 4a). When side chains are not strongly adsorbed to a surface (φa), brush molecules may switch to other conformations depending on their interactions with the surrounding environment. In a poor solvent (e.g., air), desorbed side chains attract each other and cause coiling of the backbone into a globular conformation 29


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Figure 3. Conformation of adsorbed molecular bottlebrush is confined by its interconnectivity and cylindrical symmetry of the branches. Reprinted from ref 1; Copyright 2008, with permission from Elsevier.

Figure 5. Schematic of the spreading of a brushlike macromolecule on an attractive substrate.39 Reprinted with permission from Springer Nature, Copyright 2006. https://www.nature.com/.

(Figure 4b); in a good solvent, a cylindrical conformation is stabilized by steric repulsion of desorbed side chains (Figure 4c).1 Two structural parameters of molecular bottlebrushes fundamentally affect stretching of polymer backbones through steric interactions between side chains governed by side chain length and grafting density. When deposited onto an attractive substrate, side chains of a molecular brush spread to increase the number of monomeric contacts with the substrate. This results in a tensile force along the backbone that increases with side chain length (width of the molecules, Figure 5(d)) and grafting density. In atomic force microscopy (AFM) micrographs of monolayers of PnBA brushes with short (DP = 12) (Figure 6a) and long side chains (DP = 130) (Figure 6b), curvature distribution and bond-correlation analysis indicated persistence length strongly depended on the length of side chains as lp ∝ DPSC.2,7,39 Besides changing the length of side chains, introducing spacer units in the backbone between neighboring side chains provides another approach to control steric congestion between side chains. The synthesis of molecular brushes with gradient grafting density by continuous addition of a noninitiating monomer, methyl methacrylate (MMA), during the preparation of (the precursor of) the backbone macroinitiator by polymerizing 2-(trimethylsilyloxy)ethyl methacrylate (HEMA-TMS) was reported.40,41 Because the reactivity ratios of both methacrylate comonomers were close to unity, a gradient of spacer length (DP of continuous MMA repeat units) was created in the backbone by continuous feeding of one monomer (Scheme 2).

Gradient backbones were prepared through copolymerization of monomers with substantially different reactivity ratios, i.e., acrylates vs methacrylates, in RDRP (Scheme 3).42−44 The synthesis of gradient and block brushes with tunable graft densities is not inherent to RDRP.45 Ring-opening metathesis (co)polymerization of norbornene-functionalized macromonomers with discrete endo- or exonorbornenyl diester diluents yielded copolymers with tunable gradients by varying the reactivity ratios between both macromonomers and diluents.46 When gradient brushes were adsorbed onto a surface and then compressed, the rod-globule transition started at the end of higher grafting density due to side chain desorption, leading to a molecule with a globular “head” and an extended “tail” (Scheme 4).47 3.1.2. Molecular Organization at Interfaces. Adsorption of brush macromolecules to an interface results in enhanced steric repulsion between adsorbed side chains, which causes significant tension in the brush backbone on the order of 1 nN.48 Depending on the side chain length, the magnitude of force could be sufficient to spontaneously cleave carbon− carbon bonds in the backbone of PnBa bottlebrushes on an attractive mica substrate.39 The fracture process was monitored by AFM (Figure 7), which allowed quantitative characterization of the corresponding rate constant as a function of temperature and side chain length.49 Accurate control over bond tension through variation of the grafting density and side chain length led to the creation of molecular tensile machines that enable mechanical activation of specific chemical

Figure 4. AFM height micrographs along with schematics demonstrate conformations observed for molecular brushes adsorbed on surfaces. Depending on the interaction with substrate and with the surrounding medium, the following conformations were observed: (a) ribbons (φa ≈ 1), (b) globular (φa < 1, attraction between desorbed side chains), and (c) cylindrical (φa < 1, repulsion between desorbed side chains). Reprinted from ref 1; Copyright 2008, with permission from Elsevier. 30


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Figure 6. Conformational response of PnBA brushlike macromolecules to adsorption on mica: (a) fairly flexible conformation for brushes with short side chain (DP = 12) and (b) rodlike conformation for brushes with long side chain (DP = 130). (c) Persistence length lp increases with the side chain length.39 Reprinted with permission from Springer Nature, Copyright 2006. https://www.nature.com/.

Scheme 2. Subsequent Synthesis of the Macroinitiator Precursor (I), Macroinitiator (II), and Macromolecular Brush Copolymer (III)

Adapted with permission from ref 40; Copyright 2002, American Chemical Society.

Scheme 3. Synthetic Scheme for the Gradient Copolymer, Macroinitiator, and Molecular Brush: (a) MMA/HEA-TMS and (b) HEMA-TMS/nBA Systems

Scheme 4. Surface Compression-Induced Transition from a Rodlike Conformation to a Tadpole Conformation Due to Partial Desorption of Side Chains of Cylindrical Brushes Possessing a Gradient Grafting Density along the Backbone

Adapted with permission from ref 47; Copyright 2004, American Chemical Society.

bonds.50,51 For example, brush-controlled bond tension was used to study mechanical acceleration of disulfide reduction52 and mechanochromism of bottlebrushes with polythiophene backbones.53 Intrinsic tension in molecular assemblies was observed between sister centromeres of pericentric chromatin during mitosis.54 The forces produced at centromeres were studied by monitoring the movement of a fluorescently labeled segment of pericentric chromatin in metaphase yeast. It has been demonstrated that, by organizing pericentric chromatin into a brushlike configuration (Figure 8), condensin and cohesin

Adapted with permission from ref 42; Copyright 2005, American Chemical Society. 31


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arrangement are based on experimental evidence attributed to spatial segregation of condensin, cohesin, and LacO DNA arrays. The loops repel each other, resulting in a net outward/ poleward force. This new mechanism is viewed as a sort of primordial segregation machine that underlies the biological mechanism for sister centromere separation and the springlike properties of the centromere in mitosis. The structure of pericentric chromatin may also allow it to act as a shock absorber that buffers the variable forces generated by dynamic spindle microtubules.55 This adsorption-induced behavior has allowed molecular brushes to be used as pressure sensors. When brushes undergo lateral compression on a substrate, the backbones of molecular brushes coil due to desorption of side chains.56,57 This causes each macromolecule to occupy less area on the surface of the substrate. Therefore, the variations of film pressure within flowing monolayers can be measured using the area per molecule.58 The alignment of brushlike macromolecules on the surface of highly oriented pyrolytic graphite (HOPG) was found to be independent of the direction of flow (Figure 9a−c).59 The high

Figure 7. Adsorption-induced degradation of macromolecules. (a) The molecular degradation of brushlike macromolecules with long side chains (DP = 140) on mica was monitored using AFM height imaging after each sample was exposed for different time periods (as indicated in the images) to a water/propanol (99.8/0.2wt/wt %) substrate. (b) Schematics of an adsorbed macromolecule (left) that undergoes spontaneous scission of the covalent backbone (right).39 Reprinted with permission from Springer Nature, Copyright 2006. https://www.nature.com/.

Figure 8. Bottlebrush-inspired mechanism as a basis for the extensional forces observed in packed centromere DNA loops. (A) Side and (B) end-on views of a model of pericentric chromatin in budding yeast. (C) Schematic of sister chromatid loop fluctuations (in green) over time. Spindle-pole bodies (SPBs) are red ovals, and kinetochore microtubules (kMTs) are lines. Chromatin proximal to the spindle axis is indicated as the red line; loops extending off axis are indicated in blue. The green loops depict the labeled chromatin in C. Microtubule shortening releases condensin bound at the base of a loop as the DNA transitions from a radial to an axial position (panels should be read left to right). The release of a loop results in a drop in tension due to an increase in length of DNA length along the axis. As the microtubule shortens, DNA (red) elongates along the spindle axis until it reaches equilibrium, and greater force is required to further stretch the fiber. This leads to tension-dependent microtubule rescue, allowing the DNA to recoil and adopt a random coil. DNA fluctuation off the spindle axis allows condensin binding and loop formation (panels should be read right to left). Figure created courtesy of Dr. Kerry Bloom, UNC Chapel Hill. Inspired by ref 55.

Figure 9. (a−c) Higher magnification height images were measured in different areas of the precursor film on graphite. The images reveal a lack of correlation between the flow direction and orientation of the flowing molecules. (d) Epitaxial adsorption of side chains leads to uniaxial alignment of polymer backbones along a particular crystallographic axis within the (0001) plane. Reproduced with permission from ref 59; Copyright 2006, American Chemical Society.

degree of order was attributed to epitaxial adsorption of alkyl side chains on graphite along one of the three crystallographic axes of the (0001) surface (Figure 9d). Compression of immiscible brush copolymers at the air− water interface resulted in an entropically driven mixing process that alleviated side chain stretching.60 In contrast to clear phase-separation observed in a blend of immiscible linear hydrophobic and hydrophilic polymers, perfect intercalation was observed during the mixing of two immiscible brushes. Stretching of side chains induced by surface compression

generate sufficient tension to separate sister centromeres even without the input of spindle microtubules.54 DNA loops could be formed via condensin (purple) binding to the base of loops (Figure 8). The number of loops and their geometric 32


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Figure 10. AFM height imaging of a uniform mixture of brushlike PBA and PDMA (a) and the phase separation of a mixture of linear PBA and PDMA deposited on a mica substrate (b). Mixing mechanism: whereas the hydrophilic PBA brushes play the role of mixture stabilizers, the hydrophobic species play the role of spacers (diluents) reducing the steric repulsion between the brushes (c).60 Reprinted with permission from Springer Nature, Copyright 2013. http://www.nature.com/nmat/.

resulted in a conformational entropic penalty. Thus, brushes at in interface could become intermixed, allowing for the alleviation of side chain stretching (Figure 10). 3.1.3. Mimicking Biological Mechanics. Another fundamental effect of steric repulsion between side chains in molecular bottlebrushes is reduced chain entanglement and overlap of brush macromolecules.61 Bottlebrushes display Rouse-like relaxation dynamics with no rubbery plateau in polymer melts.60,62−64 Because chain entanglement has usually defined the lower limit of moduli in most synthetic polymer materials, reduced chain entanglement in molecular brushes was crucial in the preparation of soft polymer materials. Architectural disentanglement of polymer chains enabled the synthesis of solvent-free poly(n-butyl acrylate) (PnBA) and poly(dimethylsiloxane) (PDMS) elastomers with an unprecedented combination of low modulus (∼100 Pa) and high strain at break (∼1,000%) based on molecular brushes, as recently reported.65 These properties result from side chains (i) diluting molecular entanglements and (ii) simultaneously increasing stiffness of the brush backbone. Further, independent control of three structural parameters−length of side chains (nsc), length of spacer length between side chains (ng), and length of strand between cross-links (nx)−enabled decoupling of moduli and extensibility, which used to be mutually bonded directly to the same structural parameter nx. Optimization of the triplet values [nsc, ng, nx] enables the mimicking of biological gels and tissues with high fidelity of stress−strain (Figure 11).66 The effects of grafting density on the entanglement modulus of a series of poly(norbornene-g-poly(lactic acid)) brushes with 5-norbornene-2,3-dicarboxylic acid methyl ester (DME) diluents was shown to deviate from this model.67 Samples with high grafting densities had an entanglement modulus that scaled with inverse grafting density as Ge ∼ ng1.2 and Ge ∼ ng0 following scaling predictions at high densities.65 However, at low grafting densities, the samples showed a transition from the comb to the brush regime, entirely skipping the loose brush and dense comb subregimes. This transition behavior is likely due to a broad crossover from the comb to brush regime, which makes the intermediate subregimes indistinct. Much

Figure 11. (a) Independent control of E and λmax (arrows i−iv) enabled by the combinatorial control of the architectural triplet [nsc, ng, nx]. (b) “The golden rule” in many (predominantly synthetic) materials: an inverse relationship between elongation-at-break and Young’s modulus. (c) Stress−strain data (squares) for alginate gel, jellyfish tissue, and poly(acrylamide-co-urethane) gel and curves for PDMS bottlebrush and combs synthesized via fitting analysis (dashed red lines) with the indicated architectural [nsc, ng, nx] triplets (blue lines).66 Reprinted by permission from Springer Nature, Copyright 2017. https://www.nature.com/.

longer side chains are required for observing distinct scaling behavior. An additional complexity with interpretation of the poly(norbornene)-graft-poly(lactide) (PNB-g-PLA) systems is caused by both chemical and physical dissimilarity of the 33


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Figure 12. (A) Synthesis of molecular brush carrier via the graft-through method. (B) Attachment of drug molecules to the brush carrier via “click” chemistry. The anticancer agent could be released in response to 365 nm UV light. Reproduced with permission from ref 69; Copyright 2011, American Chemical Society.

Figure 13. (a) Synthesis of PEOMA-based molecular brushes with varied aspect ratio and rigidity. Plasma concentration−time profiles of molecular brushes of different aspect ratios (b) and rigidities after intravenous administration at 5 mg/kg to rats. Reproduced with permission from ref 74; Copyright 2015, American Chemical Society.

backbone and side chains. This results in the corresponding differences in chain dimensions (Kuhn length, monomer

length, excluded volume) and may cause microphase separation. 34


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Figure 14. A bright nanotag based on antibody tethered to the molecular brushes. A molecular brush with a single specific sequence B can be hybridized to Cy5-Acomp and antibody bearing fully complementary B′comp strand and loaded with YOYO-1. Reproduced with permission from ref 75; Copyright 2015, American Chemical Society.

3.1.4. Physical Properties in Solution. The nanoscale size of molecular bottlebrushes in solution has allowed them to act as unimolecular micelles that could be used as carriers for small molecules.68 The flexible synthetic methods used to fabricate molecular bottlebrushes has enabled facile tuning of size, shape, functionality, and composition. UV-triggered release of anticancer drug molecules using molecular brushes synthesized via ROMP has shown promise in this area.69,70 The UV-labile “cargo” could be attached to the brush “carrier” between complementary azide and alkyne moieties via click chemistry (Figure 12). pH-trigged release of paclitaxel (PTXL) from a molecular brush carrier was achieved using acid-degradable macromonomers functionalized with PTXL pendant groups.71 A similar approach to drug delivery was utilized in the synthesis of drug-carrying brush-arm star polymers (BASPs). Multifunctional polymer nanoparticles with starlike conformations were prepared with the ability to simultaneously degrade and release an anticancer drug, doxorubicin, in response to light.72 The stimuli-responsive BASPs were prepared by “brush-first” ring-opening metathesis polymerization and functionalized by azide−alkyne copper-catalyzed “click” chemistry. This technique allowed for the fabrication of multifunctional polymer brushes that were able to carry and release precise molar ratios of doxorubicin, calprotectin, and cisplatin at once.73 BASPs can be designed to carry and release precise ratios of multiple drugs simultaneously, limited only by the ability to modify the molecules with ROMP-compatible functional groups. The pharmacokinetics of poly(ethylene glycol) methacrylate (PEGMA) molecular brushes nanocarriers were dependent on the size and rigidity of the carriers.74 The aspect ratios of the molecular brushes were varied by changing the length of backbone, and a polycaprolactone (PCL) core was introduced to provide rigidity and hydrophobic domains within the core of the bottlebrush (Figure 13). Despite the high molecular mass (from tens of millions to hundreds of millions of g/mol), long circulatory half-lives (up to 30 h) were observed for these brush carriers in which the clearance rates increased with size and rigidity. The high chain end functionality of brushes prepared by grafting-from ATRP has allowed for postpolymerization modification of end groups. Fluorescent nanotags were prepared by grafting DNA onto azide-functionalized hydrophilic brushes using “click” chemistry (Figure 14). 75 Thousands of noncovalently intercalated fluorescent dyes were accommodated by the hundreds of duplex DNA strands attached to one molecular brush. The DNA strands grafted onto brushes also enable incorporation of antibodies for specific targeting. Self-assembly of brush−DNA conjugates could be accomplished using either palindromic DNA or two different DNA sequences that were regiospecifically attached to both ends of a

polymer.76 The rigid bottlebrush segment prevented cyclization after DNA sequences were incorporated onto Nhydroxysuccinimidyl ester reactive groups. The conjugates formed supramolecular wormlike structures similar to a stepgrowth polymerization. Highly branched structures with long side chains could effectively shield nucleic acid sequences from the immune system response. Brush−DNA conjugates were prepared for improvement of effectiveness of nucleotides in therapeutic applications.77 Starlike brushes were prepared using ringopening polymerization with a modified second generation Grubbs’ catalyst. DNA strands containing 5′ amine groups were conjugated with the brushes along with incorporation of a fluorescein tag at the 3′ end for tracking and quantification purposes. The structure containing densely grafted side chains shielded the DNA conjugate from proteins, simultaneously allowing DNA hybridization to proceed. Use of a different mode of nucleic acid protection based on steric compaction as opposed to polyplexation allowed for implementation of uncharged polymers. A similar report highlighted the use of PEG−DNA conjugates to shield DNA from the immune response of its host. PEG−DNA conjugates were prepared using ring-opening polymerization with PEG side chains with degrees of polymerization of 113−226.78 High steric congestion of the structures resulted in higher cellular uptake, decreased immune system response, and a minor decrease in DNA−DNA conjugation between bottlebrush and host DNA. The brush−peptide conjugates, prepared by norbornene functionalized with cell-penetrating peptides, were resistant to proteolysis and could enter cells with good efficiency. In addition, the proteolytic resistance of the peptide brush polymer was tunable by adjusting the grafting density of the brush.79 A similar technique added additional Lys or Arg units onto a peptide sequence to improve cell penetration.80 This strategy allows for preservation of the particle’s sequencespecific cytotoxic function. 3.2. Brushes with Segmented Backbones. Molecular brushes composed of immiscible blocks could have two possible structures: (1) brush−coil copolymers (block copolymers composed of a brush block connected to linear block(s) along a backbone) and (2) brush−brush block copolymers (BBCPs). 3.2.1. Brush−Coil Copolymers. The addition of linear polymer chains to a molecular brush allows for functionality to be introduced in two aspects: (1) intermolecular associations and (2) enhanced interactions with the environment. 3.2.1.1. Intermolecular Associations. The compositionally inhomogeneous interface within a brush−coil copolymer provides amphiphilicity, allowing the molecular brush to behave as a macrosurfactant. Giant spherical micelles were formed in THF using brush-b-coil amphiphiles composed of 35


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Scheme 5. Molecular Structure of Amphiphilic ABA Triblock Molecular Bottlebrush and Schematic Presentation of the 2D Packing

Reproduced with permission from ref 82; Copyright 2013, American Chemical Society.

Figure 15. TEM (A) and HRTEM (B, C) images of self-assembled ABA molecular bottlebrushes at 8 h. Image (C) was titled image for 30° of (B). Sample was stained by RuO4 vapor. Inset in (A) was Fourier transferred from pattern of disk. Digits in (A) are the aggregation numbers of ABA molecules. Reproduced with permission from ref 82; Copyright 2013, American Chemical Society.

between neighboring bottlebrushes and resulted in crystallization of their linear tails. Conversely, steric repulsion between brushes with longer side chains prevented network formation by hindering intermolecular association of the semicrystalline blocks. The absence of chain entanglements in the bottlebrush B blocks, combined with crystallization of segments in the A-blocks, has enabled the thermoplastic elastomer to be remoldable while still being several orders of magnitude softer than typical thermoplastic elastomers. Microphase separation linear−brush−linear ABA triblock copolymers results in self-assembly of thermoplastic elastomers with “Chameleon-like” properties.86 The ABA triblocks consisted of a central oligo(dimethylsiloxane) methacrylate (ODMSMA) brush chain extended with either high molecular weight poly(methyl methacrylate), poly(benzyl methacrylate), or poly(oligo(ethylene oxide)methacrylate). It is remarkable for synthetic materials that amorphous polymers (PDMS side chains and PMMA linear blocks) produce highly organized structures at different length from nano- to micrometers (Figure 16D), which are routinely observed in biological systems. Furthermore, the mechanical properties of these thermoplastic elastomers fully and precisely mimic the mechanical response of biological tissues, including superlow Young’s modulus in the range of 102 to 105 Pa and intense strain-stiffening behavior. Elongation of the materials was shown to result in a blue shift in sample color because of the decrease of interdomain distance (d3). Similarly, swelling in

cylindrical polystyrene (PS) brush connected to linear poly(methacrylic acid) (PMAA) blocks. The highly soluble PS brush domains formed the corona, and the linear PMAA chains (neutralized with CsOH) formed the core when suspended in tetrahydrofuran.81 Using triblock coil−brush− coil copolymers, disk-like micelles with a highly ordered pattern were formed (Scheme 5).82 In a solvent selective for a segment (poly(N-(2-methacryloyloxyethyl) pyrrolidone) (PNMEP), the ABA molecular bottlebrushes with stiffened middle blocks self-assembled two-dimensionally into disks with a uniform thickness of ∼33 nm and a diameter of hundreds of nanometers. A hexagonal pattern of molecular bottlebrushes aligned perpendicularly to the disk plane with a periodic spacing of 9 nm was visualized by TEM through selectively staining the PS shells of brushes (Figure 15). Similar to linear block copolymers, coil−brush−coil triblock copolymers composed of immiscible blocks were also capable of forming complex structures via microphase separation. A physically cross-linked thermoplastic elastomer with an unusually low equilibrium shear modulus Ge on the order of 1 kPa was prepared.83−85 The semicrystalline poly(octadecyl (meth)acrylate) (POD(M)A) coil segments phase separated and formed a crystallinity enhanced cross-linked network, and the brush middle blocks lowered the moduli by swelling the network with covalently attached low-Tg PnBA side chains. The cross-link density was tunable by the DP of side chains, where shorter side chains allowed for stronger association 36


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Figure 16. Structural coloration of thermoplastic elastomers reported by Sheiko et al.86 (A) Self-assembly of linear−bottlebrush−linear ABA triblock copolymers yielding physical networks consisting of A linear block domains embedded in a B matrix of bottlebrush strands, where nA, nbb, and nsc are degrees of polymerization (DPs) of the linear block, the bottlebrush backbone, and the bottlebrush side chains, respectively. Macrophase separation is described in terms of the interbrush distance (d1), diameter of the spherically shaped PMMA domains (d2), and interdomain distance (d3). (B) Structural coloration in a broad spectral range is typically observed during solvent evaporation and is indicative of decreasing distance between A domains. (C) AFM height micrographs corroborate microphase separation of PMMA-b-PODMSMA-b-PMMA bottlebrushes with identical nbb values of 938, varied linear PMMA DPs, and a designated PMMA volume fraction. (D) USAXS patterns of the plastomers represented above display characteristic length scales as depicted in (A). (E) Concentrated solutions (25 wt %) of the corresponding plastomers. Evaporation of turquoise solution 4 (M900−4) yields a blue film. Reprinted from ref 86; Copyright 2018, with permission from AAAS.

triblock coil−brush−coil copolymers with alkene functionality in the two coils (Figure 18a).89 The porous materials prepared from bottlebrushes with varying backbone lengths and relatively similar side chain lengths had scalable onset pore diameters correlating to the logarithmic backbone length (Figure 18b). 3.2.1.2. Interactions with the Environment. The linear block of brush−coil block copolymers has also enabled molecular brushes to have additional interactions with the environment. A lubrication system with friction coefficients as low as ∼10−3 could be fabricated using triblock coil−brush− coil copolymers containing biocompatible poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) side chains and quaternized 2-(dimethylaminoethyl) methacrylate (qDMAEMA) and methyl methacrylate, MMA) copolymers as coil segments (Figure 19).15 The brushes adopted a looped conformation on the mica surface because both of the cationic coil segments in one triblock copolymer strongly adsorbed onto the negatively charged mica surface. This gave rise to weak and long-range repulsive forces between the surfaces. A

solvent resulted in a red shift due to an increase of interdomain distance and was confirmed by USAXS (Figure 16). The synthesis of a brush−coil block copolymer consisting of a soft PnBA and a linear protected ureido-pyrimidinone (UPy)-functionalized block was reported.87 Characterization via AFM showed minimal aggregation between A blocks when UPy units were protected; however, exposure to UV light deprotected the UPy units and caused a significant decrease in molecular size due to extensive intramolecular hydrogen bonding between functional units (Figure 17). Monitoring the deprotection via DLS showed a shift in the radius of gyration from 26 ± 7 to 20 ± 6 nm. The size of molecular brushes falls into a range of 50−500 nm, which has shown promise in the fabrication of nanoporous materials with applications in absorption and filtration of toxic materials. Utilizing the space between polymeric strands, mesopores within a network could be constructed by crosslinking PS molecular bottlebrushes using Friedel−Crafts alkylation of styrene’s phenyl rings.88 Porous materials could also be prepared through Ru-catalyzed cross-metathesis of 37


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Figure 17. Polymer structures 4c,d and 5c,d, including representative AFM height micrographs of 4d (top left) and 5d (top right) (scale bar = 50 nm), and schematic representation of the polymer structures on the mica surface (bottom). Reproduced with permission from ref 87; Copyright 2013, American Chemical Society.

further study used a library of polyzwiterrionic bottlebrush polymers of zero, one, and two PqDMAEMA cationic side segments to explore the effects of intermolecular interactions on tribological properties. A higher number of adhesive blocks in the bottlebrush polymers drastically increased the threshold pressure P* (the starting point of surface damage).90 A brushbased wear protection strategy without any chemical surface modifications by utilizing synergistic interactions between high molecular weight hyaluronic acid (HA) and PMPC molecular brushes was developed.91 In contrast to the two individual components, a mixture of the two polymers in pure water or saline had allowed for increased wear protection of surfaces over a wide range of shearing conditions. Synergy between BB

Figure 19. Schematic representation of triblock coil−brush−coil lubricant (a) and the loop conformation formed on the mica surface. Reproduced with permission from ref 15; Copyright 2014, American Chemical Society.

and HA polymers emerged from strong entanglements between both polymers in the boundary film. The entanglements prevented the lubricants from being squeezed out of the targeted protecting surface during shear tests. Over time, this brush-based lubrication system had shown minor changes in molecular conformation and partial scission of the BB polymer

Figure 18. Synthesis of mesoporous monoliths from end-reactive bottlebrush copolymer precursors (a) and linear relationship between onset pore diameter and logarithm of backbone length for porous materials prepared from bottlebrush copolymers with similar side chains and varying backbone dimensions. Reproduced with permission from ref 89; Copyright 2017, American Chemical Society. 38


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Figure 20. (a) Comparison of the molecular weights and number of carbon−carbon bonds along the backbones of linear block copolymers and comb block copolymers. (b) Chemical compositions of molecular brush. (c) Optical micrograph of one brush sample taken against a black background to show blue light reflected from the polymer coating a glass vial. Reproduced with permission from ref 97; Copyright 2007, American Chemical Society.

side chains.92 However, these changes did not significantly impact the tribological properties of the BB polymer solution nor its wear protection capacity. 3.2.2. Brush−Brush Block Copolymers. The densely grafted side chains of molecular brushes prevent interpenetration of polymer chains from different brush molecules, resulting in significantly decreased chain entanglements in the polymer melt. The combination of suppressed chain entanglement and the well-defined compositional interface in the backbone enable brush−brush block copolymers (BBCPs) to enlarge the domain sizes of self-assembled polymer melts to reach a range of several hundred nanometers. This has enabled utility in several potential applications including lithographic templates,93 solid electrolytes,94 and photonic crystals (PCs)95,96 where such a range of domain sizes is desirable but hard to reach through traditional self-assembly of linear block copolymers (BCPs). Large-domain nanostructures were afforded from the selfassembly of brush−coil block copolymers composed of brush segments containing long PS side chains and coil domains composed of short grafts (Figure 20).97 The assembly of these brushes reflected selected wavelengths of visible light by varying domain size from 100 to 200 nm. However, it is worth noting that the second coil block still needs to have very high molecular weight to have a comparable weight fraction to that of the brush segment. By changing the molecular weight of symmetric diblock BBCPs with PS and PLA side chains synthesized via the grafting-through ring-opening metathesis polymerization (ROMP) method,98 the reflectance spectra with maximum reflection wavelengths (λmax) was linearly tuned by increasing the molecular weights of the block brushes.99 Furthermore, the self-assembly of PLA−PS block brushes swollen by linear PS increased the domain size by up to 180% and shifted λmax from 910 to ∼1410 nm (Figure 21).100 Because increasing the rigidity of the grafts could (1) enhance the overall persistence, (2) decrease chain entanglement, and (3) promote more rapid self-assembly, diblock BBCPs with two types of rigid polyisocyanate grafts, (poly(hexyl isocyanate) and poly(4-phenylbutyl isocyanate), were self-assembled into blends with large domain sizes. A series of symmetrical block brushes with molecular weights (Mw) ranging from 1.5 to 7.1 M afforded a library of materials with a tunable reflectance peak ranging from ultraviolet to near-infrared regions. Similar to block brushes previously reported, reflected wavelengths scaled linearly with increasing

Figure 21. (A) BBCP/HP blends allow the photonic band gap of the self-assembled arrays to be easily tuned from 390 to 1410 nm. Each color corresponds to a specific BBCP; some BBCPs could be swollen to ∼180% of their initial domain spacing. (B) UV−vis spectra of the highest MW BBCP (brown circles in A) with increasing HP wt %. Samples were well-ordered enough to observe higher order resonances at λ/m (e.g., at ∼625 nm (m = 2) and ∼450 (m = 3) in the orange trace). Reproduced with permission from ref 100; Copyright 2014, American Chemical Society.

molecular weights of the block brushes.101 Furthermore, the blends of two BBCPs of different molecular weight were used to form highly uniform lamellar morphologies with the wavelength of the reflection peak increasing with the weight fraction of the high molecular weight component (Figure 22).102 Similar to the one-dimensional (1D) lamellar structure, 2D and 3D nanoscale patterns can also be fabricated. For a linear diblock copolymer, the change of morphology could be done by changing the relative length of each block (altering the composition of the polymer chain).103,104 In contrast, introducing a fairly high level of asymmetry (f = 0.3−0.6) into PLA/PS BBCPs would not affect their lamellar morphology, and the higher asymmetric BBCPs did not assemble into any identifiable ordered structures that could be detected by the higher order scattering peak reported by SAXS. Such a phenomenon was due to the rigidity of BBCPs 39


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suggested that transitions in phase separation in bulk for heterografted brushes are primarily influenced by polymer architecture, as opposed to spacer identity, at high graft densities. Phase separation of loosely grafted combs could be more influenced by χ of spacer units. The self-assembly of gradient block copolymer brushes with PS and PLA side chains deviated from this pattern.108 The brushes self-assembled into cylindrical microstructures, as opposed to lamellae structures observed in analogous selfassembly of diblock brushes, with tunable domain spacing through the length of the bottlebrush backbone. The shape persistence of BBCPs allowed for the fabrication of patterns with sub-30 nm line-width resolution using a highresolution negative-tone photoresist technique.109 The BBCP contained a short block with fluorinated side chains to facilitate a large-area vertical alignment of brushes on silica wafers. The other cross-linkable block of the BBCP enabled photo-crosslinking into a predefined pattern through a reaction catalyzed by UV or electron beam irradiation (Figure 24). The interference of molecular packing between molecular brushes also affected the self-assembly of BBCPs in bulk and aqueous media. A series of BBCPs composed of a poly(εcaprolactone) (PCL) block and an amorphous poly(n-butyl acrylate) (PBA) block was prepared by sequentially growing two types of side chains from a diblock copolymer backbone.110 In fact, this was the first example of block bottlebrush prepared successfully by ATRP. Crystallization of the PCL block embedded in a matrix of PBA melt was hindered and observed as a decrease in the crystallization temperature (Tc) of the BBCPs compared to that of a linear PCL control. Interestingly, BBCPs associated into flowerlike or dumbbelllike structures due to the amphiphilicity of the brush (Figure 25). When using BBCPs with a poly(lactic acid) (PLA) block and a poly(oligo(ethylene glycol) methyl ether methacrylate) (POEOMA) block as giant surfactants, highly uniform micelles with an average core radius of 19 ± 1 nm and rodlike PEO brushes with an average length of ∼20 nm were observed in cryo-TEM images (Figure 26). The core size was very close to the maximum end-to-end distance of 23 nm for a fully stretched polymer chain of 95 repeat units in PLA chains.111 The uniform assembly was attributed to the shape-persistence of the PLA brush segment. By plotting size dispersity of micelles and packing parameters (parameters used to measure geometrical constraints of self-assembly), the most uniform micelles (with lowest dispersities) were formed when the packing parameter was close to 0.3, similar to small molecule surfactants. These results suggest that the shape-persistent nature of bottlebrush amphiphiles prevented them from selfassembling into different morphological variations. 3.3. Mikto-Grafted Brushes. Molecular bottlebrushes were historically referred to as “polymacromonomers” because they were synthesized using the grafting-through method.9 The name hints at a unique structural feature afforded by this architecture, a cluster of uniform linear polymers as side chains. A mikto-grafted molecular bottlebrush contains more than one type of polymeric side chain. An intramolecular compositional interface similar to that in a block copolymer (BCP) could also form with different types of grafts pointing in different directions. Consequently, mikto-grafted molecular brushes also show interfacial activity similar to BCPs and undergo phase separation.

Figure 22. (a) Photograph of brush block copolymer blends reflecting light across the visible spectrum (top). Plots of (b) reflectance against wavelength and (c) maximum peak wavelength of reflectance against the weight fraction of the blend of the different brush block copolymer blends. Reproduced with permission from ref 102; Copyright 2012, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

preventing effective packing around curved interfaces of other morphologies, forcing the self-assembly to remain lamellae.105 The fabrication of materials with large domain spacings in higher-than-one dimension requires the shape persistence and large discrepancy between the graft lengths afforded by molecular bottle brushes. A block brush with polystyrene (PS) side chains three times as long as the polylactide (PLA) grafts was used to prepare porous materials after etching the PLA layer.106 SEM imaging of the material provided clear evidence of the formation of a porous structure. The pore size distribution was fairly narrow with a pore diameter of 55 ± 16 nm (Figure 23), which is notably larger than attainable by templating with linear diblock copolymers.106

Figure 23. (a) Chemical composition of molecular brush and (b) scanning electron micrograph of a nanoporous material prepared from an asymmetric PS−PLA bottlebrush block copolymer. Reproduced with permission from ref 106; Copyright 2011, American Chemical Society.

Self-assembly of poly(D,L-lactide) and polystyrene brush block copolymers with norbornene backbones, spanning grafting densities of 0−100%, were all found to segregate into long range-ordered lamellar structures.107 Interestingly, the relationship between the scaling exponent, α, and the backbone degree of polymerization (d* ∼ Nbbα) showed a transition at a grafting density of ∼20%, suggesting that significant changes in the chain conformations occurred in this region. Control experiments were repeated using the same 5norbornene-2,3-dicarboxylic acid, dibutyl ester (DBE) spacer, which lowered α slightly but showed the same transition. This 40


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Figure 24. Chemical structure of diblock bottlebrush copolymer building blocks (top). Schematic diagram of the overall strategy (bottom). Reproduced with permission from ref 109; Copyright 2013, American Chemical Society.

Figure 25. Association patterns observed in the phase images of the dense film: (a) flowerlike patterns and (b) some dumbbells. Reproduced with permission from ref 110; Copyright 2008, American Chemical Society.

The most straightforward method to incorporate more than one type of side chains in brushes is grafting-through. Miktografted brushes containing PEO and long alkyl (octadecyl, C18) side chains were prepared via ATRP of two macromonomers.44 The microphase segregation induced by the incompatibility between hydrophilic (PEO) and hydrophobic (C-18) segments was observed by both DSC and X-ray scattering. Interestingly, X-ray results indicated that frustration in packing of the crystallizable helical PEOMA and hexagonal

Figure 26. Cryo-TEM images of uniform spherical micelles formed by amphiphilic PLA/PEO block bottlebrush copolymers. Reproduced with permission from ref 111; Copyright 2014, American Chemical Society.

ODMA segments led to an amorphous fraction instead of a semicrystalline ODMA in the graft copolymer (Scheme 6). The most straightforward method to incorporate more than 41


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and poly(lactic acid) (PLA) grafts.112 These brushes enriched the film surface stronger than their linear analogues (PDMS-bPLA), and the surface contact angle was tunable by varying the composition and quantity of the added bottlebrush copolymer (Figure 27b). Heterografted brushes consisting of pOEOMA and poly(glycidyl methacrylate) (pGMA) were very effective at targeting tumors of xenograft models.113 Densely grafted brushes below 1 μm in size had enhanced targeting ability, which was attributed to improved permeation and retention of the brushes inside tumor cells. Such bottlebrush-based systems can achieve similar effectiveness in tumor accumulation and extravasation as well as smaller, spherelike particles. The penetration of heterografted polymer brushes spanning 40 nm to over 1000 nm in length across spherical, rodlike, and filamentous topologies into tumor spheroids was found to be dependent on the architecture of the polymer.114 Interestingly, heterografted brushes of rodlike topology were reported to be more effective at both association and penetration into the multicellular tumor spheroids than brushes with spherical or filamentous topologies. This could be attributed to cellular uptake being a diffusion-controlled process, where elongated particles with an aspect ratio between 4 and 5 had the highest association and penetration. Another method to incorporate two, or more, different side chains onto brushes is through a combination of grafting-from and -through polymerization techniques. By incorporating hydrophilic arms during grafting-through and hydrophobic arms during grafting-from (Figure 28a), a library of welldefined mikto-grafted molecular brushes with poly(ethylene oxide) (PEO) and poly(n-butyl acrylate) (PnBA) side chains was prepared with individual control over graft length, graft ratio, and backbone length.115 These brushes stabilized waterin-oil emulsion at concentrations as low as 0.005 wt % (Figure 28b). This synthetic strategy allowed for individual control over graft length, graft ratio, and backbone length. A large number fraction and length of hydrophilic grafts showed increased emulsifying efficiency and could stabilize emulsions using a lower surfactant concentration. This trend is plausibly due to the higher affinity of the brushlike surfactants toward the aqueous phase. A comparison between heterografted molecular brush copolymers and their diblock analogues during emulsifying tests indicated that a combination of multiple hydrophilic and hydrophobic grafts in one molecule could enhance adsorption at the interface and increase emulsifying efficiency. Similarly, better stabilization of droplet sizes in mini-emulsion using brushlike surfactants (synthesized by ROMP) as opposed to their model amphiphilic norbornene macromonomers was reported.116 Aside from polymerization, selective cross-linking of certain domains in self-assemblies of linear polymers can also generate backbones for mikto-grafted molecular bottlebrushes. Amphiphilic mikto-grafted brushes were prepared by cross-linking the cylindrical domains of self-assembled triblock copolymers.117 Interfacial tension was significantly reduced between the interfaces of PFO/dioxane and PFO/DMSO liquid pairs according to pendant drop experiments utilizing these miktografted molecular bottlebrushes. Mikto-grafted brushes can also function as Janus particles at the interface of two immiscible fluids due to the amphiphilicity of the heterografted polymer brushes. Compared to linear BCP amphiphiles, mikto-grafted brushes allow for more precise and flexible tuning of properties due to their complex but well-

Scheme 6. Proposed Model for a Hypothetical Bilayer Structure Formed by Graft Copolymers P(PEOMA-statODMA)


one types of side chains in brushes is grafting-through. Miktografted brushes containing PEO and long alkyl (octadecyl, C18) side chains were prepared via ATRP of two macromonomers.44 The microphase segregation induced by the incompatibility between hydrophilic (PEO) and hydrophobic (C-18) segments was observed by both DSC and X-ray scattering. Interestingly, X-ray results indicated that frustration in packing of the crystallizable helical PEOMA and hexagonal ODMA segments led to an amorphous fraction instead of semicrystalline brushes forming a lamellar self-assembly with a domain spacing of 14 nm (measured by SAXS) (Scheme 7). Structural variations indicated that the domain size and order− disorder transition temperatures (ODT) were insensitive to the backbone length. ROMP enabled preparation of brushes with varied molar ratios of poly(dimethylsiloxane) (PDMS) Scheme 7. Self-Assembly of Symmetric Mikto-Grafted Molecular Brushes

Reproduced with permission from ref 98; Copyright 2009, American Chemical Society. 42


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Figure 27. (a) Schematic for the modification of polymer thin films through the addition of bottlebrush copolymers whose arms are segregating on the film surfaces. (b) Water contact angle (WCA) of bulk PLA films (white bar) and films blended with 1 wt % (gray bar) or 5 wt % (black bar) bottlebrush copolymers in bulk PLA with respect to WCA of bulk PLA films. Copolymer additives, P(XPDMS-co-YPLA), are labeled by the ratio of PDMS (X) to PLA (Y) side-chains and represent blends from P(74PDMS-co-26PLA)56, P(46PDMS-co-54PLA)65, and P(23PDMS-co-77PLA)61. Reprinted from ref 112; Copyright 2016, with permission from Elsevier.

Figure 28. (a) Synthesis of PEO/PBA mikto-grafted molecular brushes. (b) Schematic illustration of surface adsorption of mikto-grafted molecular brushes on the liquid−liquid interface. Reproduced with permission from ref 115; Copyright 2017, American Chemical Society.

defined structures. For example, to change affinity toward the polar (aqueous) phase (hydrophilic−lipophilic balance, HLB) using a BCP surfactant, one can only change the weight fraction of the hydrophilic segment. In contrast, mikto-grafted brushes have tunability through (1) the length of hydrophilic side chain, (2) the length of hydrophobic side chain, and (3) composition of the backbone. 3.4. Brushes with BCP Side Chains. The excellent chain end functionality of controlled radical polymerization techniques, such as ATRP, can create radially layered molecular bottlebrushes through sequential growth of two or more blocks from polymer backbones.118 Molecular bottlebrushes with block copolymers as side chains have complex conformations depending on the interactions between individual blocks, underlying substrates, and the surrounding environment. If both blocks are equally attracted to a substrate, the conformation is similar to that of a brush with homopolymer side chains (Figure 29a). However, if one of the blocks has preferential attraction to a substrate, the side chains may fold into conformations depicted in Figure 29b and c. For example, when a brush molecule with PBA-b-PS side chains was deposited on mica, the inner PBA block exhibited

Figure 29. Schematics of different morphologies that can be observed upon adsorption of brush molecules with block copolymer side chains. Reprinted from ref 1; Copyright 2008, with permission from Elsevier.

stronger affinity for the substrate, whereas the outer PS block folded back, giving extra height on the surface similar to the case of Figure 29b.118 In contrast, when the thin film was prepared from a brush molecule with block-wise side chains containing crystalline PCL as the inner block and PBA as the outer on mica, a spinelike morphology was observed due to crystallization of the PCL core segregated by the PBA chains penetrating in between the crystallized PCL domain (Figure 30c).119 As the corona layer, the PBA chains prevented aggregation of brushes through steric repulsion. The order−disorder transition temperature (TOTD) of poly[(styrene-alt-N-hydroxyethylmaleimide)-random-(styrenealt-N-ethylmaleimide)]-graf t-poly(4-methylcaprolactone-blockD,L-lactide) [PSHE-g-(P4MCL-b-PLA)] brushes was investigated.120 Interestingly, brushes with graft densities between 43


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The first report on a triblock brush was on the synthesis of a core−shell−corona molecular brush. The increase in the number of blocks in the side chains allowed for an additional layer of inorganic content and a cavity within the nanoparticle to be embedded in the nanostructures131 (Figure 31).

Figure 30. (a, b) AFM height micrographs of molecular brushes with PCL-b-PBA side chains on mica. The numbers 1−4 correspond to monomers, dimers, trimers, and cyclic brush molecules, respectively, that undergo end-to-end association. (c) Model of the spinelike morphology. The adsorbed block copolymer side chains are phaseseparated on the substrate to form ribs of fully extended PCL blocks embedded into a matrix of PBA blocks. The latter stabilize the extension of the backbone. (d) Cross-sectional profile along the dashed line in (b) reveals regularly spaced ribs that are assigned to bundles of PCL chains with an average height of hPCL−PBA = 1.2 nm (between the top of the ribs and the PBA monolayer) and a spacing of dPCL = 14 ± 1 nm. Reproduced with permission from ref 119; Copyright 2009, American Chemical Society.

Figure 31. Schematic representation of triblock copolymer brushes carbonized into nanostructured carbons embedded with additional functionalities. Reproduced with permission from ref 131; Copyright 2007, American Chemical Society.

The poly(acrylic acid) (PAA) corona layer enabled fixation of 3D structures by cross-linking with a diamine while the polyacrylonitrile (PAN) shell domain outside the PBA core domain served as a precursor to carbon nanostructures. When this nano-object was deposited on mica, the average height measured by AFM significantly increased from 5.2 to 16.5 nm after cross-linking the PAA corona. This value changed to 19.0 nm when the substrate was switched to silicon instead of mica. Both indicated the formation of fixed structures. This was crucial to preserve the backbone in the following pyrolysis as reported for the analogues with only PBA−PAN diblock copolymer side chains.132 Au−Fe3O4 core−shell nanorods using a core−shell−coronastructured template with P4VP-b-PtBA-b-PS triblock side chains were formed using a fractionated and functionalized cellulose backbone (Figure 32).133 After the core domain of P4VP was loaded with Au, the anchoring functional group of acrylic acid was activated by hydrolysis, allowing for further loading of the Fe2O3 precursor. The block copolymer side chains of a molecular bottlebrush can also be used to create cavities in nanostructures by serving as either inorganic-content-free domains, which disfavor the anchoring/formation of inorganic content, or as “sacrificial” domains that can be removed. Water-soluble organosilica hybrid nanotubes were prepared using a core−shell−coronastructured molecular brush as the template (Scheme 8).134 The shell domain of poly(3-(trimethoxysilyl)propyl acrylate) (PAPTS) was used to form the inorganic layer via condensation of the trimethoxysilyl groups in aqueous ammonia solution. In addition to good control over the length of the afforded nanotubes, the diameter and thickness of each layer could be tuned by changing the degree of polymerization in the shell blocks. However, these nanotubes did not have a real porous structure because the PtBA core was not removed. For hollow nanotubes to be prepared using brush templates, a degradable block was introduced to create a “sacrificial” domain. Hollow silica nanotubes were prepared using brush

25 and 50% had nearly identical TOTD to their analogous linear P4MCL-b-PLA diblock copolymer. Grafting densities below 25% had a decreasing TOTD as chains became more loosely grafted, which was attributed to increasing contribution of the immiscible backbone with its PLA side chains. There is minimal influence of phase separation between side chains and backbone in densely grafted diblock polymer brushes. However, the effect of phase separation becomes more apparent in loosely grafted combs as the weight fraction of side chains decreases. The interface between different blocks of side chains could divide the space within a molecular bottlebrush into domains with clear boundaries. Densely grafted brushes with immiscible (PDMS-b-PLA) diblock copolymer side chains have been used to create self-assembled nanostructures with ultrasmall nanodomains.121 The size of the lamellae domains was primarily dependent on the length of the side chains; however, the length of the polymer backbone could still be varied to allow for tunability of material properties. One of the most important applications relying upon compartmentalization of side chain blocks is the use of molecular bottlebrushes as templates to create inorganic nanoobjects. In the simplest case, when the precursor of the inorganic content is loaded in the core domain of a core−shellstructured brush template, the shape of the final nano-object is clearly defined by the boundary of the core domain. Additionally, the polymer chains in the shell domain prevent aggregation of nanoparticles through steric interactions. The wormlike morphology of brush templates was reported to produce anisotropic nano-objects (referred to as nanorods, nanocylinders, or nanowires) capable of carrying various inorganic contents including TiO2,122,123 Fe2O3,124 ZnO,125 Au,122,126 Pt,122,127 silica,128,129 CdSe,129 and CdS.130 44


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Figure 32. (a) Preparation of core−shell nanorods using cellulose-g-(P4VP-b-PtBA-b-PS) as the template. (b) TEM images of Au−Fe3O4 nanorods. (c) HRTEM image showing the crystal lattice of the Au core and Fe3O4 shell (white dashed lines for guidance). Reprinted from ref 133; Copyright 2016, with permission from AAAS.

Scheme 8. Synthetic Method for Preparing Water-Soluble Organosilica Hybrid Nanotubes Using a Core−Shell−CoronaStructured Template


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Scheme 9. Synthesis of Template CPBs and Their Use in the Template-Directed Synthesis of 1D Silica Hybrid Nanostructures


PSMA) in the corona of this nanoparticle (Scheme 11) allowed for tunable surface hydrophilicity, which was observed through model cell uptake experiments.137 Similar functionalities have also been introduced in the interior surface of nanotubes by sandwiching the functional block between the removable core and cross-linkable corona in the side chains. The nanoparticle was capable of effective discrimination between dendrimers of up to a 2 nm difference in size. This implied the cavities were of well-defined size and functionality and could potentially be used as selective carriers for (1) positively charged molecules and (2) nanometer-size macromolecules.137 Molecular brushes with amphiphilic triblock copolymer branches generated 1D 92 ± 21 nm long assemblies with 4−5 molecular brushes per aggregate in solution, which were driven by end-to-end interactions between the hydrophobic cores of the brushes (Figure 33).138 Brushes with BCP side chains allow for the creation of welldefined boundaries between functional domains extending radially from a brush backbone. A nanoparticle shape could be tuned to create complex structures by using domains as either scaffolds to form solid segments or as removable/sacrificial templates to create hollow structures. The layered structures of brushlike templates with BCP side chains also allow functional surfaces to be incorporated onto these nanoparticles through the addition of functional segments as neighbors to particleforming segments. Therefore, brushes with BCP side chains provide versatile platforms to create functional nanoparticles of complex structures. 3.5. Brushes with Nonlinear Topologies. Cyclic and branched structures are two types of the most common topological variations for polymer chains. The “infinite” nature of cyclic polymers hinders intermolecular chain entanglement and can affect intermolecular packing in polymer melts, whereas the branched structures change intermolecular connections due to the existence of “arms”.139−141 Cyclic polymers typically have a smaller hydrodynamic volume, higher density, lower intrinsic viscosity, increased rate of nucleation and crystallization, higher glass transition temperature, and higher critical solution temperature than those of their linear counterparts.142−147 Similarly, the presence of branches also influences material properties of polymers. Combining the properties of branched and cyclic structures with the decreased entanglement of bottlebrushes often results in magnification of both properties; however, synthetic limitations tend to limit widespread implementation of this architecture.

templates consisting of a densely grafted poly(ε-caprolactone) (PCL) core with a poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) shell. The weak polyelectrolyte shell acted as an ideal nanoreactor for the deposition of silica. Calcination or acid treatment of the as-synthesized silica hybrids could remove the core, resulting in the formation of hollow silica nanotubes (Scheme 9).135 Porous nitrogen-doped carbons by pyrolyzing core−shell molecular brushes with PBA-b-PAN side chains were prepared.132 PAN in the shell domain formed intermolecular cross-links followed by decomposition of the PBA core to create mesopores. This method overcame the challenge of partial miscibility observed in most linear BCPs systems of low degree of polymerization (DP) because molecular brushes could function as preformed PBA-b-PAN BCPs micelles with fixed organization of side chains. Open ended nanotubes were prepared using an ABA triblock molecular template with a removable A block. A cross-linkable poly(4-butenylstyrene) (P4BS) shell was used to fix the cylindrical shape of brush precursors, and polylactide (PLA) core removal provided a pore through the center of the cylindrical nanoparticles (Scheme 10). In addition, to create open ends, poly(ethylene oxide) (PEO) or PLA “stoppers” were used at either one17 or both ends.136 Further introduction of functional block (poly(styrene-stat-maleic anhydride, Scheme 10. Chemical Compositions of Core−Shell Brushes Used in the Formation of Nanostructures with Topologies for (A) One Opened End17 and (B) Both Ends Opened136

Reproduced with permission from refs 17 and 136; Copyright 2009 and 2010, American Chemical Society. 46


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Reproduced with permission from ref. 137; Copyright 2011, American Chemical Society.

Figure 33. (a) Chemical compositions of molecular brush. (b) TEM image of the hierarchical cylindrical nanostructures comprised of PNB-g-(PSb-PMA-b-PAA) self-assembled in solution and then cast onto a carbon-coated copper grid. (c) AFM image of the hierarchical cylindrical nanostructures comprised of PNB-g-(PS-b-PMA-b-PAA) self-assembled in solution and then cast onto a mica substrate. Scale bar: 100 nm. Reproduced with permission from ref 138; Copyright 2011, American Chemical Society.

Figure 34. (a) Tubular self-assembly. (b) Aggregates of tubes and isolated tube (diameter, 100 nm; length, 600 nm). (c) Series of tubes interconnected by their polyisoprene shell (black) and image in reverse mode showing the internal PS (purple) and external PI (green) parts. Reprinted from ref 148; Copyright 2008, with permission from AAAS.

Macrocyclic brushes were prepared via grafting (1,1diphenylethylene) end-capped polystyryllithium (PS-DPELi) and (1,1-diphenylethylene) end-capped polyisoprenyllithium (PI-DPELi) onto cyclic poly(chloroethyl vinyl ether) (PCEVE). They observed tubular objects with hydrodynamic radii up to 200 nm as the result of intermolecular stacking of cyclic heterografted brushes in heptane (Figure 34a).148 The selective formation of rigid tubular objects could be observed for isolated or aggregated brushes (Figure 34b and c). Molecular brushes with cyclic backbones were also synthesized via ring expansion metathesis polymerization (REMP) of macromonomers.149 Because of the stress within the backbone induced by adsorption of densely grafted side chains, ring cleavage of the cyclic polymer was observed in the AFM images of samples deposited on the graphite surface (Figure 35).

A small library of amphiphilic cyclic brushes consisting of hydrophobic polycarbonate backbones and hydrophilic poly(N-acroloylmorpholine) (PNAM) side arms were prepared via a combination of ROP, CuAAC cyclization, and RAFT polymerization.150 The cyclic brushes showed a large difference in aqueous solution dynamics compared to that of analogous linear brushes (Figure 36). All samples selfassembled into unimolecular micelles when dispersed in water with tunable particle size based upon the length of PNAM side chains. However, short PNAM side chain lengths showed higher particle dimensions and greater loading capacity for Nile Red than the those of the equivalent linear brush. As PNAM arm length increased, the cyclic graft copolymer particles were able to adopt cylindrical conformations, whereas the linear brushes remained in a spherical conformation. The lower critical solution temperature (LCST) of the cyclic brush 47


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easier passage of linear brushes through glomeruli nanopores by an “end-on” motion more easily than cyclic polymers. The longer retention time of cyclic brushes is promising for applications where a drug carrier would circulate, releasing the drug and then being rapidly eliminated by the body. Macrocyclic “sunflower” brushes were prepared by grafting OEOMA “petals” from a cyclic poly(EGMA-st-BiBEM) macroinitiator.152 The cyclic brushes served as a pHresponsive template that could release alkyne-functionalized folate, fluorescein, or doxorubicin from the core of the cyclic brush. The cyclic brushes were mildly selective in killing for KB cells over A549 cells, whereas the analogous linear brush was similarly cytotoxic for both KB cells and nontarget A549 cells. Molecular brushes prepared via grafting-from ATRP utilize macroinitiators as templates to determine the structure of the final brush product.148 Branched brushes with three-, four-, and six-arms were prepared by growing the side chains from a branched backbone.148,153,154 As shown in Schemes 12 and 13, the introduction of multifunctional initiators creates these branches when preparing the precursor of the backbone. Because molecular brushes can be used as templates to prepare nanoparticles, this enabled preparation of branched inorganic nanostructures. These materials could generate hierarchical nanostructured networks with enhanced interconnectivity and percolation of nanoparticles compared to those of their linear analogues.149 For example, a four-arm molecular brush with PS-b-PAA side chains served as a template for preparing nanosized tetrapods.155 Four-arm molecular brushes could provide more ordered 2D structures compared to those of their corresponding linear analogues.156 When the linear and four-arm molecular brushes underwent lateral compression on the surface, visual comparison of the AFM images revealed that the monolayer of the four-arm molecules displayed more ordered selfassembly (Figure 37) in which small domains with nearly perfect hexagonal order could be identified. 2D power spectral density indicated a well-defined 6-fold symmetry in the monolayers of four-arm brush, whereas the linear brush has a less defined pattern indicating less order (insets of Figure 37). As discussed in previous sections, the grafted structures of molecular bottlebrushes interfere with chain entanglement by limiting the length of linear structures. Similarly, when nonlinear topologies are incorporated onto polymer backbones, intermolecular interactions between linear structures are interrupted. The relatively large sizes of molecular

Figure 35. (a) Synthesis of a cyclic bottlebrush polymer from ring expansion metathesis polymerization (REMP) of ω-norbornenyl MM. (b) Topographic AFM images of a cyclic bottlebrush polymer undergoing ring cleavage on the graphite surface after 2 h at room temperature. The arrow points to the cleavage site (scale bar: 100 nm). Reproduced with permission from ref 149; Copyright 2011, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

also exhibited a 20 °C increase in temperature response compared to that of the linear brush. Cyclic brushes have significantly different pharmacokinetics than linear brushes.151 The elimination half-lives of high molecular weight cyclic brush polymers above the renal filtration threshold were significantly higher than those of linear brushes. High molecular weight cyclic-grafted PEG brushes were secreted in urine 12% less than the analogous linear brushes. The difference in retention was attributed to

Figure 36. Comparison between the solution dynamics of cyclic and linear grafted PNAM brushes in water. (left) SAXS profiles of the cyclic and linear brushes. The black data points correspond to the cyclic brush, which follows the theoretical trend (red line) expected for a cylindrical micelle. The yellow data points correspond to the linear brush, which follows a spherical micelle theoretical fit (blue line). (right) UV/vis trace of the cyclic and linear brushes. Reproduced with permission from ref 150; Copyright 2016, American Chemical Society. 48


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Biomacromolecules Scheme 12. Synthesis of Three- and Four-Arm Star Molecular Brushes


Scheme 13. Synthesis of Starlike Bottlebrushes with Hexa-ATRP Initiator (MSW6‑Br) via Double Grafting-from Approach


4. CONCLUSIONS AND FUTURE PERSPECTIVES Recent progress in synthetic polymer chemistry has facilitated access to molecular bottlebrushes of well-defined structures. Increasingly effective and precise control of polymer architecture enables researchers to achieve novel properties through rational molecular design. Molecular bottlebrushes offer a versatile toolbox to address many challenges in materials science and engineering. The combination of reduced molecular overlap, higher persistent length, nanoscale size, and high local concentration of polymer chains has enabled various potential applications such as templates of well-defined nanostructures, drug carriers, supersoft elastomers, surfactants, lubricants, and stimuli-responsive materials. However, many challenges and opportunities remain. Synthetic methods and strategies that facilitate experimental setup, increase yield, and enhance control over preparation of molecular bottlebrushes will continue to be in demand. For instance, introduction of RDRP and ROMP techniques was a milestone in the development of preparative methods for molecular bottlebrushes due to functional group tolerance and preservation of chain-end functionality. Compared to linear polymers, molecular bottlebrushes contain a more complex combination

Figure 37. Height images of the compressed linear brush (a) and four-arm brush (b). The highlighted area in part b shows a domain with nearly perfect hexagonal order. The insets show 2D power spectral density measured for 1 × 1 μm2 areas of the monolayers. Six peaks are clearly visible in the four-arm PSD, indicating the presence of hexagonal order in the system. Reproduced with permission from ref 156; Copyright 2004, American Chemical Society.

bottlebrushes permit AFM visualization of the impact molecular topology on intermolecular interactions. 49


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(9) Tsukahara, Y.; Mizuno, K.; Segawa, A.; Yamashita, Y. Study on the radical polymerization behavior of macromonomers. Macromolecules 1989, 22 (4), 1546−1552. (10) Cho, H. Y.; Krys, P.; Szcześniak, K.; Schroeder, H.; Park, S.; Jurga, S.; Buback, M.; Matyjaszewski, K. Synthesis of Poly(OEOMA) Using Macromonomers via “Grafting-Through” ATRP. Macromolecules 2015, 48 (18), 6385−6395. (11) Flanders, M. J.; Gramlich, W. M. Reversible-addition fragmentation chain transfer (RAFT) mediated depolymerization of brush polymers. Polym. Chem. 2018, 9 (17), 2328−2335. (12) Gao, H.; Matyjaszewski, K. Synthesis of Molecular Brushes by “Grafting onto” Method: Combination of ATRP and Click Reactions. J. Am. Chem. Soc. 2007, 129 (20), 6633−6639. (13) Gan, W.; Shi, Y.; Jing, B.; Cao, X.; Zhu, Y.; Gao, H. Produce Molecular Brushes with Ultrahigh Grafting Density Using Accelerated CuAAC Grafting-Onto Strategy. Macromolecules 2017, 50 (1), 215− 222. (14) Matyjaszewski, K.; Xia, J. Atom Transfer Radical Polymerization. Chem. Rev. 2001, 101 (9), 2921−2990. (15) Banquy, X.; Burdyńska, J.; Lee, D. W.; Matyjaszewski, K.; Israelachvili, J. Bioinspired Bottle-Brush Polymer Exhibits Low Friction and Amontons-like Behavior. J. Am. Chem. Soc. 2014, 136 (17), 6199−6202. (16) Bernard, J.; Favier, A.; Davis, T. P.; Barner-Kowollik, C.; Stenzel, M. H. Synthesis of poly(vinyl alcohol) combs via MADIX/ RAFT polymerization. Polymer 2006, 47 (4), 1073−1080. (17) Huang, K.; Rzayev, J. Well-Defined Organic Nanotubes from Multicomponent Bottlebrush Copolymers. J. Am. Chem. Soc. 2009, 131 (19), 6880−6885. (18) Cheng, C.; Qi, K.; Khoshdel, E.; Wooley, K. L. Tandem Synthesis of Core−Shell Brush Copolymers and Their Transformation to Peripherally Cross-Linked and Hollowed Nanostructures. J. Am. Chem. Soc. 2006, 128 (21), 6808−6809. (19) Nakamura, Y.; Ogihara, T.; Yamago, S. Mechanism of Cu(I)/ Cu(0)-Mediated Reductive Coupling Reactions of Bromine-Terminated Polyacrylates, Polymethacrylates, and Polystyrene. ACS Macro Lett. 2016, 5 (2), 248−252. (20) Bamford, C. H.; Dyson, R. W.; Eastmond, G. C. Network formation IV. The nature of the termination reaction in free-radical polymerization. Polymer 1969, 10, 885−899. (21) Plessis, C.; Arzamendi, G.; Leiza, J. R.; Schoonbrood, H. A. S.; Charmot, D.; Asua, J. M. Modeling of Seeded Semibatch Emulsion Polymerization of n-BA. Ind. Eng. Chem. Res. 2001, 40 (18), 3883− 3894. (22) Ballard, N.; Asua, J. M. Radical polymerization of acrylic monomers: An overview. Prog. Polym. Sci. 2018, 79, 40−60. (23) Nakamura, Y.; Lee, R.; Coote, M. L.; Yamago, S. Termination Mechanism of the Radical Polymerization of Acrylates. Macromol. Rapid Commun. 2016, 37 (6), 506−513. (24) Vandenbergh, J.; Junkers, T. Macromonomers from AGET Activation of Poly(n-butyl acrylate) Precursors: Radical Transfer Pathways and Midchain Radical Migration. Macromolecules 2012, 45 (17), 6850−6856. (25) Van Steenberge, P. H. M.; Vandenbergh, J.; Reyniers, M.-F.; Junkers, T.; D’hooge, D. R.; Marin, G. B. Kinetic Monte Carlo Generation of Complete Electron Spray Ionization Mass Spectra for Acrylate Macromonomer Synthesis. Macromolecules 2017, 50 (7), 2625−2636. (26) Ribelli, T. G.; Augustine, K. F.; Fantin, M.; Krys, P.; Poli, R.; Matyjaszewski, K. Disproportionation or Combination? The Termination of Acrylate Radicals in ATRP. Macromolecules 2017, 50 (20), 7920−7929. (27) Xie, G.; Martinez, M. R.; Daniel, W. F.; Keith, A. N.; Ribelli, T. G.; Fantin, M.; Sheiko, S. S.; Matyjaszewski, K. The Benefits of Catalyzed Radical Termination: High-Yield Synthesis of Polyacrylate Molecular Bottlebrushes without Gelation. Macromolecules 2018, 51 (16), 6218−6225. (28) Pietrasik, J.; Hui, C. M.; Chaladaj, W.; Dong, H.; Choi, J.; Jurczak, J.; Bockstaller, M. R.; Matyjaszewski, K. Silica-Polymetha-

of structural parameters. This adds to the challenge for effective characterization by increasing (1) the relevant length and time scale, (2) distractive interference among different parameters, and (3) the required robustness of characterization against structural flaws. Although progress in synthesis, characterization, and molecular simulations has led to accurate descriptions of the molecular behavior by theoretical and experimental studies, the effect of individual structural parameters is not yet fully understood. A comprehensive structure−property relationship will be valuable for optimization of molecular design of bottlebrushes for various applications. Highly tunable properties, including topology and functionalities, allow molecular bottlebrushes to be attractive candidates for biological applications, especially as carrier systems for drugs or nucleic acids. The ability to tailor nanoparticle shapes and properties toward specific applications and penetration capabilities may lead to further development of nanomedicines for in vivo applications, where the performance might not be contingent on the surface chemistry of the drug carrier. Robust methods with minimum interference with the delicate cargo moieties such as drug molecules will be crucial for effective incorporation of various loadings. For delivery systems, new release mechanisms enabling more effective and facile control will be desirable in the near future.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sergei S. Sheiko: 0000-0003-3672-1611 Krzysztof Matyjaszewski: 0000-0003-1960-3402 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from NSF (DMR 1436219 and 1436201) is gratefully acknowledged. Special thanks to Dr. Kerry Bloom, UNC Chapel Hill, for useful discussions.

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REFERENCES

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Molecular Bottlebrushes as Novel Materials - Biomacromolecules

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