Introduction to polymerisation-induced self assembly

Steve Armes

Sébastien Perrier

Per Zetterlund

The self-assembly of amphiphilic molecules (e.g., surfactants, lipids, amphiphilic block copolymers and so on) in solution has been widely investigated both experimentally and theoretically over the years, owing to the many applications of the resulting nano-objects. In the mid-1970s, Tanford¹ proposed the concept of the ‘hydrophobic effect’ to explain how surfactants assemble in solution in a given aggregate morphology, while Israelachvili, Mitchell and Ninham² introduced the molecular packing parameter to predict the size and shape of such aggregates based on the surfactant structure. The packing parameter is defined as p = v₀/al₀, where v₀ and l₀ are the volume and length of the surfactant tail, and a is the surface area of the hydrophobic core of the aggregate expressed per molecule in the aggregate: 0 ≤ v₀/al₀ ≤ 1/3 for spheres, 1/3 ≤ v₀/al₀ ≤ 1/2 for cylinders, 1/2 ≤ v₀/al₀ ≤ 1 for flexible lamellae or vesicles and v₀/al₀ > 1 for planar lamellae. This fundamental concept has proved to be useful in the fields of chemistry, physics, materials science and biology. However, the concept of the packing parameter was not applied to amphiphilic block copolymers until 1995, when Zhang and Eisenberg³ explained how varying the length of one block while fixing that of the second block confers control over the aggregate morphology for a series of polystyrene-poly(acrylic acid) block copolymers. With the subsequent development of reversible deactivation radical polymerisation (RDRP),^4,5 it was realised that block copolymer nanoparticles could be obtained by growing the hydrophobic chain of an amphiphilic block copolymer in situ using a process now known as polymerisation-induced self-assembly (PISA). If a sufficiently asymmetric diblock copolymer is targeted, the aggregate morphology evolves from spheres to cylinders to vesicles to bilayers via various ‘exotic’ intermediates during the growth of the insoluble second block, owing to the progressive increase in the packing parameter. Over the past decade or so, many PISA formulations have been developed based on either emulsion or dispersion polymerisation and potential applications for the resulting block copolymer nanoparticles have been suggested in medicine, biology, materials science, energy, coating, and many more.

We are immensely proud to present this themed issue of Polymer Chemistry on PISA. It contains exciting contributions from many of the leaders in this rapidly growing field.

The field of PISA has been well reviewed, but its growing impact has generated new areas of research, three of which are reviewed here.

Addressing the potential issue of stability when changing conditions, Zhang and co-workers provide a detailed review on the use of cross-linking chemistry to stabilize block copolymer nanoparticles obtained via RAFT-mediated PISA and suggest various potential applications (DOI: 10.1039/D0PY00627K).

Mercader and Pearce discuss the formation of vesicles via PISA, and propose an overview of the principles, syntheses and recent advances in the controlled formation of functional vesicle structures, indicating potential applications for these hollow capsules (DOI: 10.1039/D0PY00564A).

Magenau and Lequieu review the wider concept of using chemical reactions to induce self-assembly of copolymer chains and summarise the most recent developments in this expanding sub-field (DOI: 10.1039/D0PY00722F).

One of the strengths of PISA is its versatility for the rational design of well-defined functional nanoparticles.

For instance, Delaittre and co-workers show how core–shell nanoparticles with a boron-rich core can be obtained from RAFT-mediated PISA, using a methacrylic boronate ester monomer; the biocompatibility of these structures is demonstrated and their potential use as boron delivery agents for boron neutron capture therapy is discussed (DOI: 10.1039/D0PY00710B).

Save and co-workers use PISA to engineer core–shell particles of ca. 100 nm diameter with a hydrophilic copolymer shell composed of ammonium acrylate and a Rose Bengal functionalised acrylate, and a hydrophobic core comprising poly(n-butyl acrylate), poly(ethyl acrylate) or poly(n-butyl acrylate-co-ethyl acrylate). The resulting particles exhibit a mean quantum yield for the Rose Bengal label that is comparable to that of the free dye in water, thus demonstrating the catalytic photoactivity of these novel photosensitizer nanoparticles (DOI: 10.1039/D0PY01128B).

A range of functional hydrophilic monomers can be used to generate functional nanoparticles of various morphologies. For example, Bernard and co-workers combine RAFT polymerisation with ionic liquid monomers to generate all-poly(ionic liquid) block copolymer nanoparticles with morphologies ranging from spheres to worms to vesicles (DOI: 10.1039/D0PY00698J).

Fielding and co-workers report the synthesis of anionic, sulfonate-functional diblock copolymer nanoparticles via RAFT-mediated PISA. A series of sterically-stabilised nanoparticles of fixed copolymer composition with diameters ranging 20 to 200 nm were prepared by simply adjusting the relative proportions of alcohol and water in the continuous phase. These nanoparticles were characterised by aqueous electrophoresis and remained colloidally stable and highly anionic from pH 4 to pH 10 (DOI: 10.1039/C9PY01912J).

Mecerreyes and co-workers investigated MADIX-mediated PISA of styrene using poly(diallyldimethylammonium chloride) as a cationic macroRAFT agent. They obtained latexes made of di- or triblock copolymers, and the resulting block copolymers were mixed with an ionic liquid electrolyte to form self-standing ionogel membranes. The triblock copolymers showed better self-standing properties than the diblock equivalent systems, a property the authors attributed to the physical cross-linking of the two external polystyrene blocks. The ionogels based on triblock copolymers also showed superior ionic conductivity values to previous electrolytes using homopoly(ionic liquid) matrices (DOI: 10.1039/C9PY01552C).

PISA enables various architectures to mediate polymerisation. Thus, Rieger, Colombani and co-workers report that PISA of a hydrophobic diacetone acrylamide monomer (block A) mediated by a hydrophilic poly(N,N-dimethylacrylamide) macro-RAFT agent (block B) leads to a BAB triblock copolymer that self-assembles during PISA to form a network of bridged micelles. At higher conversions of the hydrophobic monomer, these bridged micelles reach a frozen non-ergodic state, with no further exchange of the copolymer chains between micelles. Kinetic studies and light scattering analysis show how control over the polymerisation conditions (stirring, macro-RAFT agent concentration, its ionization degree and the nature of the Z group on the RAFT agent) influences this system (DOI: 10.1039/D0PY00422G).

The outer shell of PISA-derived nanoparticles is not restricted to linear hydrophilic chains. For instance, Ferji and co-workers study the morphology of glyco-nanostructures formed via photo-induced RAFT polymerisation of 2-hydroxypropyl methacrylate mediated by a dextran precursor decorated with RAFT agents. Variation of the polymerisation temperature provides some control over the copolymer morphology, which ranges from a mixture of spheres and worm-like micelles at room temperature to spheres only at 60 °C (DOI: 10.1039/D0PY00407C).

The nanoparticle core can also be functionalised. Thus, Han, Shi, Zhang and co-workers synthesised star-[poly(N-isopropylacrylamide)-block-polystyrene] [s-PNIPAM-b-PS] via RAFT-mediated PISA and crosslinked the hydrophobic chains within the nanoparticle cores during polymerisation. The solution properties, thermoresponsive behaviour and interfacial properties of these star copolymers were investigated and found to differ significantly from those of their linear counter-parts (DOI: 10.1039/C9PY01656B).

Roth and co-workers report the post-polymerisation modification of poly[poly(ethylene glycol) methyl ether methacrylate]-poly(2,3,4,5,6-pentafluorobenzyl methacrylate) nano-objects prepared via RAFT dispersion polymerisation in ethanol. The cores of the resulting spheres or worms were modified using fifteen different thiols by thiol–para-fluoro substitution reactions. Using the appropriate thiol can (i) trigger order–disorder transitions from spheres to unimers, (ii) increase the nanoparticle size, or (iii) induce a sphere-to-worm transition (DOI: 10.1039/C9PY01585J).

Although now a widely employed system, detailed mechanistic insights in PISA systems are still required. Moad, Perrier, Zetterlund and co-workers explore the influence of the nature of the RAFT agent Z group in RAFT emulsion polymerisation. They demonstrate that more hydrophobic Z groups lead to faster and more efficient chain extensions, owing to subtle differences in the exit mechanism of the RAFT agent (DOI: 10.1039/D0PY01311K).

Boyer and co-workers also explore the fundamental mechanism of PISA by gradually injecting the core-forming monomer into the reaction mixture in the presence of a solvophilic monomer. This leads to the formation of gradient copolymers that self-assemble to form spheres, worms or vesicles, depending on the nature of the monomer pairs (acrylamides or methacrylates). This facile gradient copolymerisation approach enables PISA to be conducted in a single step with readily tuneable block length and copolymer composition (DOI: 10.1039/D0PY00889C).

Understanding the PISA mechanism can provide fine control over the copolymer morphology. For example, Tan and co-workers approach PISA from an unusual angle by using a RAFT agent deliberately designed to provide poor control over the polymerisation! This leads to a large fraction of polymer chains without any RAFT end-groups being generated during photoinitiated RAFT dispersion polymerization, which produces well-defined raspberry-like particles of controllable size at high solids. Moreover, this rather unorthodox approach offers new insights into the mechanism of photoinitiated RAFT-mediated dispersion polymerization (DOI: 10.1039/D0PY00678E).

Lansalot, D'Agosto and co-workers develop the PISA of amphiphilic diblock copolymers based on poly(ethylene glycol)-poly(vinyl acetate) via MADIX emulsion polymerization. In situ self-assembly produces colloidally stable nanoparticles, whose morphology evolves from spheres to vesicles to large compound vesicles as longer poly(vinyl acetate) blocks are targeted (DOI: 10.1039/D0PY00467G).

PISA is also well suited to a range of processes. Warren and co-workers used ultrafast RAFT polymerisation in continuous flow reactors to mediate PISA formulations based on RAFT dispersion polymerisation for the synthesis of diblock copolymer nanoparticles. This approach is well-suited to fast reactions since it allows efficient heat dissipation, making it attractive for industrial-scale production. Copolymer morphologies that can be accessed include spheres, worms and vesicles, with the latter structures being obtained at relatively high degrees of polymerisation (DP > 300) (DOI: 10.1039/D0PY00276C).

Although PISA has been mainly developed as an emulsion or dispersion in water or polar (alcoholic) media, it can also be conducted in non-polar media. Armes and co-workers explore this approach by examining the RAFT-mediated PISA of polar monomers in mineral oil. This study offers a rare example of the use of a commercially available polar monomer for PISA syntheses in non-polar media that enables access to morphologies ranging from spheres to worms to vesicles. The spheres are briefly evaluated as Pickering emulsifiers (DOI: 10.1039/D0PY00562B). In a related study, Derry, Armes and co-workers generate epoxy-functional diblock copolymer spheres, worms and vesicles at 30% w/w solids via RAFT-mediated PISA of glycidyl methacrylate in mineral oil at 70 °C. Interestingly, oscillatory rheology studies of the worm gel showed that degelation could be triggered by heating up to 100 °C, which induces a worm-to-vesicle transition (DOI: 10.1039/D0PY00380H).

Beyond the use of traditional vinyl monomers, the versatility of PISA enables the use of more complex hydrophobic monomers that can profoundly influence the copolymer morphology. Semsarilar and co-workers add a new dimension to PISA by combining block copolymer self-assembly with peptide self-assembly by the aqueous solution polymerisation of hydrophobic GFF and FGD peptide monomers using a suitable macro-RAFT agent. This PISA formulation leads to the formation of fibres for FGD, and, depending on the copolymer composition and solvent, a range of morphologies for GFF (including fibre-like, flake-like, leaf-like and vesicles). Clearly, judicious combination of PISA and the peptide self-assembling core offers excellent control over the final morphology (DOI: 10.1039/D0PY00793E).

In related work, Dove, O'Reilly and co-workers explore nickel-catalysed coordination polymerisation-induced self-assembly (NiCCo-PISA) to produce poly(aryl isocyanide) amphiphilic diblock copolymers, obtaining nanoparticles with helical hydrophobic cores based on activated ester groups. These groups are subsequently modified using amines and the potential use of such systems as scaffolds for circularly-polarised luminescence, enantioselective chemistry or chiral separation is discussed (DOI: 10.1039/D0PY00791A).

An interesting take on RAFT-mediated PISA is to develop a statistical copolymer as a RAFT agent to stabilise inorganic particles. Unlike diblock copolymers, such statistical copolymers do not self-assemble in solution and polymerisation only occurs at the particle surface, thus promoting efficient encapsulation and limiting the number of ‘empty’ polymer particles. This elegant concept was first developed by Hawkett and co-workers, who in this issue use this approach to produce polymer-coated graphene oxide particles. They encapsulate graphene oxide via RAFT emulsion polymerisation using a macro-RAFT agent based on a statistical copolymer of n-butyl acrylate, acrylic acid and sodium 4-styrenesulfonate that adsorbs at the graphene oxide surface. The resulting particles were shown to be an efficient delivery vector for the anti-cancer drug doxorubicin (DOI: 10.1039/D0PY00769B).

Dos Santos, Bourgeat-Lami and co-workers synthesise LAPONITE®-based composite latexes via RAFT-mediated PISA using a macro-RAFT agent based on a statistical copolymer of acrylic acid, poly(ethylene glycol) methyl ether acrylate and n-butyl acrylate. The strong affinity of the macro-RAFT agent for the surface of the clay particles leads to their efficient encapsulation and the formation of colloidally stable nanocomposite particles, with good control over their morphology (DOI: 10.1039/D0PY00720J).

To date, RAFT polymerisation has been by far the most popular technique for PISA syntheses, but new polymerisation chemistries are now being examined. For example, van Herk, Goto and co-workers use NaI-catalyzed living radical polymerization to prepare biocompatible nanoparticles via PISA. Either spheres or vesicles could be obtained depending on the mean degree of polymerization of the hydrophilic (poly(polyethylene glycol methyl ether methacrylate)) and hydrophobic (poly(methyl methacrylate)) blocks. Both types of nano-objects can be crosslinked by employing ethylene glycol dimethacrylate as a hydrophobic comonomer during polymerization and the encapsulation ability of the vesicles was demonstrated using a hydrophilic dye, rhodamine B (DOI: 10.1039/D0PY00465K).

Last, but by no means least, Gao, Yuan and co-workers used copper-catalyzed azide–alkyne cycloaddition (CuAAC) click PISA to prepare a linear-dendritic copolymer based on a tris-triazoleamine-functionalized poly(ethylene glycol) (PEG) initiator and a trifunctional AB₂ bearing one alkynyl group and two azido groups as a monomer. The CuAAC PISA was undertaken in methanol, water, and a methanol/water mixture at 15% solids. The dendritic blocks self-assembled to form spherical micelles and large compound micelles, which were characterized by dynamic light scattering and transmission electron microscopy (DOI: 10.1039/C9PY01636H).

From the diverse contributions to this themed issue, it is clear that PISA remains a dynamic and fertile topic in polymer chemistry as exemplified by research teams all around the world. The range of polymerisation techniques used is increasing, and alongside fundamental mechanistic studies, the applications of PISA-derived nano-objects are now being developed. There is no doubt that PISA will continue to grow as a topic of research and expand its impact from polymer chemistry to (bio)materials science.

References

1. C. Tanford, The Hydrophobic Effect, Wiley-Interscience, New York, 1973.
2. J. N. Israelachvili, D. J. Mitchell and B. W. Ninham, J. Chem. Soc., Faraday Trans. 2, 1976, 72, 1525–1568.
3. L. Zhang and A. Eisenberg, Science, 1995, 268, 1728–1731.
4. G. Delaittre, C. Dire, J. Rieger, J. L. Putaux and B. Charleux, Chem. Commun., 2009, 2887–2889.
5. C. J. Ferguson, R. J. Hughes, B. T. T. Pham, B. S. Hawkett, R. G. Gilbert, A. K. Serelis and C. H. Such, Macromolecules, 2002, 35, 9243–9245.

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