Available online at www.sciencedirect.com SCIENCE ODIRECT ELSEVIER Prog.Polym.Sci.30 (2005)691-724 www.elsevier.com/locate/ppolysc Toward 'smart'nano-objects by self-assembly of block copolymers in solution J.Rodriguez-Hernandez,F.Checot,Y.Gnanou,S.Lecommandoux* e女ce9置1 Received Je received in revised;acepted 14April Available online 12 July 2005 Abstract In recent vears.the synthesis and analysis of novel copolymer-based nanomaterials in solution have been extensively pursued.The interest in such structures lies in the fact that their dimensions.in the mesoscopic range(100nm).and factors such as composition r structure lead to materials with singular properties and applications.In this article.we report the most of th discussed.A review of the methods for stabilization of the macromolecular ggregates will be then given,including selected recent examples.Finally,we will concentrate on stabilized nano-particles.so-called'smart materials'that show responses to 2005 Elsevier Ltd.All rights reserved. Keyrd Self-assembly:Micelle:Nano-objects:Block copolymers;Cross-linking:Stabilization Stmulus:Smar Contents …6 liti Theoretical aspects 2.3 ntal aspects f micelles 232 meric micelles:experimental determination of the CMC 2.3.3. Characterization of micellar size and shape........................................699 ‘g
Toward ‘smart’ nano-objects by self-assembly of block copolymers in solution J. Rodrı´guez-Herna´ndez, F. Che´cot, Y. Gnanou, S. Lecommandoux* Laboratoire de Chimie des Polyme`res Organiques, CNRS-UMR5629, ENSCPB, University Bordeaux 1, 16, Avenue Pey Berland, 33607 Pessac-Cedex, France Received 22 June 2004; received in revised form 9 April 2005; accepted 14 April 2005 Available online 12 July 2005 Abstract In recent years, the synthesis and analysis of novel copolymer-based nanomaterials in solution have been extensively pursued. The interest in such structures lies in the fact that their dimensions, in the mesoscopic range (!100 nm), and factors such as composition or structure lead to materials with singular properties and applications. In this article, we report the most significant developments in the preparation and characterization of nano-objects, presenting an organized and detailed overview of the state of the art. First, the basic principles of self-assembly and micellization of block copolymers in dilute solution will be discussed. A review of the methods for stabilization of the macromolecular aggregates will be then given, including selected recent examples. Finally, we will concentrate on stabilized nano-particles, so-called ‘smart materials’ that show responses to environmental changes (pH, temperature, ionic-strength, among others), focusing on their applications principally in the biomedical field. q 2005 Elsevier Ltd. All rights reserved. Keywords: Self-assembly; Micelle; Nano-objects; Block copolymers; Cross-linking; Stabilization; Stimulus; Smart Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692 2. Self assembly—micellization of block copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695 2.1. Generalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695 2.2. Theoretical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696 2.3. Experimental aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698 2.3.1. Preparation of micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698 2.3.2. Formation of polymeric micelles: experimental determination of the CMC . . . . . . . . . . . . . . . . . 698 2.3.3. Characterization of micellar size and shape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Prog. Polym. Sci. 30 (2005) 691–724 www.elsevier.com/locate/ppolysci 0079-6700/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.progpolymsci.2005.04.002 * Corresponding author. Tel.: C33 54000 22 41; fax: C33 54000 84 87. E-mail address: s.lecommandoux@enscpb.fr (S. Lecommandoux)
692 J.Rodriguez-Herdndez et al.Prog.Polvm.Sci.30(2005)691-724 2.4 8 2.4.2 icles 702 24.3 er morp Stahil 。 31 Stabilization via radical crosslinking polymerization 70 Polymerization of block-copolymer end-groups inside the micelle (Situation A)........ 313 3.14. Stabilization in bulk prior to micellization 707 3好 3.4 Stimulus-responsive nano-assemblies 3 42 Response to pH 43 714 Smart nano-objects Summary and outlook 719 1.Introduction monomers)used by nature.The developments achieved in the last decade in several chain-addition Very complex and diverse structures are con polymerizations [1-3]are just refinements of structed by nature from a reduced choice of methodologies of polymer synthesis,allowing better building units (amino acids,lipids,etc.).Proteins, control over composition,molar mass,and overall for instance.are formed from a few amino acids architectures,but by no means do they address an and exhibit different secondary conformations,e.g. assembly of structures of comparable complexity to B-sheet,or coiled.Proteins with well proteins!A recent approach,which is the motivation tertiary ternary stru are y.cells d peptide segments. and time consuming synthe re prod in large vanet gome by natu dres defined ie.not ch lie mers that should carry ah function (see Fig.1). info rmation to direct the self-assembly Contrary to macromolecules produced and used Furthermore,self-assembly of macromolecules pro by nature.synthetic polymers can be obtained from vides an efficient and rapid pathway for the a very large variety of monomers.Polymerization of synthesis of objects from nanometer to micrometer these monomers affords different kinds of more or range that are difficult if not impossible to obtain by less complex homopolymers and copolymers;and conventional chemical reactions.Depending on the macromolecular engineering of these gives access to morphologies obtained (size,shape,periodicity,etc. unusual architectures and shapes.However,none of these self-assembled systems have already been these structures exhibit the sophistication anc applied or shown to be suitable for a number of meric materials [5],electronics [6].drug delivery
2.4. Examples of micellar systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 2.4.1. Spherical micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700 2.4.2. Vesicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702 2.4.3. Other morphologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703 3. Stabilization of self-assembled morphologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704 3.1. Stabilization via radical crosslinking polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 3.1.1. Polymerization of block-copolymer end-groups inside the micelle (Situation A) . . . . . . . . . . . . . 705 3.1.2. Shell-crosslinking (SCL) (Situation B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706 3.1.3. Core-crosslinking (CCL) (Situation C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706 3.1.4. Stabilization in bulk prior to micellization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707 3.2. Stabilization via chemical reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708 3.3. Stabilization via H-bonding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712 3.4. Stable objects via thermodynamic parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712 4. Stimulus-responsive nano-assemblies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 4.1. Response to pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 4.2. Response to temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714 4.3. Multiresponsive systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714 5. Smart nano-objects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715 6. Summary and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719 1. Introduction Very complex and diverse structures are constructed by nature from a reduced choice of building units (amino acids, lipids, etc.). Proteins, for instance, are formed from a few amino acids and exhibit different secondary conformations, e. g. a-helix, b-sheet, or coiled. Proteins with welldefined tertiary and quaternary structures are constituted of folded peptide segments. Still higher in complexity, cells are produced in large variety by nature to address specific functions in the organism. Cell functions are fulfilled through the concerted action of few perfectly defined proteins, i.e. not every cell possesses the same proteins and only the appropriate ones can perform a determined function (see Fig. 1). Contrary to macromolecules produced and used by nature, synthetic polymers can be obtained from a very large variety of monomers. Polymerization of these monomers affords different kinds of more or less complex homopolymers and copolymers; and macromolecular engineering of these gives access to unusual architectures and shapes. However, none of these structures exhibit the sophistication and complexity attained by those derived from the combination of a mere 20 amino acids (natural monomers) used by nature. The developments achieved in the last decade in several chain-addition polymerizations [1–3] are just refinements of methodologies of polymer synthesis, allowing better control over composition, molar mass, and overall architectures, but by no means do they address an assembly of structures of comparable complexity to proteins! A recent approach, which is the motivation of the present review, looks into the possibility of reducing tedious and time consuming synthetic steps by engineering oligomers or polymers of relatively small size that can self-organize through purely physical forces (noncovalent forces) simulating the folding of peptide segments in proteins. The key point in this approach lies in the chemical structure of the synthetic oligomers that should carry all the information to direct the self-assembly process. Furthermore, self-assembly of macromolecules provides an efficient and rapid pathway for the synthesis of objects from nanometer to micrometer range that are difficult if not impossible to obtain by conventional chemical reactions. Depending on the morphologies obtained (size, shape, periodicity, etc.) these self-assembled systems have already been applied or shown to be suitable for a number of applications in nanotechnology [4], reusable elastomeric materials [5], electronics [6], drug delivery 692 J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724
J.Rodriguez-Hemdndez et al./Prog.Polym.Sci.30(2005)691-724 693 Nomenclature PEO poly(ethylene oxide)als BIEE amoyloxyethyl CCL core crosslinking critical micelle concentration PI polyisoprene CMT critical micelle temperature PIC polyion complex core-shell-corona (micelles) PLA polylactide DLS dynamic light scattering PMH poly(1.1-dimethyl-2.2-dihexylsilene) ino ethyl methacrylate) LCST ayer by pory(propy ature e)-block-Polystyren M microdomain rene NCCM non-covalently connected micelles PSMA poly(solketal methacrylate) PAA poly(acrylic acid) PSS poly(styrene sulfonate) P polvbutadiene PBA poly(tert-butyl acrylate) PBLA PTHPMA poly(2-tetrahydroxypyranyl PBO poly( ethyl methacrylate) poly(capo poly( myl phe thyl me late methacrylate) PDEA SANS small-angle neutron scattering PDMAEMA poly(2-(dimethylamino) SAXS small-angle X-ray scattering ethyl methacrylate) SCK shell crosslinked knedels PDEAEMA poly(2-(diethylamino) shell crosslinking ethyl methacrylate) static light scattering poly(dimethylsiloxane) transmission electron microscopy polyethylen aggregation numbe 7paints[cosmetics,lubricants,and detergents driving force consists in 'long-range repulsive interactions'between incompatible domains.For Among the various aggregation processes,the example,polystyrene-b-polyisoprene diblocks self- assemble in toluene into spherical micelles with acor or graft copolyme As a cons of polyisoprene ind a polystyrene corona [11].In the ar stru sin th 0 stat rm a van ety of supe hydrop an repul ce in se of are due to the nd Plat the who underscored the ths.The of int s are defined such systems of two kinds of parallel for es.The first short-range attractive intera tions'and are the
[7], paints [8], cosmetics, lubricants, and detergents [9]. Among the various aggregation processes, the most extensively studied pertain to the self-assembly of block or graft copolymers. As a consequence of their molecular structure, block copolymers in the solid state form a variety of superlattices with sizes of a few nanometers, and nanoscale periodicities. The principles of such self-organization have been recently described by Fo¨rster and Platenberg [10], who underscored the simultaneous coexistence in such systems of two kinds of parallel forces. The first driving force consists in ‘long-range repulsive interactions’ between incompatible domains. For example, polystyrene-b-polyisoprene diblocks selfassemble in toluene into spherical micelles with a core of polyisoprene and a polystyrene corona [11]. In the case of amphiphilic diblock copolymers, containing a hydrophobic and a hydrophilic block, the repulsive interactions are due to the difference in solubility, and unlike block copolymers with both segments hydrophobic, the repulsion occurs for very short block lengths. The second class of interactions are defined as ‘short-range attractive interactions’ and are the Nomenclature AFM atomic force microscopy AMPS 2-acrylamido-2-methyl-1- propanesulfonate BIEE 1,2-bis (20 -iodoethoxyl) ethane CCL core crosslinking CMC critical micelle concentration CMT critical micelle temperature CSC core-shell-corona (micelles) DLS dynamic light scattering DSC differential scanning calorimetry HEC hydroxyethylcellulose LbL layer by layer (self-assembly) LCST lower critical solution temperature MD microdomain NCCM non-covalently connected micelles PAA poly(acrylic acid) PB polybutadiene PBLA poly(b-benzylaspartate) PBO poly(butylene oxide) PCEMA poly(2-cinnamoylethyl methacrylate) PCL poly(3-caprolactone) PCMMA poly(2-cinnamoylmethyl methacrylate) PDMA poly(2-(dimethylamino) methacrylate) PDEA poly(2-(diethylamino) methacrylate) PDMAEMA poly(2-(dimethylamino) ethyl methacrylate) PDEAEMA poly(2-(diethylamino) ethyl methacrylate) PDMS poly(dimethylsiloxane) PE polyethylene PEO poly(ethylene oxide) also referred to as poly(ethylene glycol) (PEG) PGA poly(L-glutamic acid) P(hCEMA) poly(2-hydrocinnamoyloxyethyl methacrylate) PI polyisoprene PIC polyion complex PLA polylactide PMHS poly(1,1-dimethyl-2,2-dihexylsilene) PMEMA poly(2-morpholino ethyl methacrylate) PMMA poly(methyl methacrylate) PPO poly(propylene oxide) PPQ-PS poly(phenylquinoline)-block-Polystyrene PS polystyrene PSMA poly(solketal methacrylate) PSS poly(styrene sulfonate) PtBA poly(tert-butyl acrylate) PTHPMA poly(2-tetrahydroxypyranyl methacrylate) P2VP, P4VP poly(2- or 4-vinylpyridine) PVPh poly(4-vinyl phenol) RG radius of gyration RH hydrodynamic radius SANS small-angle neutron scattering SAXS small-angle X-ray scattering SCK shell crosslinked knedels SCL shell crosslinking SLS static light scattering TEM transmission electron microscopy Z aggregation number J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724 693
694 J.Rodriguez-Herdndez et al.Prog.Polvm.Sci.30(2005)691-724 Complexity Diversity Fig.1.Schematic representation of diversity vs.complexity in natural and synthetic polymers. nd linking the two In this bution first discuss The exist this link tween the two CK ponsib opnase opn ation on a sele point of stability of the groups have recentl ly shown how to 0 stabilize such structures irreversibly.Mainly based on crosslinking reactions their strategies result in the macromolecular as gates Next we will focus on formation of stable aggregates or objects that offer those nano-materials.also called smart-materials.that new applications [12].In an attempt to gain in show response to given stimulus:pH.temperature. sophistication and find many more potential appli ionic strength.among others.The aim of this review is cations,micellar systems have been designed that are thus to give a detailed overview of recent advances in adaptable to their environment and able to respond in these promising helds.Finally,we will describe rare a controlled manner to external stimuli,i.e.synthesis recent examples of the most sophisticated systems of 'nano-objects that exhibit 'stimulus-responsive which can be referred to as smart nano-object properties is a topic that gathers momentum because These shape-persistent objects formed by sel remin that exhibited assembly and crosslinking of he gn of morphology ew proteins n ient tainers functionality. that can res nent and appear suit for a wic e range present review
consequence of a covalent bond linking the two blocks. The existence of this link between the two blocks is responsible for microphase separation, preventing the system from further separation on a macroscopic scale, as with polymer blends. Copolymers that self-organize in a selective solvent (for one of the two blocks) have found industrial applications, but one point of concern is the relatively poor stability of the aggregates formed. Several research groups have recently shown how to stabilize such structures irreversibly. Mainly based on crosslinking reactions, their strategies result in the formation of stable aggregates or objects that offer new applications [12]. In an attempt to gain in sophistication and find many more potential applications, micellar systems have been designed that are adaptable to their environment and able to respond in a controlled manner to external stimuli, i.e. synthesis of ‘nano-objects’ that exhibit ‘stimulus-responsive’ properties is a topic that gathers momentum, because their behavior is reminiscent of that exhibited by proteins. The design of synthetic structures that somehow approach proteins in their complexity, functionality, and performance is the basis of the present review. In this contribution, we will first discuss the micellization behavior of block copolymers and describe the most recent developments from both theoretical and experimental perspectives through selected examples. Our purpose is not to review this field exhaustively, but to recall the basic principles. In the second part, with a view to giving a complete account of the state of the art, we will report the most significant developments in the formation of nanoobjects, by self-assembly of diblock copolymers in dilute solution [13] followed by stabilization of the macromolecular aggregates. Next, we will focus on those nano-materials, also called smart-materials, that show response to given stimulus: pH, temperature, ionic strength, among others. The aim of this review is thus to give a detailed overview of recent advances in these promising fields. Finally, we will describe rare, recent examples of the most sophisticated systems, which can be referred to as ‘smart nano-objects’. These shape-persistent objects, formed by selfassembly and crosslinking of the morphology obtained, represent a new generation of robust and efficient containers that can respond to changes in their environment and appear suitable for a wide range of applications. Fig. 1. Schematic representation of diversity vs. complexity in natural and synthetic polymers. 694 J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724
J.Rodriguez-Hemdndez et al./Prog.Polym.Sci.30(2005)691-724 695 2.Self assembly-micellization of block copolymers,not only in aqueous media but also in copolymers organic solvents [15]. Block copolymers undergo two basic processes 2.1.Generalities in solvent media:micellization and gelation. Micellization occurs when the block copolymer is for one of the polym the chains ter ability to sell-assemble nd to organ thems in The micr e(a my pac the 'corona'of the micelle formed,whereas the etc.) insoluble part will be shielded from the solvent in nbly of block ers [13,14]have been the 'core'of the structure (see Fig.2).In contrast to ublished in th last fopolym micellization,gelation occurs from the semidilute to the high concentration regime of block copolymer One special class of block copolymers of particular relevance for this review are so-called amphiphilic and results from an arrangement of ed mi hlock conolymers According to the common defi nition,amphiphilic molecules (from Greek,amphi be- both and philic attraction)have affinities for two the relative length of the ble soluble block is different environments.The two blocks in the latter r than the insoluble one,the micelles (see Fig.3) case are not only incompatible.but they interact very formed consist of a small core and a very large differently with their environment due to their corona,and are thus called 'star-micelles'.By chemical nature and behave distinctively in solution contrast,micelles having a large insoluble segment (selective solvent).These differences can induce with a short soluble corona are referred to as'crew-cut microphase separation of amphiphilic block micelles'16. 33 米 米 33 米 米米米 米米米 Fig.2.lustration of (a)micellization at the critical micelle con ration and(b)gelation at high tration from diblock copolymen
2. Self assembly—micellization of block copolymers 2.1. Generalities Block copolymers consist of two- or morecovalently bonded blocks with different physical and chemical properties. Their ability to self-assemble both in solution and in bulk, and to generate a variety of microdomain (MD) morphologies (lamellae, hexagonally packed cylinders, body-centered cubic (bcc) spheres, gyroids, etc.) is well documented. Several books and review papers that address the selfassembly of block copolymers [13,14] have been published in the last few years. One special class of block copolymers of particular relevance for this review are so-called amphiphilic block copolymers. According to the common defi- nition, amphiphilic molecules (from Greek, amphi both and philic attraction) have affinities for two different environments. The two blocks in the latter case are not only incompatible, but they interact very differently with their environment due to their chemical nature and behave distinctively in solution (selective solvent). These differences can induce microphase separation of amphiphilic block copolymers, not only in aqueous media but also in organic solvents [15]. Block copolymers undergo two basic processes in solvent media: micellization and gelation. Micellization occurs when the block copolymer is dissolved in a large amount of a selective solvent for one of the blocks. Under these circumstances, the polymer chains tend to organize themselves in a variety of structures from micelles or vesicles to cylinders. The soluble block will be oriented towards the continuous solvent medium and become the ‘corona’ of the micelle formed, whereas the insoluble part will be shielded from the solvent in the ‘core’ of the structure (see Fig. 2). In contrast to micellization, gelation occurs from the semidilute to the high concentration regime of block copolymer solutions and results from an arrangement of ordered micelles. Two extremes of micellar structures can be distinguished for diblock copolymers, depending on the relative length of the blocks. If the soluble block is larger than the insoluble one, the micelles (see Fig. 3) formed consist of a small core and a very large corona, and are thus called ‘star-micelles’. By contrast, micelles having a large insoluble segment with a short soluble corona are referred to as ‘crew-cut micelles’ [16]. Fig. 2. Illustration of (a) micellization at the critical micelle concentration and (b) gelation at high concentration from diblock copolymers. J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724 695
696 J.Rodriguez-Herndndez et al.Prog.Polvm.Sci.30 (2005)691-724 n he sie of e aeet出 balance be by a varie ety of parameters system.These force refect:the of between the blocks forming the core (the block will be more or less stretched depending on the solvent).the (b) interaction between chains forming the corona.and the surface energy between the solvent and the core of the micelle.From a theoretical point of view.the ne aggregate structure requir 米尊 he mac cromolecules inside the ags gate forces combined with the interactions between different aggregates(inter-aggregate forces)determine the type of self-assembled structure formed at equilibrium.It is then essential to understand the fundamentals that dependence d sse the rela ati (b)crew-cut micelle. architecture.and the solvents used. 2.2.Theoretical aspects Theories at different levels of refinement have been developed to describe the behavior of block copoly. The micellization process in block mers in solution and its dependence on parameters lescribed above.The theories can be classified into (CMT and the ritical m concentration (CMC).If the CMT or the CMCa wo main groups.The belongs to the reached.self-assembly will not occur.and the block copolymer will behave in the solution as a unimer.On d by No the contrary,if micelle formation is triggered,the ch de cer micelles will be in thermodynamic equilibrium with like the ag ration number or the radius for crew unimers. ype micelles from the block length and interfacial In order to characterize a micellar system,several tension data [19).Daoud and Cotton [20]extended the have to co ding the ange of applicability of this approach to the case of th MT star-like micelles nd CM More detailed studies have out along th lines by Zhulina an 21 aa c Z and its morphology.These variables affect the hydrodynamic radius r..the radius of gvration R the ratio of ru to re (which depends on the micellar for star-like micelles or mor ntly Wu and Gac shape),the core radius Rc,and the thicknessLof the (231 and Shusharina 1241 have made theoretical corona.For more detailed information the reader is contributions to this field,but a description of such referred to general books on block copolymers [14. studies is beyond the scope of this review. 16].In the next few pages,we only outline this well The self-consistent mean field theory was first emphasizing the important They
2.2. Theoretical aspects The micellization process in block copolymers depends mainly on two parameters: the critical micelle temperature (CMT) and the critical micelle concentration (CMC). If the CMT or the CMC are not reached, self-assembly will not occur, and the block copolymer will behave in the solution as a unimer. On the contrary, if micelle formation is triggered, the micelles will be in thermodynamic equilibrium with unimers. In order to characterize a micellar system, several parameters have to be considered, including the equilibrium constant, the quality of the solvent, the previously mentioned CMT and CMC, the overall molar mass Mw of the micelle, its aggregation number Z and its morphology. These variables affect the hydrodynamic radius RH, the radius of gyration RG, the ratio of RH to RG, (which depends on the micellar shape), the core radius RC, and the thickness L of the corona. For more detailed information the reader is referred to general books on block copolymers [14, 16]. In the next few pages, we only outline this welldocumented literature, emphasizing the important concepts needed for this review. The shape and the size of the aggregates are controlled by a variety of parameters that affect the balance between three major forces acting over the system. These forces reflect: the extent of constraints between the blocks forming the core (the block will be more or less stretched depending on the solvent), the interaction between chains forming the corona, and the surface energy between the solvent and the core of the micelle. From a theoretical point of view, the description of the aggregate structure requires that the thermodynamic parameters of self-assembly be accounted for as well as the forces generated between the macromolecules inside the aggregates. These two factors (thermodynamics and intra-aggregate forces) combined with the interactions between different aggregates (inter-aggregate forces) determine the type of self-assembled structure formed at equilibrium. It is then essential to understand the fundamentals that govern the interdependence between morphology and size of the aggregates obtained by self-assembly, including decisive factors such as concentration, temperature, composition, block length, copolymer architecture, and the solvents used. Theories at different levels of refinement have been developed to describe the behavior of block copolymers in solution and its dependence on parameters described above. The theories can be classified into two main groups. The first group belongs to the ‘scaling theory’ of de Gennes [17]. The second one is based on the ‘self-consistent mean field theory’ developed by Noolandi and Hong [18]. In his theoretical approach, de Gennes predicted parameters like the aggregation number or the radius for crew-cut type micelles from the block length and interfacial tension data [19]. Daoud and Cotton [20] extended the range of applicability of this approach to the case of star-like micelles. More detailed studies have been carried out along these lines by Zhulina and Birshtein [21], who proposed a classification of micelles in four main categories based on the nature of the diblock copolymers. Other authors, including Halperin [22] for star-like micelles, or more recently Wu and Gao [23] and Shusharina [24], have made theoretical contributions to this field, but a description of such studies is beyond the scope of this review. The self-consistent mean field theory was first developed by Noolandi and Hong in 1982 [25]. They were able to predict the size of spherical micelles at Fig. 3. Schematic representation of two extreme morphologies of micelles depending on the relative block lengths: (a) star micelle, (b) crew-cut micelle. 696 J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724
J.Rodriguez-Hemdndezet al /Prog.Polym.Sci.3(005)691-724 697 equilibrium.and the variation of the aggregation copolymers.If we take the particular case of number as a function of the degree of polymerization. amphiphilic molecules in aqueous solution (Fig.4). Their model is based on the molecular characteristics the major forces governing the assembly into well of the polymer,its concentration in solution,and an defined structures are,on the one hand,the hydro estimation of the core/corona interfacial tension 1261. attraction between soluble hydrophobi The results of their model are in very good agreement the hy dophi on the othe on be with X-ray and neutron scattering data.Leibler et al. e o le [27]expanded the mean field theory to the case of with th eamphiphili the attractive forc ate the inte facial are per molecule will decrease and if repulsive force e parame predominate,a will increase.The competition cnergy con core and the between these two opposing forces.which strongly g depends on the geometry of both blocks,is mirrored in va ，ofhi s sume such as the ers (see evolution of the cMC with block co olymer structure (triblocks versus diblocks).as studied by Linse [26]. hobic chains.and the ngth le of or the temperature dependence of the hydrodynamic these chains.These parameters are interrelated by radius and aggregation number [28],the transition between spherical and cylindrical micellar systems p= 29,and the influence of polydispersity,which was explained in a similar fashion by Linse [26]and where p is the packing parameter (also called the Eisenberg [30]. shape factor)that determines the final structure. In addition to the above described treatments varying from small values (less than unity)for and rkers [31]developec spherical micelles to approximately unity for bicon- appro ncal nd the tinuous bilayers to greater than unity for inverted structures(Fig.5), More hinhilic this theory can also be applied to block app obtained from 、dif rer Interfacial (hydrophobic) fesctrhaRftinhaiagaroesaatcaanrtoandheadgopepukiootemectanmofmoeeamio
equilibrium, and the variation of the aggregation number as a function of the degree of polymerization. Their model is based on the molecular characteristics of the polymer, its concentration in solution, and an estimation of the core/corona interfacial tension [26]. The results of their model are in very good agreement with X-ray and neutron scattering data. Leibler et al. [27] expanded the mean field theory to the case of spherical micelles obtained from diblock copolymers in a low molar mass solvent. They found that the free energy of a micelle is a function of three parameters: the energy components attributable to the core and to the corona, and the interfacial energy. Accordingly, the size of the micelle, the aggregation number, and the fraction of copolymer chains forming micelles could be calculated. Further development of this theory allowed its use for other aspects such as the evolution of the CMC with block copolymer structure (triblocks versus diblocks), as studied by Linse [26], or the temperature dependence of the hydrodynamic radius and aggregation number [28], the transition between spherical and cylindrical micellar systems [29], and the influence of polydispersity, which was explained in a similar fashion by Linse [26] and Eisenberg [30]. In addition to the above described treatments, Israelachvili and coworkers [31] developed a very accessible approach using geometrical considerations that predicts the micellization phenomenon and the resultant morphologies. Initially developed to address the situation of amphiphilic molecules of low molar mass, this theory can also be applied to block copolymers. If we take the particular case of amphiphilic molecules in aqueous solution (Fig. 4), the major forces governing the assembly into well defined structures are, on the one hand, the hydrophobic attraction between insoluble hydrophobic moieties, and on the other, the repulsion between the hydrophilic head groups due to electrostatic or steric interactions that both force amphiphilic molecules to be in contact with the aqueous solution. If the attractive forces predominate, the interfacial area ao per molecule will decrease; and if repulsive forces predominate, ao will increase. The competition between these two opposing forces, which strongly depends on the geometry of both blocks, is mirrored in a variety of known morphologies. The hypothesis of Israelachvili assumes geometric properties to depend on three parameters (see Fig. 4): the optimal interface ao, the volume v occupied by the hydrophobic chains, and the maximum length lc of these chains. These parameters are interrelated by p Z n aolc where p is the packing parameter (also called the shape factor) that determines the final structure, varying from small values (less than unity) for spherical micelles to approximately unity for bicontinuous bilayers to greater than unity for inverted structures (Fig. 5). More recently, and by analogy with Israelachvili’s approach, Disher and Eisenberg [7a] tried to unify the experimental results obtained from different Fig. 4. Schematic illustration of the contributing forces (interfacial attraction and head-group repulsion) to the mechanism of micelle formation in solution. Adapted from Ref. [31]. J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724 697
698 J.Rodriguez-Herdndez et al.Prog.Polvm.Sci.30(2005)691-724 1_1 32 21 1 >1 amphiphilic block copolymers.Reasoning from a manipulation of certain solution parameters,e.g. series of examples drawn from the literature.they proposed a unifying rule for the 11 selective solvent.into y prepare the total mass 35+10%.as in the of ed from the solu lipids 321.An asymmetric molecule with a cylind- dialysis.The second method to prepare micelles rical shape andf<50%presumably reflects a certain consists simply of introducing the dry copolymer balance between its hydrated part and a disproportio powder into a selective solvent.The preference for nately large hydrophobic fraction.Finally,molecules one or another method depends on the system are expected to form micelles and those the presence of glassy are expected to self-assemble into (PS)induces the fon of very st 2.3.Experimental aspects this the be fav experimental means such as heating or ultrasonic In this paragraph we briefly describe the mos stirring will be required. copo n solut the and cha of micella ination of the critical scent probes is e micelle concentration,the micelle shape and the the mos dimensions,is given.Then,some illustrative aton of examples from the abundant literature are discussed. d veak radiation in nolar n ediaThe shift of the 2.3.1.Preparation of micelles excitation peak can be used to probe the transfer of Two main procedures can be followed for the pyrene molecules into an increasingly nonpolar preparation of micelles.The first approach is to micellar environment.The ratio of intensities of introduce the copolymer in a nonselective solvent,i.e. the excitation maxima at 339 and 333 nm can be a common solvent for both bl ocks.In some cases,the plotted as a functiono desired micellar structure can be obtained through the
amphiphilic block copolymers. Reasoning from a series of examples drawn from the literature, they proposed a unifying rule for the formation of polymersomes (polymer-based vesicles) in water: i.e. a ratio f of the mass of the hydrophilic part to the total mass 35G10%, as in the case of phospholipids [32]. An asymmetric molecule with a cylindrical shape and f!50% presumably reflects a certain balance between its hydrated part and a disproportionately large hydrophobic fraction. Finally, molecules with fO45% are expected to form micelles and those with f!25% are expected to self-assemble into inverted structures. 2.3. Experimental aspects In this paragraph we briefly describe the most relevant experimental studies on the self-assembly of block copolymers in solution. First, an introduction to the preparation and characterization of micellar structures, including the determination of the critical micelle concentration, the micelle shape and the dimensions, is given. Then, some illustrative examples from the abundant literature are discussed. 2.3.1. Preparation of micelles Two main procedures can be followed for the preparation of micelles. The first approach is to introduce the copolymer in a nonselective solvent, i.e. a common solvent for both blocks. In some cases, the desired micellar structure can be obtained through the manipulation of certain solution parameters, e.g. temperature or the use of a cosolvent. In other cases, the subsequent addition of a selective solvent, into a previously prepared solution from a common solvent, may be necessary. In a second step, the common solvent is removed from the solution, usually via dialysis. The second method to prepare micelles consists simply of introducing the dry copolymer powder into a selective solvent. The preference for one or another method depends on the system investigated. For example, the presence of glassy blocks such as polystyrene (PS) induces the formation of very stable micelles with almost no exchange between unimers and micelles (‘frozen micelles’).In this case the first method will be favored, and experimental means such as heating or ultrasonic stirring will be required. 2.3.2. Formation of polymeric micelles: experimental determination of the CMC The use of fluorescent probes is the most used method for the determination of the CMC [33]. Pyrene is the preferred fluorescent probe because of its strong fluorescence in nonpolar domains and its weak radiation in polar media. The shift of the excitation peak can be used to probe the transfer of pyrene molecules into an increasingly nonpolar micellar environment. The ratio of intensities of the excitation maxima at 339 and 333 nm can be plotted as a function of concentration; the crossover value represents the CMC as depicted in Fig. 6. Fig. 5. Dependence of final micelle structure on intrinsic molecular parameters: volume v of the hydrophobic group, and area a0 and length lc of the hydrophobic block. Adapted from Ref. [31]. 698 J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724
J.Rodriguez-Hemdndez et al./Prog.Polym.Sci.30(2005)691-724 699 Wsapene2ahee In addition.if scattering from the core and the coron of the micellar system is not very different,Rcan be of the CMC.This method is based on the tautomerism also calculated.Dynamic (or quasi-elastic)light of 1-phenyl-1,3-butadione between keto and enol scattering (DLS)[37]can be used to estimate the forms that possess different absorption maxima: hydrodynamic radius (RH)of a block copolymer 312 nm for the enolic form and 250 nm for the keto micellar system from the determination of its diffusion coeffic n polar solvents,wh addition,the re H ity all changes in the din n favor of the keto configur- ering me nods such as (SAXS) static light sc (SLS).d ns to obtain and inte scattering (SAXS) density of the extensively used for small surfactants,can in principle solvent and the solute Finally small-angle neutror be used for block copolymer micelles.However,they scattering (SANS)gives information not only about have found only limited application because of the the shape.but also the cross-section.Other non scattering methods such as transmission electron copy (TEM)and atomic force microscopy molar mass surfactants [14b] (AFM)provide images whereby size,shape 0 the e m can b of m ella meth vis on of typica u tion,siz clus ize and eation number De rs such as sh e.g. magne about the system under study can be determined.It is bevond the scope of this review to explain in detail all 2.4.Examples of micellar systems the techniques that can be used [35].but the most useful ones are worth a brief descrption in the contex After this brief overview on the strategies to of micelle characterization.The most important are prepare and characterize micellar systems,we turn to scattering methods.Static light scattering (SLS) ed into several type varying from sphercal or other les 339133 CMC ogC(mg/ml) Fig.6.Experimental dete m ation of CMC from fu Increasing intensity corresponds to
UV-absorption spectroscopy has also been reported as a powerful technique for the determination of the CMC. This method is based on the tautomerism of 1-phenyl-1,3-butadione between keto and enol forms that possess different absorption maxima: 312 nm for the enolic form and 250 nm for the keto form, the former appearing in nonpolar solvents like cyclohexane and the latter in polar solvents, where Hbonding is destabilized in favor of the keto configuration [34]. Other methods, mainly scattering methods such as static light scattering (SLS), dynamic light scattering (DLS) or small-angle X-ray scattering (SAXS), extensively used for small surfactants, can in principle be used for block copolymer micelles. However, they have found only limited application because of the very low signal intensity due to the much lower CMC’s in block copolymers in comparison with low molar mass surfactants [14b]. 2.3.3. Characterization of micellar size and shape Several techniques have been utilized for characterization of typical micelle parameters such as shape, size and aggregation number Z. Depending on the method of analysis employed, a variety of information about the system under study can be determined. It is beyond the scope of this review to explain in detail all the techniques that can be used [35], but the most useful ones are worth a brief description in the context of micelle characterization. The most important are the scattering methods. Static light scattering (SLS) [36] is a powerful technique to estimate average molar masses of self-assembled structures (and their CMC). In addition, if scattering from the core and the corona of the micellar system is not very different, RG can be also calculated. Dynamic (or quasi-elastic) light scattering (DLS) [37] can be used to estimate the hydrodynamic radius (RH) of a block copolymer micellar system from the determination of its diffusion coefficient; in addition, the sensitivity and versatility of DLS allow changes in the micelle equilibrium due to variations of temperature, pH, or other parameters to be monitored. Small-angle X-ray scattering (SAXS) has been employed in the analysis of micellar solutions to obtain overall and internal sizes from differences in electron density of the solvent and the solute. Finally, small-angle neutron scattering (SANS) gives information not only about the shape, but also the cross-section. Other nonscattering methods such as transmission electron microscopy (TEM) and atomic force microscopy (AFM) provide images whereby size, shape or internal structure of the micelles can be confirmed. Further methodologies include dilute solution capillary viscometry, membrane osmometry, ultracentrifugation, size exclusion chromatography, and typical spectroscopic methods (e.g. nuclear magnetic resonance) [10]. 2.4. Examples of micellar systems After this brief overview on the strategies to prepare and characterize micellar systems, we turn to illustrative examples of self-assemblies. Micelles can be classified into several types with morphologies varying from spherical to vesicular or other less Fig. 6. Experimental determination of CMC from fluorescence measurements with pyrene as a probe. Increasing intensity corresponds to encapsulation of pyrene in a hydrophobic environment and hence with micelle formation. From Ref. [33]. J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724 699
700 J.Rodriguez-Herdndez et al.Prog.Polvm.Sci.30(2005)691-724 2.4.1.Spherical micelle with the so-called core-shell the Since the ly stu ally few selected examples R。 se of our intere in ion mechar ism.In the las en chemistry attention has bee aid to focus on micelles formed from a mphiphilic block mainly motivated by their applications as emulsifiers copolymers in aqueous solution.As reported exten- foam stabilizers or detergents and in biomedicine (as sively by Riess 391.the structure of amphiphilic stabilizing agents in dermatological creams,lotions, block copolymers in aqueous media can be divided etc into three classes depending on the nature of the PEO is a hydrophilic.biocompatible.nontoxic hydrophilic block.There are uncharged blocks such as thermoresponsive polymer,which has been widely poly(ethylene oxide)(PEO) -also referred to as used as the solubilizing block to form the shell in poly(ethylene glycol)(PEG)-positively charged spherical micelles.Hydrophobic blocks include PS. blocks such as quaternized poly(2-or 4-vinylpyr- poly(lactic acid)and polyethers like polypropylene idine).polypeptides such as poly(L-lysine).or nega oxide(PPO)or poly(butylene oxide)(PBO).PEO-b- tively charged ones such as poly(acrylic acid)(PAA and triblo comme ally avallable as poly(styren ate (PSS).or poly(L-glutamic ock)copolymers and as ind quently the extens system Chou ane reviewed o). r drug stic micellization features of these bloc copolymers (a) (c) s obtained from block
common structures, such as inverse micelles, bilayers, or cylinders (Fig. 7). Recent reviews analyze in more detail the parameters that afford one or another structure [38]. Since the literature on this topic is abundant and diverse, our discussion is limited to a few selected examples. Because of our interest in biological applications and ‘green’ chemistry we focus on micelles formed from amphiphilic block copolymers in aqueous solution. As reported extensively by Riess [39], the structure of amphiphilic block copolymers in aqueous media can be divided into three classes depending on the nature of the hydrophilic block. There are uncharged blocks such as poly(ethylene oxide) (PEO)—also referred to as poly(ethylene glycol) (PEG)—positively charged blocks such as quaternized poly(2- or 4-vinylpyridine), polypeptides such as poly(L-lysine), or negatively charged ones such as poly(acrylic acid) (PAA), poly(styrene sulfonate) (PSS), or poly(L-glutamic acid) (PGA). As indicated subsequently the characteristics of these systems make them suitable for applications in pharmaceuticals, as vehicles for drug delivery or as separating agents, etc [40]. 2.4.1. Spherical micelles Spherical micelles with the so-called ‘core-shell’ structure have been extensively studied. Formation of spherical micelles via self-assembly of diblock copolymers is directed by an entropically driven association mechanism. In the last decade special attention has been paid to aqueous micellar systems, mainly motivated by their applications as emulsifiers, foam stabilizers or detergents, and in biomedicine (as stabilizing agents in dermatological creams, lotions, etc. PEO is a hydrophilic, biocompatible, nontoxic, thermoresponsive polymer, which has been widely used as the solubilizing block to form the shell in spherical micelles. Hydrophobic blocks include PS, poly(lactic acid) and polyethers like polypropylene oxide (PPO) or poly(butylene oxide) (PBO). PEO-bPPO or PEO-b-PBO are commercially available as diblock- (and triblock) copolymers and as a consequence, have been extensively investigated. Chou and Zhou [41] reviewed in detail the characteristic micellization features of these block copolymers. Fig. 7. Examples of structures obtained from block copolymers: (i) direct micelles, (ii) vesicles, and (iii) other morphologies: (iiia) inverse micelles, (iiib) lamellar structures, and (iiic) cylindrical or tubular micelles. 700 J. Rodrı´guez-Herna´ndez et al. / Prog. Polym. Sci. 30 (2005) 691–724
