Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities

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Prog. Polym. Sci. 32 (2007) 1275–1343 www.elsevier.com/locate/ppolysci

Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities Ivaylo Dimitrova, Barbara Trzebickab, Axel H.E. Mu¨llerc, Andrzej Dworakb,1, Christo B. Tsvetanova, a

b

Institute of Polymers, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria Centre of Polymer and Carbon Materials, Polish Academy of Sciences, PL-41-819 Zabrze, Poland c University of Bayreuth, Macromolecular Chemistry II, NW II, D-95440 Bayreuth, Germany Received 23 November 2006; received in revised form 22 May 2007; accepted 13 July 2007 Available online 2 August 2007

Abstract The precise control of the formation of stimuli-sensitive sequences (block or graft) as part of copolymer architectures is fascinating because of the remarkable phase behavior of their aqueous solutions. One of the most interesting solution properties of amphiphilic water-soluble copolymers is their ability to self-assemble into micelles, lamellar aggregate, Abbreviations: AAc, acrylic acid; AAM, acrylamide; AMPSA, 2-acrylamido-2-methyl-propane sulfonic acid; ATRP, atom transfer radical polymerization; AzoVE, 4-[2-vinyloxy)ethoxy]azobenzene; BIS, N, N0 -methylenebisacrylamide; BMA, butyl methacrylate; cac, critical aggregation concentration; CDs, cyclodextrins; CIPAAM, 2-carboxyisopropylacrylamide; cmc, critical micelle concenration; cmt, critical micelle temperature; CP, cloud point; DAlAAM, N, N-dialkyl-substituted amide; DEAEMA, 2-(diethylamino)ethyl methacrylate; DLS, dynamic light scattering; DMAAPS, N, N0 -dimethyl (acrylamido propyl ammonium propane sulfonate; DMAEMA, 2(dimethylamino) ethyl methacrylate; DMAPM, N-[3-(dimethylamino)propyl]methacryl amide; DMAPS, 3-dimethyl-(methacryloyloxyethyl) ammonium propane sulfonate; DMC, double metal cyanide; DSC, differential scanning calorimetry; DTBA, dithiobenzoate; EEGE, ethoxyethyl glycidyl ether; ELPs, elastin-like polypeptides; EOEOVE, 2-(2-ethoxy)ethoxyethyl vinyl ether; HMPA, hydrophobically modified poly(sodium acrylate); HMW, high molecular weight; HMWSP, hydrophobically modified water-soluble polymers; HPMAM, poly(N-(2-hydroxypropyl) methacrylamide; HAS, human serum albumin; IPN, interpenetrating network; LCST, lower critical solution temperature; LS, light scattering; MAc, maleic acid; MALEU, N-methacryloyl-L-leucine; MC, merocyanine; Me6TREN, Tris(2-dimethylaminoethyl) amine; MEMA, 2-(N-morpholino)ethyl methacrylate; MOAB, trans-methacryloyloxyazobenzene; MW, molecular weight; MWD, molecular weight distribution; NASI, N-acryloylsuccinimide; NIPAM, N-isopropylacrylamide; NVA , N-vinylacetamide; P2VP, poly(2-vinylpyridine); PAAc, poly(acrylic acid); PAAM, polyacrylamide; PAH, poly(allylamine), hydrochloride; PDEAAM, poly(N, N-diethylacrylamide); PDEAEMA, poly(2-(diethylamino)ethyl methacrylate); PEEGE, poly(ethoxyethyl glycidyl ether); PEO, poly(oxyethylene); PEPyM, poly(N-ethylpyrrolidine methacrylate); PG, polyglycidol; PIPOZ, poly(2isopropyl-2-oxazoline); PL, poly(e-lysine); PLA, poly(lactic acid); PLGA, poly(lactic acid-co-glycolic acid); PMAAc, poly(methacrylic acid); PMPC, poly(2-methacryloyloxyethyl phosphorylcholine); PNIPAM, poly(N-isopropylacrylamide); PNIPMAM, poly(N-isopropylmethacrylamide); PO, propylene oxide; POSS; polyhedral oligomeric silsesquioxane; PPO; poly(propylene oxide); PSBMA; poly(sulfobetaine methacrylate); PSPP, poly(3-[N-(3-methacrylamido-propyl)-N, N-dimethyl]-ammonio propionate sulfonate); PT, phase transition; PVCL, poly(N-vinylcaprolactam); PVME, poly(vinyl methyl ether); RAFT, reversible addition-fragmentation chain-transfer polymerization; SAv, streptavidin; SEC, size exclusion chromatography; SP, spiropyran; TCP, cloud point temperature; TPA, trimethylsilylpropionic acid; UCST, upper critical solution temperature; VA, vinyl acetate; WSP, water-soluble polymers; Y(OTf)3, yttrium trifluoromethanesulfonate Corresponding author. Tel.: +359 29792261; fax: +359 28700309. E-mail addresses: [email protected] (A. Dworak), [email protected] (C.B. Tsvetanov). 1 Also for correspondence. Tel.: +483 22380780; fax: +483 22312831. 0079-6700/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.progpolymsci.2007.07.001

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vesicles and hydrogels. In this review we discuss the combinations of thermosensitive properties with other types of sensitivity: i.e. to pH, light, magnetic field, solvent quality, etc., and their effects on the reversible self-assembly in aqueous copolymer solutions or on the hydrogel organization. For this purpose we describe thermosensitive polymers as well as methods for their controlled synthesis. The development of multi-functional building blocks imprinted into one macromolecule will help us to obtain controllable morphologies at the nanometer scale. Obviously, the multi-sensitive copolymer systems represent an essential part of supramolecular polymer chemistry where the environment can have a large effect on the degree of interaction between the individual components in the material. r 2007 Elsevier Ltd. All rights reserved. Keywords: Thermosensitivity; Combinations of stimuli; Water-soluble copolymers; Hydrogels; Controlled synthesis; Self-assembly

Contents 1. 2. 3.

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8. 9.

10.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1277 Thermosensitive polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1278 Controlled synthesis of thermosensitive polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282 3.1. Synthesis of poly(N-isopropyl acrylamide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282 3.1.1. Reversible addition-fragmentation chain transfer polymerization (RAFT) . . . . . . . . . . . . . . . 1283 3.1.2. Atom transfer radical polymerization (ATRP). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1283 3.1.3. Cerium (IV) redox-initiated polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1285 3.2. Synthesis of poly(N,N0 -diethylacrylamide) (PDEAAM). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1286 3.3. Synthesis of poly(propylene oxide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1286 3.4. Polymerization of vinyl ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1287 3.5. Polymerization of 2-oxazolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1288 Doubly thermoresponsive polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1289 4.1. Block copolymers with blocks displaying different LCSTs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1290 4.2. Random copolymers with tunable thermosensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1291 4.3. Multi-responsive core–shell microgels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1293 Combination of thermoresponsive and zwitterionic properties: block copolymers with blocks displaying LCST and upper critical solution temperature (UCST) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1294 5.1. Intrachain interchain interactions and formation of polymeric nanoparticles of different nature . . . . . 1295 5.2. Thermoreversible hydrogels based on PNIPAM and zwitterionic comonomer. . . . . . . . . . . . . . . . . . 1299 Combination of thermo- and pH-responsive properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301 6.1. Random copolymers and hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301 6.2. Block- and graft-copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309 6.3. Interpolymer complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316 6.4. pH- and thermostimuli in homopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 Combination of magnetic field and thermoresponsive properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 7.1. Protein and nucleic acid concentration and purification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317 7.2. Immobilized-enzyme reaction control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1318 7.3. Triggered drug release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319 7.4. Chemo-mechanical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1320 Thermo- and light-sensitive polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1321 Solvent-sensitive PEO conjugates of thermoresponsive polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324 9.1. Block copolymers comprising thermoresponsive- and hydrophilic-PEO blocks . . . . . . . . . . . . . . . . . 1324 9.2. Graft copolymers comprising thermoresponsive- and hydrophilic PEO blocks . . . . . . . . . . . . . . . . . 1327 9.3. Hydrogels comprising thermoresponsive- and hydrophilic PEO blocks. . . . . . . . . . . . . . . . . . . . . . . 1332 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1333 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1334

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1. Introduction Macromolecules soluble in aqueous media represent a diverse class of polymers ranging from biopolymers that direct life processes to synthetic systems of enormous commercial utility. Watersoluble polymers (WSPs) have acquired increasing importance due to the demand for water-based instead of the traditional solvent-based technological processes. Water, being easily available and environmentally friendly, will undoubtedly become the solvent of choice for a wide range of products. For most of the 20th century, the synthesis of high molecular weight (HMW) materials relied mainly on the formation of covalent bonds between individual monomer units. Synthetic macromolecules, which could self-assemble entirely from smaller subunits owing to a series of secondary binding forces, were an exception rather than the rule. New materials based on reversible supramolecular organization have become increasingly important in recent decades. These systems may offer a number of advantages, including lower processing costs due to their reversible properties, which also applies to reversibly crosslinked networks and gels. The spontaneous formation of self-assembled structures so beautifully exemplified by the living cell is the outcome of a delicate balance between a limited number of attractive and repulsive forces, each one with its characteristic strength. For the purpose of self-assembly the attractive interactions do not have to be covalent, i.e. ‘‘permanent’’. Macromolecular self-associations are driven by noncovalent weak and complementary interactions: Coulombic, hydrogen bonding, van der Waals, exchange, repulsive, and hydrophobic interactions. Water-soluble macromolecules carrying attractive groups form an interesting and important class of the polymeric systems, called ‘‘associating polymers’’. This class includes polymers of various architectures possessing charged groups (ionomers, polyelectrolytes and polyampholytes) or groups with hydrogen bonding ability. The associations among the attractive groups lead to the formation of physical bonds. The difference between chemical covalent bonds and physical bonds is that the latter are reversible. A single noncovalent interaction is relatively weak (45 kcal/mole) as compared with the covalent bond (90–100 kcal/mole); however, when combined, noncovalent interactions can be quite strong. There has to be a substantial number of noncovalent interactions in order for them to be

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effective in holding the structures together. An additional requirement is that the surface topography should enable the areas of the interacting forces to align closely. Two types of physical bonds can be defined: weak physical bonds, which form and break on an experimental time scale and strong physical bonds, which are stable during the time of the experiment but can be disrupted by changing the experimental conditions. Some polymers bearing attractive groups are called ‘‘smart’’ or ‘‘stimuli-sensitive’’ since they show critical phenomena as, for example, phase transitions (PTs) that can be induced by external stimuli: changes in temperature, pH, solvent, ionic composition, electric or magnetic fields, light, etc. The common feature of all these associating systems is that their macroscopic properties (viscoelasticity, transparency, conductivity, etc.) can be controlled at the microscopic level by modifying the structure and organization of the polymer chains. Their considerable importance lies in their numerous applications as rheology modifiers, adhesives, adsorbents, coatings, biomedical implants, flocculants for waste-water treatment, surfactants and stabilizers for heterogeneous polymerization, as well as uses in sewage purification, concentration and extraction of metals, reduction of hydrodynamic resistance, as structure formers in soils, for enhanced oil recovery, superabsorbency, and as suspending agents for pharmaceutical delivery systems, sensors and actuators. A simplified design of the stimuli-responsive association concept in aqueous polymer solution is shown in Fig. 1. Modern synthetic chemistry enables the formation of macromolecules of almost arbitrary architectural complexity, incorporating building blocks of different chemical nature in well controlled positions. In this way every single macromolecule may be able to self-organize in aqueous medium, thus forming predetermined but highly diversified structures owing to the multiple types of interaction. The basic challenge is to design model block and graft copolymer systems that will allow us to measure and control the number and the strength (lifetime) of multi-stimuli-responsive associations (reversible bonds). The interesting physical phenomena exhibited by aqueous solutions of doubly or multi-responsive polymers and their industrial and medical importance make it worth confronting the experimental challenges, with the expectation that polymer scientists will achieve a number of major scientific breakthroughs in the near future.

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Fig. 1. Stimuli-responsive association concept in aqueous solution.

Herein, we review the thermoresponsive properties of a single macromolecule or network, which are combined with other types of sensitivity: pH, action of force field, light, solvent quality, etc. into one macromolecule. By applying two or more signals simultaneously or consecutively, different types of response in the multi-responsive polymer systems are being induced, which result in a variety of supramolecular structures. Real progress in our understanding of the fundamental aspects of behavior of complex multisensitive macromolecular systems and the rational design of new functional materials is possible only by applying a multi-disciplinary approach bringing together chemistry and physics, experiment and theory. By combining well controlled polymerization methods with the most modern physicochemical methods, leading research laboratories are trying to synthesize assemblies of amphiphilic copolymers in aqueous environment that will be capable of self-organization on macro- and supermolecular levels, resembling the assemblies of biopolymers invented by nature. 2. Thermosensitive polymers In this review we focus on temperature-responsive polymers, which are also sensitive to another stimulus. Therefore we start with a short survey of the most important thermosensitive polymers. Most synthetic macromolecules become more soluble when heated, but some WSPs separate from

solution upon heating. This unusual property, referred to as inverse temperature-dependent solubility, is characteristic of polymers which dissolve when cooled and phase separate when heated above the PT temperature, known as a lower critical solution temperature (LCST). This temperature corresponds to the region in the phase diagram where the enthalpic contribution of the water hydrogen bonded to the polymer chain becomes less than the entropic gain of the system as a whole. The LCST is largely dependent on the hydrogenbonding capabilities of the constituent monomer units. The simplest explanation is that the dissolution enthalpy DH due to the hydrogen bonding of the basic sites on the polymer with the solvent favors dissolution. In contrast, the entropic organization DS of the solvent required to achieve this hydrogen bonding is unfavorable. Since the free energy of dissolution is equal to DHT DS, it can change from negative (favorable) to positive (unfavorable) as the temperature increases. Thus, polymers are known to exhibit LCST behavior in strongly interacting solvents such as water. What makes synthetic polymers somewhat more versatile than their biological counterparts in this respect is that the synthetic polymers often redissolve when cooled (proteins usually do not ‘‘renature’’). Moreover the temperature, at which the phase separation of a synthetic polymer from solution occurs, can be changed by altering the structure of the polymer. Thermosensitive polymers undergo reversible conformational or phase changes in response to negligible variations of temperature. There is a rather delicate free-energy balance involving hydrophobic, hydrophilic, and H-bridge-mediated interactions, which determines the solubility of the LCST polymers in water. The key parameter defining the ‘‘responsive’’ or the ‘‘smart’’ behavior of the polymers is a nonlinear response to an external signal. As in nature, the bulk response of the thermosensitive polymer is usually due to multiple cooperative interactions such as loss of H-binding, which, although individually weak, ultimately evokes a large structural change in the material when summed up over the whole polymer. The quality of the response (abrupt PT, high sensitivity) can be demonstrated by the cloud point temperature (TCP) and by calorimetric measurements. The coupling of microcalorimetry with TCP measurements constitutes a successful approach to the explanation of the LCST phenomena in aqueous solutions of thermosensitive polymers (Fig. 2).

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It is important to study the cyclic turbidity curves, i.e. the PT by a controlled increase of the temperature followed by redissolution by controlled cooling. As expected, most of the turbidity curves show hysteresis. As seen in Fig. 3, the PT can be reversible (a), with hysteresis (b), and with a gradual rather than an abrupt change (c). An example of polymer exhibiting behavior (a), where the heating and cooling cycles are roughly comparable, is the copolymer poly(2-(20 -methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol) methacrylate) [2]. Poly(N-isopropylacrylamide) (PNIPAM) exhibits a very sharp transition when heated, but a broad hysteresis can be observed in the cooling (behavior (b)) [3]. The shape of thermograms (Fig. 4) is also very informative. It is preferable to work with thermosensitive homopolymers or sequences that display high enthalpy of PT and narrow almost symmetric endotherms (a) with a very short time of PT. These requirements are especially important for the formation of well defined monodisperse polymer aggregates in the course of the PT. Below the

critical temperature the coiled structure is favored as this allows maximum interaction between the polymer and the water. In systems where strong hydrogen bonding is possible, such interactions lower the free energy of dissolution considerably. At higher temperature, the hydrogen-bonding effect weakens; concomitantly the entropy-controlled ‘‘hydrophobic effect,’’ the tendency of the system to minimize the contact between water and hydrophobic surfaces increases; hence, the transition from coiled to a denser globule structure. An endothermic transition enthalpy corresponding to the loss of roughly one hydrogen bond per repeat unit has been determined for certain thermosensitive polymers, as shown in Table 1. Polymers bearing amide groups form the largest group of thermosensitive polymers. Elastin-like polypeptides (ELPs) are biopolymers comprised of elastin-based repeating motifs such as (Val-Pro-GlyXaa-Gly), where the ‘‘guest residue’’, Xaa, can be any combination of natural amino acids except Pro. These polymers are biocompatible and display temperature-dependent phase behavior in aqueous

Fig. 2. TCP curve and microcalorimetric endotherm of PNIPAM. Reproduced from Schild and Tirrell [1] by permission of the American Chemical Society, USA.

Fig. 4. Different thermogram shapes for LCST polymers.

Fig. 3. Cyclic turbidity curves depending on polymer properties and architecture.

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Table 1 Thermodynamic properties of some LCST polymers Polymer

Mn (g mol1)

Mw/Mn

TCP (1C)

DH (kcal mol1)

PNIPAM

5400 11 000 13 000 160 000 300 000

2.3 6.9 1.16 2.8

34.3 34.2 32.6 32.2 31.8

0.3 1.4 0.8 1.5 1.4

PDEAAM

2300 4200 4000 20 400

1.17 1.13 1.12 3.13

33.2 40.8 39 33

0.01 0.62

PVCL

30 000 330 000

1.4 1.6

35.7 31.7

1.0 1.05

[11] [11]

PIOZ

1900 2400 4600 5650

1.05 1.04 1.03 1.03

72.5 62.8 51.3 48.1

0.36 0.72 0.9 1.35

[5] [5] [5] [5]

3.0

35

PVME

20 500

Remarks

Ref. [4] [4] [5] [4] [6]

Heterotactic Isotactic Isotactic Heterotactic

0.7

TCP depends on concentration. Endotherm composed of two peaks

[7] [8] [9] [10]

[12]

PNIPAM, poly(N-isopropylacrylamide); PDEAAM, poly(N,N,-diethylacrylamide). PVCL, poly(N-vinylcaprolactam); PIOZ, poly(2-isopropyl-2-oxazoline). PVME, poly(vinyl methyl ether).

solution, which makes them attractive for drug delivery and tissue engineering [13]. The LCST behavior of ELPs can be varied with the amino acid sequences, MW and concentration [14] or by introducing functional groups into the protein backbone [15]. By attaching either acidic or basic amino acids in the fourth position as a ‘‘guest residue’’, the ELPs become both pH- and temperature-dependent [16]. Recent advances in controlled radical polymerization techniques allow the synthesis of hybrid triblock copolymers comprising a central synthetic block of poly(oxyethylene) (PEO) and elastin-based side-chain outer blocks with pH and temperature sensitivity [17]. The most studied synthetic responsive polymer is PNIPAM, which undergoes a sharp coil-to-globule transition in water at 32 1C, changing from a hydrophilic state below this temperature to a hydrophobic state above it. PNIPAM can be considered as a simple but relevant protein model. From the chemical point of view, PNIPAM is homologous with poly(leucine) (Fig. 5). However, an important difference between PNIPAM and poly(leucine) is that PNIPAM has a nonpolar backbone and contains amide groups in its side chain while poly(leucine) includes peptide groups in its backbone and has entirely nonpolar side chains.

Fig. 5. Schematic structures of PNIPAM and poly(leucine).

The PT of PNIPAM is shown schematically in Fig. 6. As already discussed, the origin of the ‘‘smart’’ behavior, arises from the entropic gain as water molecules associated with the side chain isopropyl moieties are released into the bulk aqueous phase as the temperature increases above a critical point. The thermoresponsive properties of PNIPAM are presented in the excellent reviews by Schild [18], Pelton [19], and Gil and Hudson [20].The thermodynamic properties of aqueous PNIPAM solutions have been thoroughly investigated in order to model cold denaturation. The transition from coil to a collapsed structure by increasing the temperature resembles the transition of a protein from unfolded to folded structures at its cold renaturation temperature [21]. As already mentioned, research in the

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Fig. 6. Illustration of temperature induced PNIPAM phase transition.

field of thermosensitive polymers has been mostly focused on PNIPAM, but some other N-substituted poly(acrylamides) exhibit similar behavior in aqueous solution. Homopolymers of N,N0 -diethylacrylamide, N-cyclopropylacrylamide, and N-ethylacrylamide have been reported to display LCSTs in the 30–80 1C range [22]. It is to be expected that N,N0 -dialkyl-substituted amides are more lipophilic than N-monoalkyl substituted PNIPAM. For aqueous PDEAAM the enthalpy of separation was in the range of 0.6–0.7 kcal mol1 [10], and even much lower (see Table 1). This value is lower than the 1.1–1.5 kcal mol1 for PNIPAM, reported by Fujishige et al. [23] and by Schild and Tirrell [4]. Considering that the amide groups of PNIPAM can be proton donors as well as proton acceptors, while the amide groups of PDEAAM can be only proton acceptors, this result is quite reasonable. The more ordered structure of isotactic PDEAAM prepared by anionic polymerization, shows a significantly higher TCP than the polymers obtained by radical polymerization (Table 1). Poly(N-vinylcaprolactam) is a very important nonionic WSP, which undergoes heat-induced phase separation in water. It has a repeat unit consisting of a cyclic amide where the amide group nitrogen is directly attached to the hydrophobic polymer backbone (Fig. 7). Thus, unlike the thermosensitive poly(N-alkylacrylamides), it does not produce small amide derivatives upon hydrolysis. This feature, together with its overall low toxicity, high complexing ability and good film forming properties enables its use in many industrial and medical applications, in particular in the biomedical field. Aqueous

Fig. 7. Structure of poly(N-vinylcaprolactam (PVCL).

solutions of PVCL exhibit a PT at ca. 31 1C. The LCST shifts to lower values with increasing molar mass of the polymer [24]. The similarity between the LCSTs of solutions of PVCL and PNIPAM masks significant differences in the thermodynamic and molecular mechanisms underlying the PT. High sensitivity microcalorimetry studies have revealed that aqueous PVCL undergoes two heat-induced transitions: a lowtemperature transition at 31.5 1C attributed to a microsegregation of hydrophobic domains and a higher temperature transition at around 37.5 1C attributed to the gel volume collapse [11]. The endotherm relating to the PT of a PNIPAM solution is sharp whereas in the case of the PVCL solutions it is much broader (Fig. 8). Measurements of the volume change that accompanies the PT clearly show that the PVCL monomer units have poorer water structuring properties than the PNIPAM monomer units. It has to be noted that the monomers N-isopropylacrylamide (NIPAM) and N-vinylcaprolactam show dramatically higher cytotoxity than the corresponding polymers [25]. PNIPAM is more cytotoxic than PVCL. The repeating unit of poly(2-isopropyl-2-oxazoline) (PIPOZ) is isomeric to that of PNIPAM

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Fig. 8. Microcalorimetric endotherms for PVCL and PNIPAM aqueous solutions. Reproduced from Laukkanen et al. [11] by permission of the American Chemical Society, USA.

Fig. 9. Structures of poly(2-isopropyl-2-oxazoline) and PNIPAM.

(Fig. 9). Indeed, PIPOZ in water presents a TCP, as revealed by turbidity studies [26]. The cloud point (CP) of a solution of PIPOZ (Mn 16700) ranges from 36 to 39 1C depending on polymer concentration. The second group includes the thermosensitive polyethers. Poly(propylene oxide) (PPO) is a most intensively studied thermosensitive polymer. Only PPO oligomers are soluble in cold water. DSC revealed an extremely broad transition width (12 1C) for an oligomer (MW 1000), with LCST at ca. 41 1C [27]. When the molecular weight (MW) reaches 3000, the LCST is already below 20 1C. Another thermosensitive polymer in this group is poly(vinyl methyl ether) (PVME). A molecular complex can be formed between water and PVME with a maximum of two water molecules strongly bound to the chain repeat unit. It can be concluded that such a complex will be stable at a temperature very close to the melting point of water [12]. An excess of water in the composition of the complex leads to hydration of this molecular complex. The degree of hydration increases with increasing water content. A serious drawback is that the LCST behavior of PVME is bimodal and the two maxima show different molecular mass dependences. TCP

curves by DSC measurements at different scanning rates on solutions of two samples of PVME in water show two minima in a temperature-composition plot. The miscibility gap is bimodal at a large enough average molar mass of the polymer. This involves the existence of three two-phase areas, arranged around a narrow three-phase range [28]. Copolymers based on oligo(ethylene glycol) side chains could become popular materials for biotechnological applications in the near future. Copolymers poly(2-(20 -methoxyethoxy)ethyl methacrylate-cooligo(ethylene glycol) methacrylate) with an average 5% of oligoether per chain exhibit thermoresponsive behavior generally comparable to, and in some cases superior to PNIPAM [2b]. These novel stimuli-responsive copolymers are very relevant for many applications in material science and technology. However, their stimuli-responsive properties still have to be carefully evaluated. Biodegradable polyorganophosphazenes constitute the third group of thermosensitive polymers. LCST behavior was observed in several polyorganophosphazenes substituted with alkyl ether groups [29,30]. They are potential candidates for application in drug delivery systems as some of them are known to degrade to harmless by-products during hydrolysis [31]. 3. Controlled synthesis of thermosensitive polymers Over the past two decades, polymer chemistry has made substantial progress in the design of amphiphilic copolymers with well-defined and novel macromolecular architectures. ‘‘Living’’/controlled radical polymerization, anionic polymerization and ring-opening polymerization methods have permitted the preparation of narrowly dispersed diblock and multi-block thermosensitive polymers. 3.1. Synthesis of poly(N-isopropyl acrylamide) Because of their acidic proton, the direct ‘‘living’’ anionic polymerization of N-monoalkylacrylamides such as NIPAM is not possible. NIPAM can be polymerized only by a radical mechanism to obtain a WSP with wide applications either as thermoresponsive polymer gel or as polymeric nanoparticles. In aqueous solution, NIPAM undergoes rapid free-radical polymerization to give high MW polymers with broad molecular weight distribution (MWD). Recent advances in controlled radical polymerization processes have enabled a

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polymerization of NIPAM that allows well-defined and efficient control over MW and MWD. 3.1.1. Reversible addition-fragmentation chain transfer polymerization (RAFT) Reversible addition-fragmentation chain transfer is a controlled free-radical polymerization process for producing polymers with narrow polydispersity indices (usuallyo1.2). This process has a distinct advantage over the other conventional free-radical controlled processes (e.g. nitroxide mediated, atom transfer radical polymerization (ATRP)) in terms of its use for a wide range of monomers, which can be polymerized in various solvents under a wide range of experimental conditions. Due to the inertness of the process to protic solvents such as water, and its efficiency, even in dilute monomer solutions, the RAFT process turns out to be very promising even for the synthesis of complex hydrophilic block copolymers [32]. Aqueous RAFT polymerization will be at the forefront of nano- and microscale selfassembly in electronics and biotechnology. The RAFT process takes place in the presence of a dithiocarbonyl compound, which serves as a reversible addition-fragmentation chain transfer agent. The system also includes a monomer, a good solvent for both the monomer and the resulting polymer, and an initiator for the free-radical polymerization (an azo- or peroxy-compound). The selection of transfer agent is essential for the synthesis of low-polydispersity products with predictable MWs. Small changes in the RAFT agent structure can impact the reaction kinetics and the degree of structural control [33]. The MW control in the RAFT systems is efficient, regardless of the solvent used and is based on a dynamic equilibrium between the propagating radical and the dormant species with a dithiocarbonyl group derived from the RAFT agent. The preparation of linear narrow-disperse PNIPAM by RAFT polymerization was recently reported [34–37]. The polymerization process shows an induction period that seems to correlate with a retardation of the rate. The induction period might be explained in terms of the different stabilities of the respective radicals that add to the monomer in the re-initiation step. The McCormick team demonstrated RAFT polymerization of NIPAM at room temperature in DMF [37]. Homopolymerizations remained controlled even at monomer conversions exceeding 90% and bore all of the characteristics of a

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controlled system. They also found that NIPAM can be polymerized in a controlled fashion directly in water at room temperature using the RAFT process. Under these conditions, excellent control of the MW and MWD was achieved, even at high monomer conversion [38]. After establishing the conditions for a controlled RAFT polymerization of NIPAM in water, they synthesized a series of diand tri-block copolymers with constant hydrophilic block lengths and variable NIPAM block lengths in order to study systematically the temperaturedependent micellization. Ray et al. [36] were able to perform RAFT polymerization of NIPAM in the presence of the Lewis acid (yttrium trifluoromethanesulfonate, Y(OTf)3 and thus achieved simultaneous control over the MW and the steric structure. The polymers showed controlled MW (polydispersity indices in the 1.4–1.9 range) and a high isotactic content (m ¼ 80–84%). Tenhu et al. applied the ‘‘grafting from’’ [39] and ‘‘grafting to’’[40] strategies in order to obtain Au nanoparticles protected by a well-defined polymer monolayer of PNIPAM. In the first case nanosized PNIPAM-coated gold clusters were prepared by surface-induced controlled RAFT polymerization. It was shown that the optical properties of gold could be varied by the thermally responsive polymer monolayer. For the ‘‘grafting to’’ strategy for the preparation of monolayer protected gold clusters two types of PNIPAM ligands synthesized by RAFT polymerization bearing thiol or disulfide end groups were used. PNIPAM hydrogels were prepared applying RAFT polymerization of NIPAM in the presence of N,N0 -methylenebisacrylamide (BIS) as a crosslinker and 4-cyanopentanoic acid dithiobenzoate (DTBA) as a chain transfer agent [41]. The swelling property of the gels obtained was investigated and showed an unexpectedly accelerated shrinking kinetics compared to the conventional hydrogels thus providing a new and simple method for the synthesis of rapidly responsive hydrogels. Moreover, the functional hydrogels could initiate ‘‘grafting from’’ RAFT polymerization of another batch of NIPAM. The derivative PNIPAM-graft-PNIPAM hydrogels showed even more accelerated deswelling kinetics. 3.1.2. Atom transfer radical polymerization (ATRP) ATRP is especially attractive as it can provide good control over both the polymer MW and the

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end group functionality. However, the ATRP of acrylamides (AAMs) including NIPAM has remained challenging. ATRP has been attempted with several catalytic systems but too many difficulties were encountered. When linear amines or bipyridine based ligands were employed, very low conversions were achieved in either bulk or solution [42]. Using 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane as a ligand, high yields were obtained in a short time, but the polymerization was not controlled. These results were attributed to the occurrence of slow deactivation in conjunction with fast activation and to the loss of bromine end groups through a cyclization reaction involving nucleophilic Br displacement by the penultimate amide nitrogen [43]. Initial attempts using tris(2-dimethylaminoethyl) amine (Me6TREN) as a ligand gave good control of the MW and the polydispersity. However, nonlinear first-order kinetics and limited conversions were observed, which could be attributed to the loss of activity of the catalyst system [44]. Masci et al. [45] reported the first example of a well controlled ATRP of NIPAM by using a CuCl/Me6TRENbased catalytic system in DMF/water at 20 1C. Linear first-order kinetics was obtained up to very high conversions, as well as controlled MW and narrow MWD. The living character of the polymerization was demonstrated by the synthesis of

block copolymers. Xia et al. [46] showed that ATRP of NIPAM in i-PrOH and t-BuOH leads to a narrow-disperse PNIPAM with high conversion and good MW control. These branched alcohols are believed to hydrogen-bond to monomer and polymer, thereby reducing the known deactivation of the ATRP catalyst by AAMs and their polymers. ATRP is a preferred ‘‘grafting-from’’ method in surface-initiated polymerization from colloidal particles or surfaces [47] as it offers the advantage of a controlled mechanism leading to linear chains with low polydispersity, with good control of the MW and fairly good resistance to additional reaction components and impurities. It therefore shows the preconditions required to create a well-defined polymeric shell bearing linear arms with high graft density, referred to as a polymeric brush. PNIPAM was grafted from the gold surface of an alkanethiol monolayer on gold by ATRP (Fig. 10) [48]. The collapse of end-grafted PNIPAM brushes depends on the grafting density and MW of the chains. The thermally induced chain collapse is only evident at high MW and at high grafting density. Thermosensitive PNIPAM nanotubes were fabricated by surface-initiated ATRP within a porous membrane followed by template removal [49]. These polymeric nanotubes have high flexibility and a controllable diameter.

Fig. 10. Strategy used to graft PNIPAM from alkanethiol monolayers on gold by ATRP. Reproduced from Plunkett et al. [48] by permission of the American Chemical Society, USA.

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Comparison between ATRP and RAFT polymerization methods shows that they can be successively applied (Table 2). It should be mentioned that the best results are obtained in highly polar reaction media. 3.1.3. Cerium (IV) redox-initiated polymerization PNIPAM–PEO copolymers with linear [51,52] and branched [53,54] architecture can be conveniently synthesized via radical polymerization of NIPAM by applying the cerium (IV) initiating system. As a result of the redox reaction, the hydroxyl groups of the PEO are oxidized to give macroradicals. By performing the polymerization process in aqueous media above the LCST of the PNIPAM, the resulting copolymer forms micelles in the early stages and the subsequent monomer addition occurs exclusively in the micellar core. Topp et al. [55] made a detailed analysis of the course of NIPAM polymerization initiated by PEO macroradicals and established their quasi-living nature. They found that only about 10% of the PEO chains were converted into radicals during the redox reaction with the ceric ions. Part of the remaining PEO was incorporated in the micelle shells thus increasing their stability. The stabilized core radicals survived for several hours thus allowing the sequential polymerization to proceed at an almost identical rate with the first monomer addition. Motokawa et al. [52] synthesized PNIPAM-bPEO copolymers through the quasi-living radical polymerization technique using the Ce (IV) redox system and studied their self-assembly behavior in aqueous media. Zhu and Napper [56] prepared

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PNIPAM-b-PEO microgel using a redox system consisting of Ce (IV) and PEO followed by addition of BIS. They found that the nanoparticle formation in aqueous solution could be controlled efficiently by changing the heating rate. Smaller particle dimensions with narrower size distribution could be obtained by fast heating. A family of block and star copolymers with a central hydrophilic-PEO segment and more than one terminal PNIPAM segment were synthesized by Ce(IV)/OH redox initiated free-radical polymerization [53]. The resulting copolymers formed liquid aqueous solutions at low temperature and transformed into relatively strong elastic gels upon heating. Multiple-arm copolymers formed gels via a physical cross-linking mechanism, while diblock copolymers gelled by a micellar aggregation. Hasan et al. [54] synthesized novel, water-soluble graft copolymers, with a high MW PEO-co-glycidol backbone and relatively short PNIPAM grafts. The PNIPAM was grafted, using a ceric ion redox initiation system, from the OH groups located either randomly along the backbone or as a second block. The associative properties of the copolymers were studied by viscometric and rheological measurements. Wang et al. [57] carried out surface modification of glass substrates via silanization with 3-aminopropyltriethoxysilane followed by surfaceinitiated graft polymerization of NIPAM using a Ce(IV)/NH2 redox initiating system (Fig. 11). The ceric ion redox method and ATRP were applied and compared in order to synthesize PNIPAM-b-PPO-b-PNIPAM tri-block copolymers [58]. It was found that the ATRP method is much more effective. The highest initiator efficiency was

Table 2 ATRP and RAFT polymerization of NIPAM Method

Conversion (%)

Solvent

T (1C)

Mw/Mn

Mn (g mol1)

Ref.

ATRP

92 87 79 72

DMF/water DMF/water i-PrOH i-PrOH

20 20 25 25

1.19 1.22 1.13 1.09

6700 22 200 17 300 57 000

[45] [45] [46] [50]

RAFT

75 89 39 90 38 76 – 86

H2O H2O DMF DMF Benzene Benzene Dioxane Toluene/methanol

25 25 25 25 60 60 60 60

1.07 1.06 1.04 1.06 1.20 1.51 1.09 1.39

61 600 73 000 24‘000 44 500 20 000 40 000 15 200 21 200

[38] [38] [37] [37] [34] [34] [35] [36]

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achieved with ATRP in water/propanol at a very low, 20 1C temperature. 3.2. Synthesis of poly(N,N0 -diethylacrylamide) (PDEAAM) Living anionic polymerization remains the best synthetic way to obtain well-defined block copolymers up to complete monomer conversion, high MW, low MWD, and desired microstructure. N,N-dialkyl-substituted amides (DAlAAMs), such as PDEAAM, undergo anionic polymerization. Moreover, the physical properties of PDEAAM make it a useful alternative to PNIPAM as it displays the LCST at ca. 33 1C, which is very similar to that of PNIPAM [10]. N,N0 -dialkyl-substituted amides (DAlAAM) are polymerized by classical anionic polymerization using cesium as the counterion, which proceeds without significant chain transfer and termination [59]. In the last decade, a group of Japanese scientists [60–62] developed a synthetic route for a well controlled polymerization of DAlAAM, which has highly regulated structures. The ‘‘ligated’’ polymerization of DAlAAM was successfully carried out by using organolithium or organopotassium initiators as well as Grignard reagents in the presence of the Lewis acid derivatives ZnEt2 [60,61], BEt3 [62], or AlEt3 [63]. The effect of the Lewis acid derivative on the anionic polymerization process is a slow propagation reaction and a narrow polymer MWD. As a consequence, the resulting polymers possess mostly predicted MWs. With the aid of the ‘‘ligated’’ anionic polymerization, welldefined block copolymers with double-responsive properties poly[(tert-butyl acrylate)-b-DEAAM] [64] and poly[(2-vinylpyridine)-b-DEAAM] [65] were obtained.

3.3. Synthesis of poly(propylene oxide) PPO is another polymer exhibiting LCST behavior [4]. The triblock copolymers PEO–PPO–PEO (Pluronics, BASF) form micelle structures above a ‘‘critical micelle temperature’’ (cmt) due to the dehydration of the PO block [66]. For most Pluronics copolymers the cmt value ranges from 25 to 40 1C, i.e. below or close to body temperature, making them an essential part of drug formulations. The potassium base-catalyzed ring-opening anionic polymerization of PO in bulk, mainly performed on an industrial scale, involves three stages depicted in Fig. 12 [67]. It has been accepted that reaction (3) is responsible for the presence of oligomers possessing a terminal unsaturation in anionically polymerized PPO [68]. The extent of transfer relative to propagation can be reduced by using crown ethers to change the nature of the active ion pair [69] or aluminum–porphirin-based initiators [70,71]. As a substitute for these expensive complexing agents and initiators a new initiator system composed of ammonium salts associated to a bulky bisphenoxy aluminum electrophile was recently reported [72]. However, only ‘‘controlled’’ synthesis of oligomers (Mno5000 g/mol) has been achieved with this system. Very recently, Deffieux et al. [73] reported an active simple initiating system for anionic PO polymerization based on the association of a simple alkali metal derivative or ammonium salt initiator with triisobutylaluminum as the catalyst. The experimental PPO molar masses were close to theoretical values and the MWDs were narrow (1.1–1.3) suggesting a ‘‘controlled’’ PO polymerization without any significant contribution of the monomer transfer reaction.

Fig. 11. Chemical strategy of surface graft polymerization of NIPAM on a glass substrate. Reproduced from Wang et al. [57] by permission of Elsevier Science Ltd., UK.

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Fig. 12. Anionic ring-opening polymerization of PO: (1) propagation; (2) cation exchange; (3) proton abstraction reaction.

Another attractive initiating system for epoxide polymerization is the so-called double metal cyanide (DMC) catalytic system based on Zn3[Co(CN)6]2 [74]. Compared with conventional KOH catalysts, DMC is much more active, producing polyethers with much lower extent of unsaturation and much narrower MWD. DMC catalysts for epoxide polymerization are usually obtained by reacting a watersoluble metal salt (ZnCl2) with a water-soluble metal cyanide salt (potassium hexacyanocobaltate) in aqueous medium and then treating the water insoluble DMC (Zn3[Co(CN)6]2) with a low MW complex ligand (ether or alcohol) (Fig. 13). Despite its advantages, unlike KOH, DMC catalysts must be activated before monomer can be added to the reactor. Usually a polyol initiator (or starter) and DMC are heated under vacuum prior to the addition of small portion of monomer [74d]. The induction periods depend on reaction temperature, water content, and the type and amount of catalysts, regulators, and solvents [75]. A series of DMC catalysts were synthesized by varying the type and amount of the co-complexing agents and were utilized for PO polymerization [76]. DMC catalyst prepared by using K3[Co(CN)6]2 and ZnCl2 in the presence of t-BuOH as a complexing agent and polytetramethylene ether glycol as a cocomplexing agent showed very high activity (2672 g PPO/g cat). The resulting polymers exhibited a very low unsaturation level (0.003–0.006 meq/g) and narrow MWD (1.02–1.04). 3.4. Polymerization of vinyl ethers The living cationic polymerization of vinyl ethers and related monomers was discovered in the early

Fig. 13. Mechanism of DMC-catalyzed ring-opening polymerization of propylene oxide.

1980s by Miyamoto et al. [77] They found that hydrogen iodide in combination with iodine (HI/I2 initiator) induces nearly perfect living polymerization of various alkyl vinyl ethers yielding monodisperse polymers. Since then, several methods for stabilization of carbocations have been developed [78]. The acidity of the Lewis acid and the presence of additives is crucial for achieving of living cationic polymerization. For example, a base is needed for EtxAlCl3x and a salt should be added to SnCl4 in order to ensure the living cationic polymerization of vinyl ethers [79,80].

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Armes et al. [81] synthesized a series of thermosensitive block copolymers containing vinyl ether sequences by living cationic polymerization. The dihydrophilic block copolymers of methyl vinyl ether and methyl triethylene glycol vinyl ether were water soluble at room temperature and exhibited double PT behavior [81a]. The TCP’s of these polymers cover a wide range from 26 to 79 1C, depending on the copolymer composition. Thermosensitive homopolymers and copolymers bearing pendant hydroxy groups were synthesized via the living cationic polymerization of Si-containing vinyl ethers [82]. The cationic homopolymerization and copolymerization of various vinyl ethers with silyloxy groups, each with a different spacer length, were examined with a cationogen/ Et1.5AlCl1.5 initiating system in the presence of an added base. When an appropriate base was added, the living cationic polymerization of Si-containing monomers became feasible, resulting in homo- and block- copolymers with narrow MWD. Subsequent desilylation gave well-defined polyalcohols, in both water-soluble and water-insoluble forms. One of these polyalcohols, poly(4-hydroxybutyl vinyl ether), underwent LCST-type, thermally induced phase separation in water at a critical temperature of 42 1C. One of the drawbacks of the living cationic polymerization systems is their relatively low polymerization rate, especially in the presence of polar functional groups. Recently, the Aoshima group reported fast living cationic polymerization of vinyl ethers with SnCl4 combined with EtAlCl2 (SnCl4/ EtAlCl2) in the presence of an ester as an added base (Fig. 14) [83]. The polymerization rate of this

system was greater by three to five orders of magnitude than that with a conventional EtxAlCl3x initiating system, regardless of the pendant substituent. Consequently, living polymerization can be finished within 5 min for most vinyl ethers, the shortest reaction time ever reported for living cationic polymerization. 3.5. Polymerization of 2-oxazolines Poly(2-alkyl-2-oxazolines) display LCST behavior in water [84]. PIPOZ, for example, has a CP around 36 1C, close to the temperature of the human body [26]. For over 40 years the 2-oxazolines have been known to polymerize via cationic ring-opening polymerization. They constitute one of the classical monomers, which have been used to study this process, and especially the role of the ionic and the covalent active centers in the chain growth [85]. The process shows the characteristics of a ‘‘living’’ polymerization. It may be easily controlled, especially when the substituent does not bear protons in the b position to the heterocyclic ring (e.g. 2-phenyl2-oxazoline). The reaction can be initiated by electrophiles such as alkyl halides, alkyl tosylate or triflate, Lewis acids, stable cationic salts, or strong protonic acids [86]. The initiation consists in Nsubstitution of the oxazoline ring. The resulting active centers add monomer (Fig. 15). Under proper conditions, transfer and termination may be suppressed to a great extent. In the polymerization of oxazolines the cationic and the covalent active centers coexist at each stage of the process. The position of the ionic–covalent

Fig. 14. Living cationic polymerization initiated by SnCl4/EtAlCl2. Reproduced from Yoshida et al. [83] by permission of John Wiley & Sons Ltd., UK.

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Fig. 15. Ring-opening polymerization of 2-oxazolines.

equilibrium depends upon the basicity of the oxazoline and the nucleophilicity of the counter ion: the less nucleophilic the counter ion and the more basic the monomer, the more the cationic centers prevail. In any case, the rate constant for chain growth on the cationic centers is much higher than on the covalent centers, so that the former contribute exclusively to the chain growth [86a]. Very recently telechelic polyoxazolines with the antimicrobial dodecylammonium group and a biologically inactive function at the starting end, the so-called satellite group, were synthesized [87]. Hybrid star-shaped polyoxazolines with a polyhedral oligomeric silsesquioxane (POSS) core were prepared by ring-opening polymerization of 2methyl-2-oxazoline using various octafunctional POSS as initiators by changing the POSS-tomonomer feed ratio [88]. Star-shaped polymers were thermally more stable than the linear polyoxazolines. The synthesis and living cationic ring-opening polymerization of 2-[3,4-bis(n-alkan-1-yloxy)phenyl]-2-oxazolines (minidendritic 2-oxazolines) was reported [89]. The structural analysis of the resulting polymers with well-defined MW and narrow MWD showed a change in the 3-D shape as a function of their degree of polymerization. A number of thermosensitive polyoxazolinebased hydrogels have been synthesized by various techniques [90–92] involving the ‘‘macromonomer method.’’ Nonionic hydrogels were prepared by homopolymerization of polyoxazoline bis(macromonomer)s obtained by ‘‘living’’ cationic ringopening polymerization of 2-substituted 2-oxazoline

initiated by a bifunctional initiator 1,4-dibromo-2butene. The reaction was terminated with acrylic acid (AAc) in the presence of a proton trap [90]. The same authors obtained series of segmented networks with LCST behavior by free-radical polymerization of polyoxazoline bis(macromonomer) with the comonomers 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, or methyl methacrylate [93]. The LCST behavior of the water-swollen networks could be tailored by varying the fraction of polyoxazoline precursor and the philicity of the comonomer used. Applying the macroinitiator method, Rueda et al. [92] synthesized novel amphiphilic and lypophilic polymer networks by the copolymerization of 2methyl-2-oxazoline, and/or 2-nonyl-2-oxazoline and 2,2-tetramethylenebis(2-oxazoline). The copolymerization was initiated by random copolymers of chloromethylstyrene and methyl methacrylate or of chloromethylstyrene and styrene. Structure, polarity, and thus the swelling behavior, can be finetuned by the macroinitiator structure, the oxazoline comonomer feed ratio, and the amount of crosslinker.

4. Doubly thermoresponsive polymers Block copolymers and copolymer hydrogels consisting of two or more different thermosensitive moieties display intriguing temperature-induced self-assembly behavior in water. The doubly thermoresponsive copolymers comprise block copolymers forming micellar structures, random copolymers and core–shell microgels.

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4.1. Block copolymers with blocks displaying different LCSTs Recently, complex thermosensitive polymers having two blocks, each exhibiting an individual LCST, were reported. The architecture of the double thermoresponsive block copolymers includes AB, ABA, and ABC structures. The block copolymers dissolve in water molecularly or in colloidal form, or they are insoluble, depending on the temperature. Usually the micelles formed after the first PT have a thermosensitive corona that may undergo another PT at a higher temperature [58,94–100]. Mertoglu et al. [101] synthesized stimuli-responsive block copolymer with two switchable blocks via RAFT polymerization. The block copolymer of NIPAM and N-acryloylpyrrolidine shows a twostep thermally induced aggregation in water, as revealed from temperature-dependent dynamic light scattering (DLS) experiments. It is well known that homopolymers of vinyl ethers with oxyethylene units display extremely sensitive and reversible phase separation. The phase separation can be controlled by varying the length of either the pendant oxyethylene units or the oalkyl groups. Thus, Aoshima et al. successfully synthesized well-defined AB and ABC di- and triblock copolymers of vinyl ethers with pendant oxyethylene groups (Fig. 16) [94,96,98]. The narrow MWD of the polymers obtained via controlled cationic polymerization contributes to the high thermosensitivity of the system. Aoshima et al. also found that aqueous solutions of the double thermosensitive diblock copolymers of vinyl ethers with pendant oxyethylene units exhibit four different PTs, as shown in Fig. 17. Some other block copolymers with pendant oxyethylene moieties namely poly(methoxytri(ethylene glycol) acrylate)-b-poly(4-vinylbenzyl methoxytris(oxyethylene)ether (PTEGMA62-b-PTEGSt98) were synthesized by Hua et al. (Fig. 18) [100]. As in the case of Aoshima’s copolymers, they showed that the aqueous solutions underwent multiple transitions, from transparent, to cloudy, to clear bluish, and turbid, with increasing temperature. The association/dissociation processes were reversible upon cooling (Fig. 19). Another group of doubly thermoresponsive block copolymers comprises PPO sequences: the PPO exhibits LCST behavior in aqueous solution. Dimitrov et al. [95] prepared a number of ABA and BAB triblock copolymers of ethoxyethyl

Fig. 16. Structures of diblock copolymers of vinyl ethers with oxyethylene pendant groups. Reproduced from Sugihara et al. [98] by permission of the American Chemical Society, USA.

glycidyl ether (EEGE) and propylene oxide (PO) by sequential anionic polymerization. Since the oligomeric poly(ethoxyethyl glycidyl ether) (PEEGE) is water soluble below 11 1C, i.e. it exhibits LCST properties, the copolymers are built of two thermosensitive blocks (Fig. 20). Since the LCSTs of the PEEGE and the PPO blocks are very similar the clouding process of the PO/EEGE copolymers is presented by a sharp sigmoidal curve. The presence of only one transition and NMR measurements on the polymer solutions indicate that the PT can be attributed mainly to the intermolecular collapse of the more hydrophobic PEEGE blocks. The aggregation behavior of PPO/ PEEGE/PPO block copolymers strongly depends on the polymer composition and the MW. In solutions above the critical micelle concenration (cmc) and at low temperature, core/corona micellar particles are formed. The micelles are stable and temperature dependent from 10 to 30 1C, and the width of this temperature interval is composition dependent, as shown in Fig. 21. The PEEGE blocks can be converted easily into polyglycidol (PG) blocks [102]. Thus, quite different species of block copolymers: double-hydrophilic, amphiphilic, and hydrophobic can be obtained from an almost identical block copolymer backbone depending on the temperature. Following the above described synthetic procedure, a series of well defined PG-PPO–PG triblock copolymers, considered as analogs of the commercially available polymeric surfactants Pluronics, was synthesized [103]. The most important finding in this work is that the interactions of the PPO and PG blocks with

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Fig. 17. Unique physical gelation of aqueous solution of double thermosensitive diblock copolymers. Reproduced from Sugihara et al. [98] by permission of the American Chemical Society, USA.

Fig. 18. Structure of PTEGMA62-b-PTEGSt98 copolymers.

water, due to the thermal stimulus, change in opposite manner, depending on the delicate balance between the constituent blocks, imparting peculiar aqueous solution properties. The synthesis of doubly thermoresponsive block copolymers comprising PPO and PNIPAM blocks was recently described [58,97,99]. In this case, the less hydrophilic PPO formed the core of the micelles after the first PT, while the PNIPAM blocks constituted the thermosensitive shell. Hasan et al. [58] synthesized PNIPAM–PPO– PNIPAM triblock copolymers with different lengths of the outer PNIPAM blocks. Since the LCST of PPO is significantly lower than that of PNIPAM, two thermal PTs were anticipated from the ABA block copolymer. The transition curves clearly show that the TCP of the copolymers strongly depends on the ratio between PO and NIPAM units. In most cases, two TCPs are observed (Fig. 22). This behavior offers an attractive opportunity to obtain

Fig. 19. Optical transmittances of aqueous solutions of PTEGMA66-b-PTEGSt72 upon heating (m) and cooling (.), PTEGSt (K), PTEGMA (’), and mixture (E) of PTEGSt and PTEGMA at various temperatures. At each temperature, solutions were equilibrated for 10 min. Reproduced from Hua et al. [100] by permission of the American Chemical Society, USA.

nanoparticles or microaggregates according of the protocol of dissolution and thermal treatment. 4.2. Random copolymers with tunable thermosensitivity Random copolymers containing comonomers, which when dissolved in water become sensitive to the changes in temperature, further extend the field of application of temperature-sensitive polymers. A novel class of thermosensitive and biodegradable polymers, poly(N-(2-hydroxypropyl) methacrylamide

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Fig. 20. Influence of MW on TCP of PEEGE (K) and PPO (J) aqueous solutions, c ¼ 20 g/L. Reproduced from Dimitrov et al. [95] by permission of the American Chemical Society, USA.

Fig. 22. Turbidimetric curves of 0.1% aqueous solutions of PPO precursor (K), NIPAM5–PO34–NIPAM5 (.), NIPAM22–PO34– NIPAM22 (’), and NIPAM58-PO34-NIPAM58 (m). Reproduced from Hasan et al. [58] by permission of Taylor & Francis Group, USA.

Fig. 23. Structure of: (a) poly(HPMAM-monolactate (n ¼ 0); (b) poly(HPMAM-dilactate) (m ¼ 0); (c) poly(HPMAM-monolactate-co-HPMAM-dilactate (m,n6¼0). Adapted from Soga et al. [104] by permission of the American Chemical Society, USA. Fig. 21. Variations of hydrodynamic radii, R90 h of: PO4EEGE5PO4 (U); PO2EEGE6PO2 (K); PO5EEGE16PO5 (n) as functions of temperature. Reproduced from Dimitrov et al. [95] by permission of the American Chemical Society, USA.

(HPMAM) mono/di lactate has been synthesized (Fig. 23) [104]. The TCPs of poly(HPMAM-monolactate and poly(HPMAM-dilactate) in water were 65 and 13 1C respectively. The lower TCP for poly(HPMAM-dilactate) is likely due to the greater hydrophobicity of the dilactate side group as compared to the monolactate side group. The TCP of the polymer can be tailored between 10 and 65 1C by the copolymer composition. The TCP of poly (HPMAM-monolactate-co-HPMAM-dilactate increased linearly with the mol% of HPMA-mono-

lactate, which demonstrated that the TCP was tunable by the copolymer composition. Fig. 24 shows that thermohysteresis of about 5 1C is observed between the heating and the cooling curve. The hysteresis is likely due to the decreased chain flexibility as a result of the a-methyl group in the polymer backbone. These copolymers are thermosensitive and biodegradable, which makes them attractive as materials for drug delivery and in other biomedical applications. A facile synthetic route to thermosensitive polyoxazoline gradient polymers was recently reported by Park and Kataoka [105]. The living cationic copolymerization of 2-isopropyl-2-oxazoline mixed with a specific amount of 2-ethyl-2oxazoline as a hydrophilic comonomer resulted in

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Fig. 24. Light scattering intensity-temperature curve for poly (HPMAM-monolactate-co-HPMAM-dilactate) in isotonic ammonium acetate buffer. Reproduced from Soga et al. [104] by permission of the American Chemical Society, USA.

gradient copolymers with various compositions and narrow MWD. Thus, the authors were able to modulate precisely the copolymer LCST over a broad temperature range from 38.7 to 67.4 1C simply by varying the mole ratio of comonomers. Amphiphilic copolymers of PEG–methacrylate and methyl methacrylate comprising a hydrophobic backbone and hydrophilic PEG-pendant chains were prepared by Sto¨ver et al. [106] The copolymers containing more than 57 wt% oligoether are water soluble. Their aqueous solutions exhibit PT temperatures that increase with increasing oligoether content of the copolymer. The water solubility of the copolymers arises from hydrogen-bonding interactions between the pendant PEG chains and water molecules. Lutz et al. [2] described the synthesis via ATRP of PEG analogs with a tunable thermosensitivity. The random copolymerization of two oligo(ethylene glycol) macromonomers of different chain-lengths leads to the formation of thermosensitive copolymers with precisely adjustable LCST (between 26 and 90 1C), just by varying the comonomer composition. These copolymers have structures that combine both the properties of PEO (nontoxicity, anti-immunogenicity) and PNIPAM (thermosensitivity) in one macromolecule [2b]. Mori et al. [107] synthesized random copolymers of AAc and N-vinylacetamide (NVA) (Fig. 25). By studying their solution behavior, the authors focused on the role of the intramolecular hydrogen bonding. The copolymers failed to show a PT in

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aqueous media in the absence of salt (at any pH). In the presence of salt, however, the copolymers revealed a reentrant soluble–insoluble–soluble transition with increasing temperature under acidic conditions (Fig. 26). Below the soluble–insoluble transition temperature Tp1, a small portion of the NVA amide groups form hydrogen bonds with the AAc carboxyl groups, and the remainder are hydrated. With increasing the solution temperature, the stability of the hydration around the amide group decreases. During the first transition at Tp1, cooperative dehydration of the NVA amide groups occurs, accompanied by the simultaneous formation of intra- and inter-chain hydrogen bonds between the NVA amide and the AAc hydroxyl groups. With further increase in the solution temperature, the intra- and inter-chain hydrogen bonding cooperatively dissociates at the insoluble–soluble transition temperature Tp2 because of the activated motion of the copolymer chains. 4.3. Multi-responsive core– shell microgels There are many potential applications of multi-responsive cross-linked core–shell particles

Fig. 25. Chemical structure of poly(N-vinylacetamide-co-acrylic acid).

Fig. 26. Transmittance curves for heating and cooling of 10g/L, pH 2.6, [Na2SO4] ¼ 0.5 M. Reproduced from Mori et al. [107] by permission of the American Chemical Society, USA.

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composed of two or more environmentally sensitive polymers. Such materials represent potentially diverse chemo-mechanical systems for study, as these particles would be expected to display quite complex PT behavior. This is especially true in the core–shell systems where one polymer has either a chemical or a mechanical influence over the swelling of the other polymeric component. Richtering et al. prepared core–shell microgels based on PNIPAM as the core and poly(Nisopropylmethacrylamide) (PNIPMAM) as the shell polymer with LCST of ca. 45 1C [108,109]. An inverse system with a PNIPMAM as the core and PNIPAM as the shell was also prepared. In this way doubly temperature-sensitive core–shell microgels were synthesized. Since both PNIPAM and PNIPMAM are thermosensitive polymers, a general size decrease is observed with an increase of temperature. However, the characteristic swelling behavior depends on the thickness and the cross-link density of the shell. The results clearly show that the swelling behavior of the thermosensitive core–shell microgels can be controlled by the mass and the cross-link density of the PNIPMAM shell. Chemical cross-linking of the micellar core or the shell can be utilized to address the problem of insufficient stability of block copolymer micelles. Block copolymer micelles undergo an exchange between micelles and unimers. Therefore, they tend to be destroyed under shear forces, dilution or salinity fluctuations. According to Xu et al. [110] an alternative facile approach is to prepare unimolecular micelles. Compared to the conventional block copolymer micelles, dendritic macromolecules or polymeric unimolecular micelles offer much higher stability in aqueous solution since they contain only covalently linked branching points. For this purpose, successive RAFT polymerizations of NIPAM and 2-(dimethylamino) ethyl methacrylate (DMAEMA) were conducted using a fractionated fourthgeneration hyperbranched polyester (Bolton H40) based macroRAFT agent. Double PTs of aqueous solutions of unimolecular dendritic three-layer core–inner-shell–corona nanostructures with dual thermoresponsive coronas exhibit two-stage thermoresponsive collapse or reswelling upon heating and cooling, as presented in Fig. 27. Luo et al. [111] studied aqueous solutions of H40PNIPAM dendritic copolymer. The results from light scattering (LS), microdifferential scanning calorimetry (DSC) and excimer fluorescence all support the conclusion that the densely grafted

PNIPAM brush exhibits double thermal PT behavior. The inner part of the PNIPAM brush collapses below 30 1C. Above that temperature the second PT occurs which can be ascribed to the collapse of the outer region of the PNIPAM brush. These authors provide the first direct evidence of the collapsing sequence of a PNIPAM brush tethered to a spherical hydrophobic core. Novel materials that display dual LCSTs were developed by forming block copolymers, laminate structures and interpenetrating networks (IPNs) of crosslinked polymer systems possessing independent temperature sensitivity [112]. These systems are composed of N-alkylacrylamides and N,N0 -dialkylaminoethyl methacrylates. The polymer structure was found to profoundly influence the thermal sensitivity, as polymer formulation techniques led to materials with varying degrees of temperature sensitivity. These materials can be used in designing drug delivery strategies where the release rate must be finely tuned, or in bioseparations, where a single membrane could be used for molecular separations of four different size ranges, simply on the basis of the temperature surrounding the membrane (Fig. 28). 5. Combination of thermoresponsive and zwitterionic properties: block copolymers with blocks displaying LCST and upper critical solution temperature (UCST) Polyampholytes are zwitterionic polymers that possess both positively and negatively charged moieties located either at the pendant side chains of different monomer units or at the same monomer unit. There are cases when one or both of the charges may be located along the polymer backbone. While polymers containing cationic or anionic groups exhibit electrostatic repulsion, those with zwitterionic groups exhibit electrostatic dipole-dipole association [113–115]. Phosphobetaine, sulfobetaine, and carboxybetaine are zwitterionic groups that have been very well studied. These zwitterionicbased materials have received growing attention because of their biocompatibility and interesting solution properties. Poly(sulfobetaine)s are the most widely studied zwitterionic polymers. They are insoluble or sparingly soluble in water, and they exhibit hydrogel characteristics. Their poor water solubility is a result of the formation of polyelectrolyte complexes due to ionic cross-links between two opposing

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Fig. 27. Phase transitions in H40–PNIPAM–PDEAEMA dendritic macromolecules. Reproduced from Xu et al. [110] by permission of the American Chemical Society, USA.

charges in the polyions. However, water solubility of poly(sulfobetaine) can be achieved by the addition of a simple salt: this phenomenon has not been observed with ordinary polyelectrolytes. The solvating power of the electrolyte is determined by the site-binding abilities of the cation and the anion. As a salt (e.g. KCl or NaCl) is added to an aqueous solution of polybetaine, Cl binds to the quaternary ammonium group to a greater extent than does the alkali cation to the sulfonate group. The overall result is that the poly(sulfobetaine) starts to behave increasingly as a polyanion with extension of the chain conformation [116]. Poly(3-[N-(3-methacrylamido-propyl)-N,N-dimethyl]-ammonio propionate sulfonate) (PSPP), like other zwitterionic polymers, exhibits a UCST in water that increases with the molar mass. This is attributed to the strong mutual intermolecular attraction of the zwitterionic betaine groups [117]. Among the common properties of the poly(sulfobetaines) are also the preferential binding of the zwitterionic groups to ‘‘soft’’ cations and anions, and the increase in viscosity with increasing salt concentration known as an ‘‘antipolyelectrolyte’’ effect.

5.1. Intrachain interchain interactions and formation of polymeric nanoparticles of different nature Because of the LCST and the UCST of the thermosensitive and the zwitterionic blocks, different kinds of polymeric aggregates can be formed in aqueous solutions. In order to prepare well-defined and narrowly dispersed nanoparticles, controlled polymerization methods are required. Armes et al. reported the first examples of directly synthesized narrow MWD poly(sulfopropylbetaine) homopolymers and block copolymers where the comonomer can, in principle, be any alkyl methacrylate [116,118]. The direct synthesis takes advantage of the highly effective process of betainization of the tertiary amine residues of preformed homo/ block copolymers of DMAEMA with an alkyl methacrylate under mild conditions (Fig. 29). Aqueous size exclusion chromatography (SEC) has confirmed that the narrow MWDs of the precursors are retained in the conversion into poly(sulfopropylbetaine)s, and it has also shown micelle formation in the block copolymers. Recently, Arotcarena et al. [119] synthesized PNIPAM-b-PSPP block copolymers employing

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Fig. 28. Application of dual temperature-sensitive networks in membrane separations. Reproduced from Stoltz and Brazel [112] by permission of John Wiley & Sons Ltd., UK.

Fig. 29. Conversion of precursor (co)polymers into the corresponding poly(sulfopropyl betaine). Adapted from Lowe et al. [116] by permission of the American Chemical Society, USA.

Fig. 30. Structure of PNIPAM-b-PSPP block copolymers obtained by the RAFT method. Adapted from Arotcarena et al. [119] by permission of the American Chemical Society, USA.

RAFT polymerization (Fig. 30). In aqueous salt solutions used for screening the electrostatic interactions, and within an appropriate temperature range, the PNIPAM-b-PSSP block copolymers behave like double hydrophilic block copolymers. The peculiar structure of double-hydrophilic block copolymers, i.e. copolymers combining two differ-

ent hydrophilic blocks, enables one of the blocks to undergo a physical or a chemical transformation in an aqueous solution, which renders it insoluble, while the copolymer stays in solution by virtue of the hydrophilicity of the other block. Such block copolymers exhibit double thermoresponsive behavior in water: the PNIPAM block shows an LCST,

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whereas the PSPP block displays a UCST. Appropriate design of the block lengths can lead to block copolymers that stay in solution within the full temperature range from 0 to 100 1C. Both blocks of these polymers dissolve in water at intermediate temperatures. At high temperatures the PNIPAM block forms colloidal hydrophobic associates, which are kept in solution by the PSPP block; whereas at low temperatures, the PSPP block forms colloidal polar aggregates that are kept in solution by the PNIPAM block (Fig. 31). In this way colloidal aggregates, which switch reversibly so that their ‘‘inside’’ can turn into the ‘‘outside’’ and vice versa can be prepared in water without an additive. The aggregates provide microdomains and surfaces of different character, which can be controlled by a simple thermal stimulus. The mechanism of aggregation of PNIPAM-bPSSP was studied in detail by Virtanen et al. [120]. The aggregation processes are strongly dependent not only on the temperature but also on both the salt and polymer concentrations. The addition of NaCl enhances the solubility of the zwitterionic PSPP block, leading to disappearance of the UCST. On the other hand, the solubility of PNIPAM in water decreases as NaCl is added. The effect of salt on the solubility of PSPP is best observed at low salt concentrations, and that on PNIPAM at high salt concentrations. Miyazawa and Winnik [121] synthesized watersoluble phosphorylcholine-based hydrophobically modified betaines (Fig. 32). The synthetic route they described involves the attachment of phosphorylcholine groups to a preformed hydrophobically modified copolymer, resulting in polymers with various compositions comprising PNIPAM, N-(phosphorylcholine)-N0 -(ethylenedioxybis(ethyl)) acrylamide and hydrophobic comonomers. ‘‘Phosphocholine polymers’’ can impart remarkable bio- and hemo-compatibility to the surfaces onto which they are coated and thus have found applications in many biomedical devices.

Fig. 31. Simplified model of changing association of PNIPAM-bPSPP block copolymers with temperature. Reproduced from Arotcarena et al. [119] by permission of the American Chemical Society, USA.

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Fig. 32. Structure of phosphorylcholine-based polybetaines. Adapted from Miyazawa and Winnik [121] by permission of the American Chemical Society, USA.

Chang et al. [122] designed three well-defined diblock copolymers containing zwitterionic poly (sulfobetaine methacrylate) (PSBMA) and PPO as thermoresponsive moieties. These copolymers were synthesized via the ATRP method (Fig. 33), which allows control over the PSBMA chain length within a narrow MWD, while the chain length of the PPO segment is fixed. While the authors did not discuss the thermosensitivity, it was demonstrated that physically adsorbed diblock copolymers containing sulfobetaines PPO-b-PSBMA on a hydrophobic surface are highly resistant to protein adsorption when the surface PSBMA densities are well controlled. Weaver et al. [123] reported the synthesis of nearmonodisperse methacrylate-based diblock copolymer displaying both UCST and LCST. The authors synthesized well defined poly(2-dimethylamino)ethyl methacrylate-b-2-(N-morpholino)ethyl methacrylate (DMA-b-MEMA) via group transfer polymerization, followed by selective quaternization of DMAEMA using 1,3-propane sultone (Fig. 34). Molecular dissolution occurs in dilute aqueous solution at 30–40 1C. Polydisperse, hydrated PSBMA-core micelles are formed below the LCST of approximately 20 1C and near monodisperse, relatively dehydrated MEMA-core micelles are formed above the UCST of about 50 1C (Fig. 35). Maeda et al. [124] prepared another type of double temperature-responsive diblock copolymer consisting of poly(3-dimethyl(methacryloyloxyethyl) ammonium propane sulfonate) as the UCST block and PDEAAM as the LCST block (Fig. 36). As in the previous studies in aqueous solutions the block copolymer formed micelles at temperatures below the UCST and above the LCST of the blocks.

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Fig. 33. Reaction scheme for block copolymerization of poly(SBMA) with PPO via ATRP. Adapted from Chang et al. [122] by permission of the American Chemical Society, USA.

Fig. 34. Synthesis of thermoresponsive SBMA–MEMA diblock copolymers. Adapted from Weaver et al. [123] by permission of the Royal Society of Chemistry, UK.

Nedelcheva et al. [125] used an alternative approach by employing specific interactions between unlike polymer chains (Fig. 37). Thus, they studied the ability of PNIPAM copolymers containing up to 10 mol% sulfobetaine groups to form graft-like complexes with PEO bearing charged terminal groups. The complexes were formed by dipole–ion interactions between sulfobetaine-containing PNIPAM copolymers and PEO bearing either cationic or anionic terminal groups. At temperatures above the LCST the complexes formed gels stable over a wide temperature range. Kameda et al. [126] used another monomer with zwitterionic properties, namely acrylated spirobenzopyran, to study the change in the hydrophilic–hydrophobic balance during the temperature-

Fig. 35. Intensity of scattered light measured by DLS of 1% aqueous solutions of SBMA-MEMA diblock copolymer at different temperatures. Reproduced from Weaver et al. [123] by permission of the Royal Society of Chemistry, UK.

Fig. 36. Structure of double temperature-responsive diblock copolymers. Reproduced from Maeda et al. [124] by permission of Wiley–VCH Verlag GmbH, Germany.

induced phase separation. They introduced spirobenzopyran residues on PNIPAM as a side chain (Fig. 38).

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Spirobenzopyrans have at least two isomerization states whose physical properties are remarkably different: the zwitterionic merocyanine (MC) state and the nonionic spiropyran (SP) state. MC has a strong optical absorption band in the visible region due to its extensive p-electron conjugation, while SP is basically colorless. In several derivatives of spirobenzopyran whose activation energies of isomerization are relatively low, isomerization between MC and SP is induced not only by light irradiation but also by the solvent effect; the zwitterionic MC state is stabilized in protic solvents, while the nonionic SP state occurs predominantly in less polar solvents. Therefore, this chromophore, which is introduced as a comonomer into the PNIPAM chain, is sensitive to the change in the dielectric environment around the thermoresponsive PNIPAM. It was confirmed that the isomerization of the chromophore is highly sensitive to the surrounding dielectric environment and that it is feasibly detectable by measuring UV–visible absorption

Fig. 37. Structures of complex-forming polymers via dipole–ion interactions. Adapted from Nedelcheva et al. [125] by permission of Elsevier Science Ltd., UK.

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spectra. Measurements on an aqueous polymer solution at various temperatures showed that the dielectric environment surrounding the thermoresponsive polymer was changing continuously even in the temperature range far below the LCST. This result suggests that the local weak orientation of water molecules around the polymer diminishes gradually in a preliminary stage of shifting to thermally induced phase separation. These observations are expected to provide an important clue to the elucidation of the detailed mechanism of the PT of the thermoresponsive polymers in solution. 5.2. Thermoreversible hydrogels based on PNIPAM and zwitterionic comonomer The most widely studied thermosensitive hydrogels are those based on NIPAM and its comonomers such as AAc, methacrylic acid and sodium-2methylpropyl sulfonate. Thus, the PNIPAM gels acquire polyelectrolyte properties. It is well known that polyelectrolyte hydrogels with charged groups produce an electrostatic repulsion force among the electrolyte groups when swelling in water, thus increasing the expansion of the hydrogel network. The essential drawback, however, is the fact that the Coulombic forces within the polyelectrolyte hydrogels with dissociable polyions are very sensitive to the internal pH and the amount of mobile ions in the external solution. The addition of salt to the swollen polyelectrolyte hydrogel may cause a volume collapse because of the changes in the water structure induced by ion hydration and by the reduced charge repulsion due to the shielding effect

Fig. 38. Isomerization among SP, MC, and protonated MC states of spirobenzopyran. Reproduced from Kameda et al. [126] by permission of the American Chemical Society, USA.

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of the salt. This limitation is of great importance in the application of thermoreversible hydrogels for concentrating of materials found in electrolyte solution, e.g. biogenic materials such as bacteria or proteins. To retain the advantage of reversible thermosensitivity without reducing the swellability in aqueous salt solutions, zwitterionic moieties were included in the thermosensitive hydrogels. In this way materials with both temperature reversibility and high water swelling in aqueous salt solutions were expected to emerge [127]. In a series of papers, Lee et al. studied thoroughly the differences in the swelling characteristics of PNIPAM gels containing cationic, anionic and zwitterionic monomer units by using the following zwitterionic sulfobetaine comonomers: 3-dimethyl-(methacryloyloxyethyl) ammonium propane sulfonate (DMAPS) [128,129], and N,N0 -dimethyl (acrylamido propyl ammonium propane sulfonate (DMAAPS) [130–133]. Xue et al. [134] studied the role of another zwitterionic comonomer 1-(3-sulfopropyl)-2-vinylpyridiniumbetaine. In saline solution, the swelling ratio of pure PNIPAM gel did not significantly decrease with increasing salt concentration until the salt concentration became higher than 0.5 M [129]. The copolymer gels displayed polyelectrolytic behavior under lower salt concentration (105–101 M); they exhibited nonionic gel behavior at salt concentrations from 0.1 to 0.5 M, and showed antipolyelectrolytic behavior (polyzwitterionic effect) at salt concentration above 0.5 M. When the salt concentration is lower than 0.5 M, the ionic strength is insufficient to open the inner ring of the zwitterionic monomer units, so the net charge on the polyzwitterionic chain is still zero. However, when the salt concentration is increased

(40.5 M), some of the positive and negative charges of the salt can site-bind at the sulfonate group and quaternize the amine group. In all cases the anti-polyelectrolyte effect is not very pronounced, and the changes are insignificant, owing to screening by the primary monomer (88%) NIPAM moieties. Recently Li et al. [135] reported the synthesis of reasonably well-defined biocompatible thermoresponsive ABA triblock copolymers, where the outer A blocks comprise PNIPAM and the central B block is poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC). ATRP initiated with a commercially available bifunctional initiator was used; the reaction scheme is shown in Fig. 39. These copolymers are water-soluble in dilute aqueous solution (o7 wt%) at 20 1C and pH 7.4 but form free-standing physical gels at 37 1C. The gelation is reversible and the gels are believed to contain micellar domains, suggesting possible applications in drug delivery systems and in tissue engineering. The same authors prepared doubly thermoresponsive PPO–PMPC–PNIPAM triblock copolymer gelators by ATRP initiated with PPO-based macroinitiator [97]. Provided that the PPO block was sufficiently long, DLS and DSC confirmed that two separate thermal transitions, corresponding to micellization and gelation, occurred as shown in Fig. 40. However, these triblock copolymers are rather inefficient gelators: formation of free standing gels at 37 1C requires much higher copolymer concentration compared with the previously described PNIPAM–PMC–PNIPAM triblock copolymers. It was found that the separation of the micellar self-assembly from the gel network formation did not lead to enhanced gelator efficiency.

Fig. 39. Reaction scheme for synthesis of the NIPAM–MPC–NIPAM triblock copolymers via ATRP. Adapted from Li et al. [135] by permission of the American Chemical Society, USA.

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Fig. 40. Schematic representation of aqueous solution behavior PPO–PMPC–PNIPAM triblock copolymers: molecular dissolution at 5 1C, formation of PPO-core micelles between 10 and 20 1C, and formation of a micellar gel network above 33 1C (which corresponds to the LCST of the outer PNIPAM chains). Reproduced from Li et al. [97] by permission of the American Chemical Society, USA.

6. Combination of thermo- and pH-responsive properties Polyelectrolytes are an intriguing class of polymers with broad technological applications. The solution properties of polyelectrolytes differ considerably from those of uncharged polymers. The presence of charges along the chain leads to complex intra- and inter-molecular interactions, which have a strong impact on the structural, dynamical and rheological properties of the system. The properties of the polyelectrolytes are governed by factors such as charge density, counterions, ionic strength, polyelectrolyte concentration and, when they are crosslinked, the network topology. The effects of these factors on viscoelasticity have not been significantly studied. The combination of the intrinsic properties of the polyelectrolyte and those of thermoresponsive macromolecules represents a challenge in the fabrication of highly specialized WSPs. Temperature and pH have been the solution variables of greatest scientific and technological interest, primarily because these variables can be changed in typical biological and chemical systems. By substituting either weakly ionizable cationic or anionic pendant groups onto a polymer backbone, the polymer can be made to respond to either an increase or decrease in the pH. The ability of the polymer to respond both to temperature and pH offers an additional control over the polymer phase behavior. In this way a highly diverse set of ‘‘smart’’ materials can be prepared, which will be able to mimic the responsive macromolecules found in nature. Indeed, there is growing interest in obtaining macromolecules and hydrogels whose aqueous solutions and swelling properties can abruptly and

reversibly change in response to simultaneous pH and temperature changes. The pH- and temperature-sensitive polymer sequences with their dual function are an example of systems that can respond to a combination of external stimuli. In recent years, a variety of strategies have been employed to simultaneously tailor the temperatureinduced PT to temperatures appropriate for use in drug delivery systems and an environmental stimulus such as the pH [136]. The development of systems that fulfill these requirements with respect to the PT and the pH sensitivity has been achieved in most cases by random, block, and graft copolymerization employing hydrophobic and hydrophilic monomers containing ionizing and thermosensitive groups. Our objective in this section is to determine the extent and to clarify the mechanism of the combined influence of pH and temperature on the properties of aqueous copolymer solutions and hydrogels. It is well known that the PT temperature, and the strength and sensitivity of doubly sensitive hydrogels can be modulated by incorporating different amounts of charged monomers [137]. Above the LCST the temperature-sensitive entities of the copolymers become amphiphilic and thus they can easily form micelles or particles with thermosensitive cores and pH-sensitive shells. In general, temperature- and pH-sensitive polymers can be classified in three groups: random copolymers and copolymer hydrogels, block- and graft-copolymers; and homopolymers bearing groups with double sensitivity. 6.1. Random copolymers and hydrogels The behavior of temperature-sensitive polymers is based on their amphiphilic character, which in-

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cludes changes in the efficiency of hydrogen bonding. On the other hand, pH-sensitive polymers are usually based on the presence of ionizable units, which induce neutralization of opposite charges. In this sense, it has to be pointed out that the vast majority of the polymers that respond to more than one stimulus, in particular to temperature and pH, are prepared by the simplest method—random copolymerization reactions of monomers sensitive to temperature and pH. It is well known that the TCP of aqueous solutions of PNIPAM can be largely modified by introducing a small amount of hydrophilic or hydrophobic comonomer into the chain [22]. It is important to know whether hydrophobic effects or hydrogen bonding is the main factor responsible for the LCST behavior of the PNIPAM-based random copolymers. Recently, NIPAM has been copolymerized with different monomers in order to change and tune the PT temperature of aqueous copolymer solutions as well as their sensitivity (enthalpy factor and transition width). The use of comonomers with ionizable groups such as carboxylic acids or tertiary amines presents an advantage over other comonomers as their hydrophobicity/hydrophilicity can be modified by changes in the pH of the solution, leading to a pH-tunable LCST [138]. When hydrophilic monomers are copolymerized with NIPAM, the LCST of the resulting polymer will shift to higher temperatures while copolymerization with hydrophobic monomers will lead to more hydrophobic polymers and thus the LCST will shift to lower temperature. Moreover, copolymerization with monomers containing ionizable groups is an interesting approach because it makes it possible to adjust the thermosensitivity close to human body temperature. AAc is the most commonly employed monomer for this purpose, but it restricts the resulting thermosensitivity to a limited pH range because at high pH the carboxylic groups are ionized and the polymer becomes rather hydrophilic, thus decreasing its thermosensitivity This might be attributed to the combined ability of the ionic monomer residues to break the PNIPAM chain sequences into short uncooperative segments. The imposed excess hydration and electrostatic repulsion of the ionized monomers such as AAc will weaken the thermally driven hydrophobic aggregation of the collapsing PNIPAM chains. Therefore, in the case of statistical copolymers the comonomer content cannot be increased too much, since the LCST may disappear

as the copolymer becomes water-soluble at all temperatures. Changes in LCST caused by the random incorporation of comonomers are due to changes in the overall hydrophilicity of the polymer [139]. Both the hydrophilic and the charged comonomers, while having no direct effect on the structuring of the water around the hydrophobic moieties, increase the LCST because of the increase in the hydrophilicity of the polymer. These results may have important implications for the understanding of the cold denaturation processes of proteins, since these processes are similar to the PTs of solutions of LCST polymers. Another issue that needs to be understood more thoroughly is the effect of hydrogen bonding on the LCST behavior of the NIPAM copolymers, as it is evident that hydrogen bonding plays an important role in the case of acid comonomers. To elucidate the problem, Salgado-Rodriguez et al. [140] synthesized a series of random NIPAM copolymers of similar composition, which could be split into two groups. One group had a controlled number of units with a free acid group while the other had this group methoxy-protected. In this way the effect of possible hydrogen bonding on the LCST behavior of these copolymers could be clarified. In the case of the most studied copolymer system, poly(NIPAM-co-AAc), the carboxylic acid groups can form hydrogen bonds with the amide groups in the PNIPAM structure (Fig. 41). This will lead to additional polymer–polymer interactions, making phase separation by heating a less endothermic process than in pure PNIPAM since fewer sites will be available for the water to bind to the NIPAM units. The proposed hydrogen-bonding interactions play an important role in the case of a pH-tunable LCST. In general terms, if a strong base is added to a PNIPAM/acid copolymer solution, it is expected that the protons of the carboxylic acid groups will be bound and the resulting carboxylates will no longer be able to bind by hydrogen bonds to the amide groups of the NIPAM units. Moreover, the electrostatic charge repulsion will weaken the polymer–polymer interactions, shifting the LCST to higher temperature. However, this is only true if all acid units are ionized at once, which will depend on the acidity constant of the acid. At intermediate stages, when the ionization is partial, the electrostatic charge repulsion between the ionized units will be diminished by hydrogen bonding attractive

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Fig. 42. Structures of ionically modified NIPAM-based random copolymers. Adapted from Hahn et al. [141] by permission of the American Chemical Society, USA.

Fig. 41. Proposed hydrogen-bonding interactions in NIPAM– carboxylic acid random copolymers. Reproduced from SalgadoRodriguez et al. [140] by permission of Elsevier Science Ltd., UK.

forces arising from the nonionized units. As a result two types of pH transitions are to be expected. In the first pH range when the majority of the units are not ionized (low pH) the LCST will decrease with an increasing number of acid units. A second pH range may also be observed when the majority of the units are ionized (high pH) so that the LCST will increase with an increasing number of acid units. The role of the charged moieties was investigated by a series of ionically modified NIPAM copolymers with various cationic, anionic and amphiphilic functional groups, synthesized by free-radical polymerization (Fig. 42) [141]. Owing to the comparable reactivity ratios of the various acrylic derivatives used, sufficiently narrow MW and composition distributions could be obtained. The fraction of ionic units in the copolymers was adjusted to about 6–7 mol%. In aqueous solutions, cationically modified products (and also the polymer containing an ampholitic betaine structure) showed phase separation upon heating, whereas for the anionically charged products this behavior could not be observed. The different properties can be explained by a markedly higher hydrophobicity of the cationic groups. A PT was found to be initiated by conformational changes of the dissolved macromolecules at a temperature still below TCP, which were then followed by aggregation and phase separation. In

Fig. 43. Biotin structure.

most cases the phase-separated ionic copolymers formed colloidal particles that were electrostatically stabilized in pure water. Low MW copolymers of AAc and NIPAM with reactive OH groups at one chain end have been synthesized, using a chain-transfer polymerization technique [142]. The copolymers display both pH and temperature sensitivity over a wide, useful range of pH and temperature, which permits both pH and temperature control of the polymer conformation. These copolymers have been conjugated to a specific cysteine thiol site inserted by genetic engineering close to the recognition site of streptavidin (SAv). The noncovalent bond formed between biotin (Fig. 43) and avidin or SAv has a bonding affinity that is higher than most antigenantibody bonds and similar in strength to a covalent bond. This is one of the strongest known biochemical interactions. In their earlier studies, Hoffman et al. conjugated a temperature-sensitive polymer, PNIPAM, to a genetically engineered SAv at a site specifically designed to resemble the biotin-binding site of the natural SAv. It was found that small changes in temperature, which caused the polymer coil to collapse, could simultaneously prevent biotin from binding to SAv. The thermally induced

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collapse of this conjugated polymer can cause the release of a significant fraction of the already bound biotin from the SAv-binding pocket. The authors found that: (a) the decrease of the pH, which causes the polymer to collapse results in blocking biotin binding as well; (b) raising the pH so as to cause the polymer to fully hydrate allows biotin binding, and (c) lowering the pH once again to cause the collapse of the polymer results in partial ejection of the already bound biotin (Fig. 44). This bioconjugate can provide pH control of both the biotin binding and its triggered release from the mutant SAv. These actions are relevant to affinity separations, biosensors, diagnostics, enzyme processes, and targeted delivery of drugs or chemical agents, labels and other signals. The effects of pH and temperature on the biotin binding and its release could be useful in a variety of separations and diagnostic applications and may also be useful for pHtriggered drug delivery at specific sites in the human body where the pH is significantly below 7.0 such as the stomach, vagina, salivary glands and within intracellular vesicles such as endosomes and lysosomes. Bokias et al. [143] studied the shear-thickening behavior of hydrophobically modified copolymers based on NIPAM. These copolymers contain amphiphilic units comprising an alkyl group and cationic charge (Fig. 45). The copolymers have two characteristic features: (a) they consist of a thermosensitive backbone, and (b) they contain equal amounts of charges and side alkyl groups with each

Fig. 44. Proposed conformations of polymer chain coils of poly(NIPAM-co-AAc) conjugated to SAv. Reproduced from Bulmus et al. [142] by permission of the American Chemical Society, USA.

Fig. 45. Chemical structure of hydrophobically modified NIPAM-based copolymers. Reproduced from Bokias et al. [143] by permission of the American Chemical Society, USA.

charge being directly linked to the alkyl group. Their phase behavior is governed by the competition between the hydrophobic character of the alkyl groups and the hydrophilic character of the charges. When the alkyl groups are not very long, for instance octyl groups, the hydrophilic character of the positive charges prevails over the hydrophobic contribution of the alkyl chains. The phase and rheological behavior of the copolymer solutions significantly changes upon increasing the length of the alkyl groups (dodecyl and octadecyl). The hydrophobic character of the dodecyl group seems to be strong enough to prevail over the hydrophilic character of the charges. The rheological properties of aqueous solutions of these polymers are remarkable. At low shear rate, the polymer coils adopt a rather compact conformation, probably due to the formation of intrachain hydrophobic aggregates. Under flow, the disruption of some of these aggregates and their replacement by interchain ones leads to a dramatic viscosity enhancement, or even gelation in some cases. Kim et al. [144] attached a hydrophobic block of poly(lactic acid), (PLA), known for its biocompatibility, biodegradability, and good mechanical properties, to a random copolymer of NIPAM and AAc. The resulting terpolymer was used to expand the concept of cell sheet engineering. In this strategy, functional three-dimensional tissues can be constructed by stacking two-dimensional cell sheets of one or more cell types on top of one another. The cell sheets are harvested by lowering the ambient temperature of the cells, which are usually grown on tissue culture polystyrene dishes grafted with PNIPAM. Because of their multi-functional properties, such as thermosensitivity, biodegradation, good mechanical strength, and balance of hydrophobicity and hydrophilicity, the biomaterials designed by Kim et al. (1) can control the release

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of therapeutic agents during their degradation; (2) can foster the mechanical functionality of the cells; (3) can be fabricated into a variety of two- and three-dimensional shapes to support cell adhesion, proliferation and differentiation and, (4) in view of their thermoresponsive behavior, can be used for rapid two- and three-dimensional noninvasive cell sheet harvesting. Another combination of copolymers sensitive to both temperature and pH are the random copolymers of NIPAM and N-[3-(dimethylamino)propyl]methacryl amide (DMAPM) presented in Fig. 46 [145]. The copolymers are sensitive to the albumin concentration in aqueous media. The PT temperature of the copolymer showed a linear change with albumin concentration at different pH values. A new method for determination of protein concentration is based on the chemical interaction between the dimethylamino-groups of the copolymer and the carboxyl groups of the protein molecule (Fig. 47). Electrostatic interactions may also play a role in the binding of the hydrophobic protein bovine serum albimin (BSA) to the copolymer molecules. The binding of albumin molecules to the poly(NIPAMco-DMAPM) chains would probably result in a decrease in the solubility of the copolymer. Cationic copolymers of NIPAM represent quite interesting systems related to conventional flocculants. Deng et al. [146] studied the flocculation of

Fig. 46. Structure of PNIPAM-co-PDMAPM. Adapted from Tuncel et al. [145] by permission of John Wiley & Sons Ltd., UK.

Fig. 47. Schematic representation of chemical interaction between PNIPAM-co-PDMAPM random copolymer and albumin. Reproduced from Tuncel et al. [145] by permission of John Wiley & Sons Ltd., UK.

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colloidal TiO2 dispersions with a cationic copolymer of NIPAM and diallyldimethylammonium chloride (2.2 mol%). Reversible temperature-sensitive flocculation was observed at intermediate copolymer concentrations. At room temperature the copolymer concentration was high enough to sterically stabilize the TiO2 whereas flocculation occurred at 42 1C when the copolymer was present as cationic colloidal particles. Both physical forms of the copolymer adsorbed/deposited TiO2 at pH 7 because of favorable electrostatic interactions. Water-soluble thermosensitive copolymers including phosphonium groups represent another type of doubly responsive flocculants bearing cationic moieties (Fig. 48) [147]. The relative viscosity of the aqueous solutions of the copolymers increased with the increase of the phosphonium content due to the repulsion of the cationic charges of the phosphonium groups. An abrupt decrease in the relative viscosity around LCST of PNIPAM was not observed. This indicates that the association of the PNIPAM moieties above the LCST becomes difficult because of the presence of cationic charges. The thermosensitivity of the copolymers was greatly affected by the addition of KCl. These copolymers have high flocculating abilities against bacterial suspensions as well as some antibacterial activity. A straightforward expectation for such copolymers is that they will not only respond to temperature and pH, but also to other stimuli such as ionic strength and mechanical stress. To explore this aspect a third monomer was included. The copolymerization of AAc, ethyl methacrylate, and NIPAM allowed the preparation of terpolymers displaying varied aqueous solution properties [148]. The PT temperatures of these terpolymer solutions are progressively shifted to temperatures higher than those observed for PNIPAM, and their solution behavior is highly dependent on both the solution pH and the ionic strength. These results confirmed the possibility of tailoring polymer solutions to display a desired PT temperature by

Fig. 48. Structure of PNIPAM-based random copolymers containing phosphonium groups.

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controlling their composition or solution parameters. DSC measurements revealed further characteristics of the transition processes such as increased transition width and decreased enthalpy changes when the polymer chains carried a greater number of electrical charges. The temperature- and the pH-controlled association of terpolymers of NIPAM with 1-vinylimidazole (VI) and PEG were investigated by Bisht et al. [149]. VI was chosen because of its attractive pKa suitable for a variety of biomedical applications, and PEG was chosen because of its high solubility in water. While the imidazole units provide the polymers with pH-sensitivity in a slightly acidic pH range, the presence of PEG grafts permits control over the polymer association above the PT temperature. Spafford et al. [150] prepared a new type of pHresponsive and temperature-sensitive polymer, which possesses not only temperature-sensitive groups (NIPAM) and pH-responsive groups (glycine) but also hydrophobic groups consisting of a pyrene group linked to a secondary amide group (Fig. 49). Contrary to what could be expected, the LCST of the hydrophobically modified copolymer was not significantly lower than that of the unmodified analog. This is evidence that the alkyl groups are not exposed to the water but rather form the inner core of micellar structures protected from the aqueous environment by PNIPAM–glycine chains. Another approach to prepare a useful bifunctional copolymer containing both reactivity and temperature sensitivity is to include charged groups without destroying the PNIPAM main chain. Okano et al. assumed that the homopolymer-like structure of the polymer chain would be required to

Fig. 49. Structure of hydrophobically modified dual-responsive copolymer PNIPAM–Gly–Py. Adapted from Spafford et al. [150] by permission of the American Chemical Society, USA.

maintain a sensitive temperature response with functional groups. Therefore, they designed a novel reactive monomer, 2-carboxyisopropylacrylamide (CIPAAM), and investigated its copolymerization with NIPAM [151]. CIPAAM contains both an isopropylamide group similar to NIPAM and a carboxyl side group similar to AAc (Fig. 50). Moreover, the carboxyl group of CIPAAM is bonded trough the isopropyl group, while that of AAc is directly bonded to the acrylate group. The important characteristic of the poly(NIPAMco-CIPAAM) structure is that it is composed of the same polymer backbone and isopropylamide groups as PNIPAM with some additional carboxyl groups. As a result, the PT occurred within a very narrow temperature range in phosphate buffered solution at pH 6.4, 7.4, and even at pH 9.0. The PT profiles were almost the same as those of the PNIPAM homopolymers under the same conditions whereas the PT properties of the poly(NIPAM-co-AAc) solution were considerably influenced by the inclusion of even a very small AAc content. Kuckling et al. [152,153] synthesized another type of comonomers resembling NIPAM, namely AAM derivatives bearing carboxylic groups attached to alkyl spacers of different lengths (CnAAM). They prepared various temperature- and pH-sensitive polymers by free-radical copolymerization of NIPAM with CnAAM (Fig. 51). It is possible to adjust the LCSTs over a wide range of temperatures by changing the copolymer composition or the pH. At high pH, a PT of the polymer chains could be observed; but because of electrostatic interactions of the charged polymer chains, there was no phase separation. The fact that most bacteria are negatively charged at ambient pH suggests that control over bacterial adsorption might be achieved by utilizing PNIPAM copolymers containing anionic or acidic comonomers as the surface-displayed brushes. Alarcon et al. [154,155] chose copolymers of PNIPAM with an acrylamidoalkanoic acid to control cell attachment. They considered the bacteria as ‘‘living colloids’’.

Fig. 50. Chemical structures of NIPAM, CIPAAM, and AAc.

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Fig. 51. Synthesis of NIPAM-based copolymers containing carboxylic groups attached to spacers with different length. Adapted from Kuckling et al. [152] by permission of Wiley–VCH Verlag GmbH, Germany.

Adsorption of Salmonella typhimurium and Bacillus cereus was not significantly altered as a function of the pH, but the attachment of both bacterial strains increased at temperatures above the polymer coilto-globule transition, indicating the importance of switching surface hydrophobicity in controlling short-term bacterial adsorption. The results are of great significance since they suggest that short-term attachment via hydrophilic–hydrophobic switching within relatively simple random copolymers could allow better control over cell attachment via better regulated polymer architectures capable of more selective switching. Bignotti et al. [156] investigated the solution behavior of NIPAM copolymers bearing a-amino acid residues in the side chains. They reported on the synthesis and properties of a series of copolymers obtained by radical polymerization of NIPAM with N-methacryloyl-L-leucine (MALEU) with the general structure shown in Fig. 52. The aqueous solutions of the copolymers synthesized exhibit a CP at temperatures, strongly dependent on the polymer composition and the pH. Thus, by varying the amino acid structure and content, polymers with a wide range of properties can be synthesized. Because of the presence of asymmetric carbon atoms, such systems can also be employed in applications where chiral recognition is required, such as temperature-responsive chromatography of chiral molecules. Another representative thermosensitive polymer is poly(N-vinylcaprolactam) (PVCL). The aqueous solution behavior of PVCL-co-poly(methacrylic acid) (PMAAc) random copolymers with various compositions (thus differing the charge density) was studied by Khokhlov et al. [157]. They performed DLS measurements on copolymers with different density of macromolecular charges, at different pHs of the medium and also on complexes of PVCL-coPMAAc with oppositely charged surfactant, so as to

Fig. 52. Structure of NIPAM/MALEU random copolymers. Adapted from Bignotti et al. [156] by permission of Elsevier Science Ltd., UK.

vary the hydrophobic/electrostatic balance. It was demonstrated that a tailored delicate balance between hydrophobic and hydrophilic segments in the macromolecules enables novel thermosensitive swelling behavior in aqueous solution. In some cases evidence was found supporting the hypothesis that the collapse of the macromolecules leads to the formation of ion pairs, which could further aggregate. Jones et al. [158] described the synthesis and thermal properties of random copolymers of MAAc and different PEG–methyl ether methacrylates. Variation of the copolymer composition, the solution pH and the content of hydrophobic comonomers was used to adjust the thermal response of these copolymers. Under acidic conditions the CP falls below 0 1C because of the formation of hydrophobic H-bonded ether-acid complexes. Recently, hydrogels that demonstrate swelling dependence on more than one variable, in particular, temperature and pH, have been investigated. The addition of a weakly ionizable comonomer to a temperature-sensitive gel may affect dramatically its swelling behavior. Incorporation of both temperature- and pH-sensitive monomers in a simple network provides flexibility in controlling the swelling behavior under various solution conditions. The most studied comonomers with weakly ionizable groups are the anionic sodium acrylate and the cationic 2-dimethylamino ethyl methacrylate [159].

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The studies suggest that pH and temperature may affect gel swelling not only independently of each other, but that in some cases there is a combined effect as a result of their mutual influence. pH- and temperature-sensitive poly(NIPAM-co-AAc) copolymers were used to form doubly sensitive nanoparticles. Lyon and Jones [160] demonstrated that the versatility of PNIPAM microgels could be enhanced by the preparation of core–shell microgels, in which the core and the shell have different properties. Core particles composed of cross-linked PNIPAM or poly(NIPAM-co-acrylic acid) were synthesized via precipitation of poly(acrylic acid) (PAAc) and PNIPAM. Thus, two different responsive hydrogels, PNIPAM (temperature responsive) and PNIPAM– PAAc (temperature and pH responsive), are arranged as the core and shell of a submicron-sized particle. As expected, the resulting environmental sensitivity is strongly dependent on the respective locations of the two materials. At pH 6.5, particles with a thin PNIPAM shell surrounding a PNIPAM–PAAc core display two distinct volume PTs between 25 and 40 1C, corresponding to a PNIPAM transition and a mixed PNIPAM/PNIPAM–PAAc transition. However, when the arrangement of the two materials is reversed, three distinct volume PTs are observed between 25 and 60 1C, reflecting a more heterogeneous nanostructure in the submicron-sized hydrogel. This approach can generate multi-responsive hydrogels with physicochemical properties that do not arise from a simple summation of the individual properties of the two hydrogels. Tailoring of the PT behavior of the PNIPAM-based core/shell microgels is possible via copolymerization of AAc and by variation of the cross-linker concentration [161]. The ability of a PNIPAM-co-PAAc core to swell back to its original volume is hindered after the addition of a PNIPAM shell, which also imparts a volume PT and compresses the core above the LCST. Addition of a small amount of the hydrophobic butyl methacrylate (BMA) localized in the particle shell is sufficient to induce a large decrease in the swelling rate [162]. On the basis of CIPAAM, Ebara et al. [163] have developed temperature-responsive hydrogels of PNIPAM containing mobile PNIPAM grafted side chains with improved extreme temperature responsiveness. Unhindered temperature-sensitive grafted polymer side chains undergo more rapid dehydration in response to a small increase in temperature

due to their freely mobile ends. These grafted chains readily form hydrophobic aggregates above the LCST, which prompts the polymer backbone network to shrink rapidly as well, owing to hydrophobic sites created inside the polymer network. The authors propose that the NIPAM-CIPAAM gel maintains strong hydrophobic aggregation forces within the PNIPAM network, which are necessary for an effective collapse to occur, despite the introduction of a large number of carboxyl groups. This is due to the retention of a continuous chain of isopropylamide groups similar to a NIPAM homopolymer. Relatively small amounts of the AAc comonomer can decrease the hydrophobic aggregation forces in the PNIPAM gels as the result of both charge–charge repulsion and disruption of water cluster formation around the isopropylacrylamide side groups. Therefore, the charged species rearrange themselves remotely in the side chain away from the PNIPAM backbone. Consequently, the gel hydration/dehydration behavior changes without influencing the gel hydrophilic/hydrophobic balance. The deswelling kinetics of temperature-responsive NIPAM copolymer gels containing functional CIPAAM monomer were compared to those of previously studied temperature-sensitive gels of pure PNIPAM and NIPAM–AAc ionic gels [164]. The conventional PNIPAM gel becomes opaque just above the LCST and shows limited deswelling changes over a long time period, due to the collapse of the ‘‘skin layer’’. In contrast, familiar NIPAM–AAc gels shrink rapidly without an opposing internal hydrostatic pressure buildup because the hydrophilic AAc suppresses the collapse of the hydrophobic polymer ‘‘skin layer’’. However, gel deswelling rates and the volume changes decrease with increasing AAc content since the network chain aggregation forces are weakened by the incorporation of AAc ionomer. In contrast to the NIPAM–AAc gels, the de-swelling rate of the ionized NIPAM–CIPAAM gels gradually increases with increasing CIPAAM content. Despite the large amount of carboxyl groups, this gel maintains the collective NIPAM chain aggregation forces despite a thermally induced collapse, in contrast to the NIPAM–AAc gels. Hydrogels bearing a positive charge were synthesized with NIPAM as the temperature-sensitive component, (diethylamino)ethyl methacrylate (DEAEMA) as the pH-sensitive component, and BMA as the hydrophobic component to increase the

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mechanical stability of the gels [165]. It was shown that poly(NIPAM-co-BMA-co-DEAEMA) hydrogels possess unique swelling properties. Even if more than 20% of the ionizable monomer was included, the gel collapsed at high temperatures (at pH 7.4), because of the increased neutralization of the ionizable monomer at high temperature. The temperature range in which the temperature-induced swelling transition occurs is determined by the amount of ionizable monomer.

6.2. Block- and graft-copolymers While the phase separation of the NIPAM-based systems has been frequently studied in random copolymer solutions and hydrogels, little attention has been paid to thermo- and pH-sensitive (polyelectrolyte) copolymers containing blocks and grafts of PNIPAM. Aqueous formulations based on block and graft copolymers of PNIPAM whose viscosity increases reversibly upon heating are considered thermothickening systems. Basically there is no limitation for the temperature range as the requirements vary depending on the application, starting at body temperature for biological purposes and going as high as 200 1C for oil drilling fluids or well cementing processes. It must be expected that ion-containing associating block and graft copolymers will exhibit more complicated behavior than is observed with the corresponding neutral copolymers. Compared to neutral hydrophobically associating polymers, one of the main effects of introducing charges onto the polymer backbone is the lowering of the degree of association. In addition to the well known charge screening effect, another important effect is the decrease in the solubility of the hydrophobe. Both effects are responsible for associative behavior. For a very long time, polyelectrolytes have been known as efficient thickeners, especially in salt-free solutions. The effect is due to the intramolecular charge–charge repulsion leading to coil expansion. WSPs that contain both hydrophobic and ionic groups provide thickeners with improved properties

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combining the advantages of macromolecular association and the polyelectrolyte effect [166]. A new family of thermoassociative graft copolymers has recently been synthesized by Hourdet et al. [167–170]. Schematically, their structure combines a weak polyelectrolyte backbone of poly(sodium acrylate) and thermosensitive side chains containing mainly NIPAM. The synthesis of the PNIPAM graft copolymers proceeds by a two-step mechanism: (1) synthesis of functional oligomers carrying an amino end group and (2) grafting of these oligomers onto a poly(acrylic) precursor (Fig. 53). In this way it is possible to control almost all the main structural parameters of the graft copolymers in order to adjust their solution properties. It is evident that hydrogen bonding between NIPAM and AAc units in poly(AAc-g-NIPAM) graft copolymers strongly influences their behavior in solution. In the literature, hydrogen-bonded interpolymer complexes between PAAc and poly (acrylamide) derivatives have been reported where AAM acts as a strong hydrogen acceptor and the AAc units provide hydrogen for bonding [171]. Taking these findings into consideration. it can be assumed that intermolecular hydrogen bonding takes place between PAAc and PNIPAM. Indeed it is found that PNIPAM forms compact hydrogenbonded interpolymer complexes with PAAc by precipitating out from aqueous solutions, even at pH as high as 4 [172]. The first important factor that has to be considered is the charge density on the main chain, as this controls the magnitude of the electrostatic repulsions. Moreover, by varying the pH, one can tune the interactions between PAAc and the PNIPAM grafts from repulsion at intermediate or high pH to attraction at low pH. The extent of grafting and the length of the PAAc backbone are other very important parameters in relation to the number of elastically active chains. While the usual goal would be to increase these parameters, there are some important drawbacks associated with: (1) macrophase separation, which can occur at high extent of grafting; and (2) increasing entanglements with increasing MW at a given concentration. In semidilute aqueous solution,

Fig. 53. Grafting of PNIPAM onto a polyacrylic backbone. Adapted from Durand and Hourdet [167] by permission of Elsevier Science Ltd., UK.

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when the temperature is increased above a critical value, the side chains self-aggregate into hydrophobic microdomains that act as reversible crosslinks between macromolecules. This microscopic phase separation causes a large increase in viscosity, as shown in Fig. 54. It has been clearly shown that the self-assembling properties of the graft copolymers are closely related to the thermodynamic properties of the PNIPAM grafts. The thickening at a given shear rate will depend basically on two parameters: the number of the elastically active chains in the network and the lifetime of a ‘‘sticky’’ chain inside a hydrophilic cluster. Upon heating, the PNIPAM grafts self-aggregate into hydrophobic domains and their NMR signals are no longer detectable. This phenomenon is attributed to the glassy structure of the aggregate core and allows direct detection of the aggregation process [169]. The strong interaction between the PAAc backbone and the PNIPAM grafts, as already shown, restricts the application of poly(AAc-g-NIPAM) copolymers at alkaline and neutral pH. Alternatively, Chourdakis et al. [173] propose to use as a backbone a copolymer of AAc and a strongly anionic monomer, 2-acrylamido-2-methyl-propane sulfonic acid (AMPSA) (Fig. 55). A large fraction of AMPSA units in the backbone ensures strong

Fig. 54. Viscosity of a 6% solution of poly(AAc-g-NIPAM) (J) and of a mixture of PAAc and PNIPAM (’) as a function of temperature. Inset: Arrhenius plot of data obtained with 6% solution of PAAc-g-PNIPAM. Reproduced from Durand and Hourdet [167] by permission of Elsevier Science Ltd., UK.

Fig. 55. Structure of poly(AAc-co-AMPSA) grafted with PNIPAM. Adapted from Chourdakis et al. [173] by permission of John Wiley & Sons Ltd., UK.

hydrophilicity of the graft copolymer even at very low pH, as it does not allow the formation of intrachain hydrogen-bonding complexes between the remaining AAc units and the PNIPAM side chains, even if they are all in the acid form of the carboxylic groups (at low pH). The strongly charged AMPSA units dominate the behavior of the polymer, imposing an extended conformation of the polymer backbone and a highly reduced viscosity of the graft copolymer poly(AAc-co-AMPSA-g-NIPAM). For this reason, the copolymer is water-soluble at acid pH, contrary to the behavior of the corresponding poly(AAc-g-NIPAM) graft copolymer. As a result, thermally induced aggregation of the PNIPAM side chains and corresponding thermothickening behavior in semidilute aqueous solutions are observed, even at low pH. Staikos et al. reported the synthesis of thermoresponsive graft copolymers based on a carboxymethylcellulose backbone [174,175]. Because of the srongly hydrophilic backbone, a macroscopic phase separation on increasing the temperature above the LCST of the PNIPAM is not allowed for pHX3. In semidilute aqueous solutions a pronounced thermally induced viscosity enhancement is observed. This thermothickening phenomenon is almost independent of pH, and it remains quite constant even at pH as low as 3. Thermoresponsive graft copolymer consisting of maleic acid/vinyl acetate (VA) alternating copolymer backbones (poly(MAc-alt-VA) and PNIPAM side chains was synthesized by utilizing the ‘‘grafting onto’’ method [176]. Unlike the interpolymer complexes between PNIPAM and poly(MAc-altVA) in water, which phase separate when heated at pH lower than 2.7, the graft copolymer does not phase separate macroscopically upon heating, even if the pH is as low as 2. Moreover, in semidilute aqueous solutions, a pronounced, thermally

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induced, viscosity increase is observed. This thermoresponsive behavior has been attributed to the interconnections of the hydrophilic poly(MAc-altVA) graft copolymer backbones via the hydrophobic PNIPAM side-chain aggregates, which are formed as the temperature is increased above the LCST of this polymer. Among the polyelectrolytes employed so far in layer-by-layer assemblies, poly(allylamine), generally in the hydrochloride form (PAH), is one of the most frequently used. Gao et al. [177] combined the properties of this cationic polymer with those of PNIPAM. They synthesized poly(allylamine)-gpoly(NIPAM) (PAH-g-PNIPAM) copolymers by grafting carboxylic end-capped PNIPAM onto PAH chains as shown in Fig. 56. The molecular structure of the copolymer impedes the aggregation into condensed core–shell particles, characteristic for block copolymers, because of the strong repulsion arising from the large quantity of ionized NH+ 3 groups. The porous-sphere model would be more suitable as a particle structure at temperatures above the LCST. A temperature cycle could cause a completely reversible polymer aggregation above the LCST and polymer dissolution below the LCST (Fig. 57). Since the PNIPAM chains are rather short (MW 2700), the hydrophobic interaction between these chains can produce hydrophobic phase domains only on a very small scale. Accumulation of these domains in a given spatial volume will then result in a particle with a porous inner structure and with all the interfaces covered by PAH segments. Hydration, and particularly charge repulsion, of this ‘‘shell layer’’ might prevent any further agglomeration of the particles induced by collisions due to Brownian motion. The PAH-g-PNIPAM copolymers have been assembled into multi-layers to demonstrate their possible application as thermosensitive polyelectrolytes.

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Temperature- and pH-responsive graft copolymers can be used for preparation of smart colloidal nanogels. Kuckling et al. [178] achieved this synthesis by photo-cross-linking of PNIPAM graft terpolymers. The graft terpolymers were synthesized from NIPAM, poly(2-vinylpyridine) (P2VP) macromonomers and a chromophore monomer based on dimethylmaleimide (Fig. 58). Solutions of the resulting nanogel with a temperature-responsive core and chemically bonded, pH-sensitive P2VP arms exhibited enhanced stability upon heating, and at low pH, as compared to the corresponding PNIPAM nanogels. A large change of the average hydrodynamic diameter of the gels could be observed by increasing either the temperature above 32 1C or the pH above 5. These authors demonstrated that it is possible to obtain response to one stimulus without interfering with the other stimulus. The effects of temperature, concentration, composition and length of the PNIPAM grafts in the poly(L-lysine)-graft-PNIPAM copolymers on their association in aqueous solutions were investigated by LS [179]. These copolymers were originally designed as potential thermoresponsive polymeric gene carriers. They form well-defined monodisperse particles upon heating at temperatures above 31 1C.

Fig. 57. Schematic illustration of PAH-g-PNIPAM particle structure after phase separation. Reproduced from Gao et al. [177] by permission of Elsevier Science Ltd., UK.

Fig. 56. Synthetic route for preparation of PAH-g-PNIPAM copolymers. Adapted from Gao et al. [177] by permission of Elsevier Science Ltd., UK.

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Fig. 58. Synthesis of graft terpolymers. Adapted from Kuckling et al. [178c] by permission of the American Chemical Society, USA.

The particles formed by the association of copolymers with longer PNIPAM grafts are more compact than the particles formed by the corresponding copolymers with short grafts. The hydrodynamic radii and the MWs of these particles are strongly concentration dependent. The pH- and thermoresponses have also been achieved by applying host–guest chemistry. Recently Choi et al. [180,181] reported pH- and thermosensitive supramolecular hydrogels, of cyclodextrin (CD)-conjugated poly(e-lysine) (PL) and specific guests. Their ability to respond to the stimuli was the result of cooperative ionic interactions as well as specific host–guest interactions. Because of these dual complexation interactions, the supramolecular assemblies showed rapid and reversible responses upon small changes of pH and/or temperature [181,182]. The PL studied is a polycationic antibacterial substance, which consists of about 30 Lys residues, obtained from the culture broth for Streptomyces abulus. It has been used in many biomedical applications because of its biodegradability and high biocompatibility. CDs are composed of six, seven or eight Dglucopyranose units and possess truncated cone-

shaped hydrophobic cavities. The narrow side is occupied by primary hydroxyl groups, while the wide side carries secondary hydroxyl groups. There are no hydroxyl groups inside the cavity so that this region of the molecule is hydrophobic and can incorporate hydrophobic guests such as organic, inorganic and biological molecules to form stable host–guest inclusion complexes. The inclusion complexation of these host–guest systems occurs through various interactions such as hydrogen bonding, van der Waals, electrostatic or hydrophobic interactions. Although the magnitude of the individual bond energy is not as large as that of a covalent bond, the cooperative physical interactions play a key role in many chemical and biological systems. In this sense the CDs have been extensively studied as supramolecular receptors. A pH- and thermosensitive supramolecular hydrogel system was constructed by inclusion complexation of b-CD-conjugated PL (b-CDPL) with 3-trimethylsilylpropionic acid (TPA) (Fig. 59) [181]. The hydrogel showed a reversible gel-sol PT upon heating and cooling typical for the UCST. The ionizable a-amino groups of PL and the carboxylic groups of TPA played an important role in controlling intermolecular aggregation in response

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to a change of the pH in aqueous media. This rapid and delicate supramolecular-assembling system is of great importance as a model, not only for molecular recognitions and enzyme–substrate interactions in biological systems, but also for practical applications such as drug delivery, separation operations in biotechnology, processing of agricultural products, sensors and actuators. Complex block pH- and thermoresponsive micellar materials have been wildely studied during the last decade. Liu et al. [183] prepared doubly sensitive diblock copolymers containing PPO as the hydrophobic and thermosensitive segment with poly(2-(diethylamino)ethyl methacrylate) (PDMAEMA) as a pH-sensitive block by a facile ATRP synthesis (Fig. 60a). This diblock copolymer dissolves molecularly in cold dilute aqueous solutions but undergoes reversible micellar self-assembly to give either PPO-core micelles or DEAEMA-core micelles (Fig. 60b). The two micellar PTs are dictated solely by the solution temperature and the pH.

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Quite recently Schilli et al. [184] found that the well-defined poly(NIPAM-b-AAc) may form micelles or other aggregates depending on solvent, temperature, pH and block lengths (Fig. 61). They synthesized poly(NIPAM-b-AAc) by the RAFT process for the first time. The block copolymerization was performed using PAAc as a macromolecular chain transfer agent. The solubility of the PAAc block in aqueous solution depends on the pH of the medium. The lower the pH the more carboxylate groups of the PAAc blocks are protonated, and the less soluble this block becomes in aqueous media. At pH 4 8 virtually all carboxylate groups are deprotonated and the PAAc segment is readily soluble in water. The PNIPAM’s LCST is altered through the attachment of AAc chains. It is expected to rise if the AAc block is hydrophilic and to fall if the AAc block is hydrophobic. In some cases the LCST behavior can even be lost if the acrylic block is too long [137b]. Turbidimetric curves of PNIPAM-b-PAAc at different pH values are shown in Fig. 62. When the

Fig. 59. Schematic illustration of interactions between cationic b-CDPL and anionic TPA molecules controlling PT. Reproduced from Choi et al. [181] by permission of the American Chemical Society, USA.

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Fig. 60. (a) Synthesis of the PPO-block-PDMAEMA copolymer by ATRP. (b) Schematic representation of formation of micelles and reverse micelles by this diblock copolymer in aqueous solution. Reproduced from Liu et al. [183] by permission of Wiley–VCH Verlag GmbH, Germany.

Fig. 61. Possible modes of aggregate formation for poly(NIPAM-b-AAc) in aqueous solution. Reproduced from Schilli et al. [184] by permission of the American Chemical Society, USA.

Fig. 62. Turbidimetry of buffered aqueous solutions of (NIPAM)50-b-(AAc)110: (K) pH 4.5; (’) pH 5-7. Reproduced from Schilli et al. [185] by permission of the American Chemical Society, USA.

temperature is raised above the LCST of the PNIPAM the transmission decreases only slightly at pH 5.0–7.0. This suggests the presence of micelles with PNIPAM forming the micellar core at T4CP and PAAc forming the corona. When the temperature is raised above the CP, the transmission drops to zero at pH 4.5, thus indicating the formation of larger aggregates due to the increasing insolubility of the protonated PAAc corona. Consequently, the forma-

tion of this type of micelle is dependent on both pH and temperature. DLS measurements suggest the formation of aggregates, even at room temperature, as the hydrodynamic radii of the particles are smaller than those of the micelles observed at a higher temperature, but they are too large for unimers. Conjugation of drugs and proteins to PNIPAM-bPAAc generates thermo- and pH-responsive entities that can be addressed through external stimuli.

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Meyer and Schlaad [186] reported the synthesis of diblock copolymer comprising a thermosensitive PIPOZ block [26] and a pH-sensitive poly(Lglutamate) block (Fig. 63). The PT of polypeptide-based polyacids like poly(L-glutamate) is accompanied by a change of the polypeptide secondary structure [187]. The chains adopt an insoluble a-helical conformation at pHopKa and a soluble random coil conformation at a higher pH. This feature of the polypeptides makes them potentially useful, not only for biomedical applications but also for the bioinspired generation of complex superstructures. Weberskirch et al. [188] favor the cationic polymerization of oxazolines over the controlled radical or anionic polymerization of AAMs since products of higher quality with respect to the MWD and functionality can be obtained. By utilizing ATRP, Determan et al. [189] developed a relatively easy method for the synthesis of amphiphilic ABCBA pentablock copolymers based on commercially available Pluronics F127 block copolymers and various amine-containing methacrylate monomers. The block architecture and the copolymer chemical composition were designed to exhibit both temperature- and pH-responsive selfassembly. Reversible gelation at temperatures close to the physiological ones and pH-dependent micellization make these pentablock copolymers poten-

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tial candidates for use in injectable drug delivery devices that exhibit pH-regulated release and in injectable gene delivery applications. The copolymers were successfully used for the formation of complexes with DNA (polyplexes) [190]. The positively charged groups of the polycation enable formation of polyplexes with the negatively charged phosphates of DNA via electrostatic interactions. This leads to DNA condensation and protection against nuclease digestion. In addition it provides a more efficient delivery of the plasmid DNA into the cell. These injectable delivery systems have several advantages over other common gene delivery systems: simple preparation without organic solvents, no need for surgical procedures to implant matrices, easy storage at 4 1C, ability to vary polymer fractions to tailor and minimize toxicity, and controlled release of polyplexes to circumvent the repeated administrations needed with other polymers. Glinel et al. [191] (Fig. 64) obtained not very well defined block copolymers of PNIPAM and poly(diethylammoniumethyl methacrylate) or poly(styrene sulfonate). The exact block copolymer structure has not been specified as the real structure is very likely a mixture of diblock and triblock copolymers. However, very interesting thermosensitive hollow capsules were fabricated. For this purpose the block copolymers were deposited layer-by-layer onto

Fig. 63. Synthesis of poly(2-isopropyl-2-oxazoline)-block-poly(L-glutamate). Adapted from Meyer and Schlaad [186] by permission of the American Chemical Society, USA.

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colloid particles [191,192]. By removal of the template cores, the hollow microcapsules were obtained. Apparently, thermosensitive polymers incorporated in thin films or capsules may intelligently gate the permeability and selectivity for specific molecules or materials. 6.3. Interpolymer complexes One way to improve the rheological properties of hydrophobically modified water-soluble polymer (HMWSP) is by mixing two appropriately chosen, HMWSPs. The mixed aggregates formed between the alkyl groups of the two polymers lead to viscous solutions, as in the case of HMWSP/surfactant mixtures. PNIPAM is able to interact strongly with hydrophobically modified poly(sodium acrylate) (HMPA) in aqueous solutions [193]. This specific interaction is due to the hydrophobic character of the two polymers: at 25 1C the hydrophobicity of the PNIPAM is high as this temperature is close to its LCST; and the HMPA copolymers, although they are composed of the hydrophilic poly(sodium acrylate) backbone, also contain strongly hydrophobic octadecyl groups. The hydrophobicity of both polymers is a prerequisite for the development of attractive interpolymer interactions. If poly(sodium acrylate) is not hydrophobically modified, no association is observed. The mixed aggregates act as cross-linkers between the PNIPAM and the HMPA chains, and consequently the viscosity of the mixtures increases (Fig. 65). These interactions are temperature dependent and thermothickening behavior has been observed with increasing temperature. A schematic illustration of the principle of hydrogen-bonding-driven thermoresponsive volume PT in the PAAc–polyacrylamide (PAAM)-based interpenetrating network (IPN) is shown in Fig. 66. The IPN hydrogels form intermolecular complexes via hydrogen bonding below the UCST whereas

Fig. 64. Structures of PNIPAM-based block copolymers. Adapted from Glinel et al. [191] by permission of Wiley–VCH Verlag GmbH, Germany.

they dissociate at temperatures above the UCST. Driven by the hydrogen bonding, the PAAM/ PAAc-based IPN hydrogels shrink at lower temperatures and swell at higher temperatures, thus revealing a positive thermoresponsive volume-PT behavior, which is opposite to that of PNIPAM [194]. Hydrogen-bonded interpolymer complexes between PNIPAM and PMAAc were studied in aqueous solutions by high-sensitivity DSC, analytical ultracentrifugation and LS [195]. The composition of the complexes was varied by changing the PNIPAM/PMAAc mole ratio and the pH. The PT of the PNIPAM was dramatically changed by complexing with PMAAc. The solubility of the complexes increased with increasing PMAAc content and decreased with decreasing pH. Because of the hydrophobic–hydrophilic balance controlled by the pH and the polymer ratio, the complexes were able to undergo a reversible intramolecular cooperative conformational transition from a coil to a more compact folded state without loss of solubility. This transition takes place at temperatures below the LCST of the PNIPAM and is not related to the phase separation. Zhang and Peppas [196] prepared IPN hydrogels composed of PNIPAM and PMAAc via a sequential UV-induced solution polymerization. These hydrogels exhibit a swelling transition at 31–32 1C (LCST of the PNIPAM), and pH ca. 5.5 (pKa of PMAAc), indicating that the responses of each network are relatively independent. Permeation studies indicate significant size exclusion behavior while model drugs of different sizes permeate through the IPN membranes. The permeability of the IPN membrane was significantly affected by varying the pH and temperature. A model drug had the highest permeability at the physiological state of

Fig. 65. Proposed association mechanism between PNIPAM and HMPA. Reproduced from Bokias et al. [193] by permission of the American Chemical Society, USA.

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Fig. 66. Principle of hydrogen bonding-driven thermoresponsive volume phase transition. Reproduced from Xiao et al. [194] by permission of Elsevier Science Ltd., UK.

37 1C and pH 7.4, which is obviously desirable in membrane and drug delivery applications. 6.4. pH- and thermostimuli in homopolymers Usually polymers that respond to more than one stimulus, in particular to temperature and pH, are prepared by copolymerization reactions of monomers, sensitive to both temperature and pH. Two homopolymers sensitive to dual stimuli (pH and temperature) are poly(N-acryloyl-N0 -propylpiperazine [197] and poly(N-ethylpyrrolidine methacrylate) (PEPyM) [198]. PEPyM exhibits a PT in water at 15 1C, and is also sensitive to pH changes. The LCST of the polymer can be modulated by copolymerization reactions with dimethylacrylamide when required for specific applications. At pH 1–4 PEPyM behaves (when cross-linked) as a superabsorbent hydrogel with low sensitivity to temperature changes, whereas at pH 5–7.4, temperature sensitivity is clearly observed. At basic pH, the PEPyM hydrogels are in a collapsed state at the temperature of the study, as their PT temperature is lower than 10 1C. Pulsatile (on–off) behavior in the swelling–deswelling ability was also observed when the stimuli were removed or reversed. 7. Combination of magnetic field and thermoresponsive properties Some hydrogels and nanoparticles have been developed to combine field- and thermoresponsive mechanisms within a single polymer system. Attempts at developing stimuli-responsive gels are often complicated by the fact that structural changes, such as volume changes, are kinetically restricted by relatively slow swelling or deswelling. This disadvantage often hinders efforts to design gels optimally for different purposes. In order to accelerate the response rate and to achieve agitation without contact a new driving mechanism, involving

magnetic and electric fields could be applied and appears to be very promising. Moreover, for any technical application it is of great importance to have a quick and reliable control system. Obviously, electric and magnetic fields are the most practical stimuli with respect to signal control. Other applications require noncontact modes of deformation and high flexibility. In order to enhance the influence of external fields on the solution and/or gel properties, it is necessary to combine solid-like and fluid-like behavior. Therefore, new colloidal solutions termed ‘‘complex fluids’’ have been thoroughly investigated. Electrorheological fluids, magneto-rheological fluids and ferrofluids contain dispersed small particles in the size range from nanometers to micrometers. These fluids respond to applied fields by rapidly changing their apparent viscosity and yield stress. Since polymer gels contain a substantial amount of liquid as a swelling agent, it is possible to design fieldsensitive gels by using a polymer network swollen in a complex fluid. The colloidal particles incorporated within the gel, which are characterized by strong adsorptive interactions between solid particles and polymer chains, allow fast response to an external field. These field-sensitive gels can be exploited to construct new types of soft actuators, sensors, microengines, biomimetic energy-transducing devices and controlled delivery systems. 7.1. Protein and nucleic acid concentration and purification In recent years, increasing interest has been devoted to the preparation of magnetic latex particles for diagnostic applications. The pioneer work in this field has been done by Ugelstad et al. [199] who reported the preparation of magnetic microspheres with narrow size distribution and also described their utilization as a support for biomolecules [200]. The introduction of thermosensitive

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microgel particles with LCST behavior is of great interest in biomedical research, since their physicochemical properties and protein adsorption–desorption behavior can be controlled by pH, temperature and salinity of the medium [201]. Ding et al. [202] prepared thermosensitive magnetic particles with core/shell structure by copolymerization of styrene and NIPAM in the presence of Fe3O4 magnetic fluid in an ethanol/water medium. Particles with various diameters were obtained, depending on the initiator concentration and the NIPAM/styrene mole ratio. Ding et al. [203] investigated the adsorption–desorption behavior of human serum albumin (HSA) protein on these particles. The extent of adsorption was influenced by the pH, the incubation time, and by the initial protein concentration. The results from adsorption–desorption cycles implied that magnetic particles covered by thermosensitive polymers are potential tools for protein separation (as presented schematically in Fig. 67). The adsorption of HSA was governed principally by hydrophobic interactions above the LCST of PNIPAM. The desorbed amount of protein below the LCST was drastically affected by experimental conditions such as incubation time, pH, salinity, and temperature of the medium. The results obtained indicate that such particles could serve as an alternative route for protein concentration and purification, thus supplementing other techniques such as the familiar precipitation in a high salt medium, the Sepharose gel column system, and concentration via specific capture of species [204]. Elaissari et al. [205] prepared cationic core–shell magnetic latex particles bearing the PNIPAM copolymer in the shell, where the second comono-

mer was 2-aminoethylmethacrylamide hydrochloride, by encapsulation of the magnetic core using a precipitation polymerization process. The cationic character of the particles was favorable for nucleic acid adsorption–desorption by controlling the pH and the salinity of the medium. The efficiency of the magnetic latex particles in concentrating the nucleic acids was demonstrated both with synthetic and biological targets. The magnetic latex particles are thus useful as purification and concentration tools in a sample preparation step preceding amplification technologies in the diagnostic field. Chang and Su [206] prepared thermosensitive magnetic particles suitable for adsorption and desorption of emulsifiers by linking g-methylacryloyl oxypropyl trimethoxysilane with magnetic powder followed by hydroxylation and grafting of NIPAM (Fig. 68).

Fig. 67. Protein separation with thermosensitive magetic particles (TMP). Reproduced from Ding et al. [203] by permission of John Wiley & Sons Ltd., UK.

Fig. 68. Formation of modified magnetic particles. Reproduced from Chang and Su [206] by permission of Elsevier Science Ltd., UK.

7.2. Immobilized-enzyme reaction control It is known that a reaction catalyzed by an enzyme immobilized in a gel can be accelerated by repeating an up-and-down temperature change, which results in reiterating the deswelling–swelling of the gel. Park and Hoffman [207] proposed that a thermosensitive gel acts like a ‘‘hydraulic pump’’ during a cyclic thermal operation, and thus sucks up the fresh substrate on cooling and squeezes out the product on heating. They speculated that the isothermal heating from the outside of gel might result in a formation of a hydrophobic ‘‘skin layer’’ which plays an important role in the deswelling process. Kato et al [208] and Takahashi et al. [209] proposed a different performance of the ‘‘hydraulic pump’’ under magnetic heating. The heat was generated inside the gels due to the hysteresis loss of the entrapped ferromagnetic powder under

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exposure in an alternating magnetic field. Formation of the ‘‘skin layer’’ did not appear to be caused by the magnetic heating as the gels were heated from inside. These authors proposed that a shorter deswelling–swelling cycle might lead to a higher conversion in the enzyme reaction [208]. A thermosensitive NIPAM/AAM gel in which gFe2O3 particles are entrapped swells or shrinks in response to magnetic heating. Since the heating occurs inside the gel, a dehydrated, dense ‘‘skin layer’’ is not formed on the gel surface upon heating, as in the case of heating by a surrounding heat source. Takahashi et al. [209] immobilized invertase and g-Fe2O3 in a copolymer gel of NIPAM and AAM in order to study the sucrose hydrolysis in a column packed with NIPAM/AAM hydrogel immobilized enzyme in a magnetic field. When the magnetic field was applied, the overall concentration of the reducing sugars in the outlet solution increased initially and then decreased due to thermal shrinkage of the gel support. This result clearly demonstrates the potential utility of the gelentrapment system for magnetic control of immobilized enzyme reactions. The column temperature rose from 24–25 to 31–56 1C due to heat generated from magnetic hysteresis loss. It should be emphasized that magnetic heating of the NIPAM/AAM gel is energetically more efficient than heating the whole column. Kondo and Fukuda [210] prepared magnetic hydrogel microspheres by copolymerization of IPAM, MAAc and BIS in the presence of ultrafine magnetite particles. The microspheres obtained had average diameters from 150 to 250 nm. All the magnetic hydrogel microspheres showed a reversible transition between flocculation and dispersion as a function of temperature; and the thermo-flocculated microspheres could be separated quickly in the magnetic field. Trypsin and a fusion enzyme consisting of affinity tag AG (immunoglobulin G binding domains) and b-galactosidase were covalently immobilized on the thermosensitive magnetic microspheres. Depending on the MAAc content in the hydrogel, the enzymes showed high activity proving that magnetic microspheres are suitable for applications in biotechnology. Guo et al. [211] recently fabricated organic/ inorganic composite microspheres with well-defined core–shell structure comprising a cross-linked PNIPAM shell and silica cores dotted centrally by magnetite nanoparticles. Since the permeability is triggered by changes of exterior temperature, the

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silica layer sandwiched between the magnetic core and the PNIPAM shell could be quantitatively removed by treatment with aqeous NaOH. As a result, PNIPAM microcapsules with mobile magnetic cores were obtained. For the development of multi-functional microcapsules, modification of the unetched silica surface interiors can be achieved by treatment with a silane coupling agent containing functional groups that can easily bind to catalysts, enzymes or labeling molecules. 7.3. Triggered drug release Schmidt [212] have developed a new strategy for thermoreversible stabilization of magnetic particles by the use of a well-defined polymeric shell exhibiting critical solution behavior in the carrier fluid. Thermoresponsive ferrofluids are first synthesized by combining a magnetite core with a polycaprolactone shell exhibiting a critical solution temperature in the DMSO carrier medium. Under the influence of a magnetic field, the core warms up owing to magnetic induction and causes a thermal transition in the shell. Thermoreversible stabilization of the particles offers an opportunity to combine the dispersibility and quasi-homogeneous conditions for specific binding and catalytic activity as well as easy magnetic separation at temperatures beyond the stabilizing conditions. For this purpose Gelbrich et al. [213] synthesized novel thermoreversible magnetic fluids based on magnetite (Fe3O4) coated with a covalently anchored polymeric shell of poly(2-methoxyethyl methacrylate) (Fig. 69). The core–shell particles form stable dispersions in methanol at temperatures above an UCST, while the particles precipitate below that temperature and can easily be separated by a magnet. The combination of thermoresponsive polymers with properties of magnetic fluids, together with tailorable hydrodynamic diameter and critical temperature, contributes to the development of easily recoverable polymer-supported magnetic separation kits and catalytic systems. The established procedures for the preparation of spherical polymer beads require reaction times between 3 and 24 h. However, Mueller-Schulte and Schmitz-Rodeet al. [214] developed a novel inverse suspension polymerization technique that allows bead preparation within minutes. The key parameter for finding appropriate conditions for stable droplet formation, which is a prerequisite for the final bead formation, is the oil phase, and

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Fig. 69. Synthesis of Fe3O4/poly(2-methoxyethyl methacrylate) hybrid nanoparticles by surface-initiated ATRP. Reproduced from Gelbrich et al. [213] by permission of the American Chemical Society, USA.

particularly its viscosity and surfactant composition. This approach ultimately resulted not only in a fast synthesis of the beads, but also in a very simple encapsulation of drug model substances and the necessary magnetic colloids. Spherical thermosensitive micro and nanoparticles based on NIPAM were synthesized by using this novel inverse suspension polymerization technique (Fig. 70). This suspension technology provides a broad platform for a simple, simultaneous encapsulation of diverse species such as magnetic colloids and bioactive substances; and it offers an intriguing basis for a combinatorial application of two basic therapeutic procedures and one diagnostic procedure, viz. drug release and hyperthermia as well as use of a contrast agent in tumor tissue imaging.

7.4. Chemo-mechanical devices Kato et al. [215] used magnetically triggered PNIPAM gel to construct a simple chemo-mechanical device. Using NaCl solution instead of a water medium, they improved their initial device so that it could not only lift more weight but also accelerated gel deswelling process. Thus, they demonstrated energy conversion from heat to mechanical work. Furthermore, they found that the thermally sensitive PNIPAM gel in NaCl solution would deswell by Joule’s heat within the gel after application of an AC voltage (100 V, 50 Hz) [216]. Since this device could reduce heat loss due to radiation, the electric heating could have an advantage over magnetic heating in saving energy. The unique magnetoelastic properties of the magnetic gels make it possible for them to mimic

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Fig. 70. Flow diagram of NIPAM bead preparation. Reproduced from Mueller-Schulte and Schmitz-Rode [214] by permission of Elsevier Science Ltd., UK.

muscular contraction [217]. If magnetic field is created inside the gel by incorporating small powerful electromagnets and the field is co-coordinated and controlled by a computer, the magnetic-fieldsensitive gel may find use as an artificial muscle. 8. Thermo- and light-sensitive polymers While temperature and pH are well-known signals which induce phase separation in polymer systems, the use of light as another type of signal has not yet found a wide application. Nevertheless, the fact that light can be directed at a very short distance to a target without making contact makes it a potential trigger inducing a PT. The combination of thermal and light sensitivity within the same polymer was investigated in the mid 80’s by Irie and Kungwatchankun [218] They synthesized PNIPAM partly modified with azobenzene chromophores. Upon UV-irradiation the azobenzene groups in these polymers turn from the more hydrophobic trans- to the more hydrophilic cis-configuration. This results in an increase of the LCST of the dual-responsive polymers depending on the degree of isomerization. Later, Kroeger et al. [219] found a 20 1C photoinduced LCST shift in the aqueous solution of another azobenzene-modified thermosensitive polymer— poly(N,N0 -dimethylacrylamide) Desponds and Freitag [220] applied free-radical chain transfer telomerization of NIPAM and three different succinimide-containing comonomers to obtain thermoresponsive semitelechelic cotelomers

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characterized by a statistical distribution of the comonomers, low polydispersity and a controlled molar mass. The ‘‘activated ester’’ N-hydroxysuccinimide groups were then replaced by primaryamine-terminated chromophores (Fig. 71). The temperature-induced PT of these telomers can be controlled by UV–visible irradiation. The photoisomerization of the incorporated chromophores results in LCST shifts of up to 3 1C. The change of the PT behavior upon irradiation is mainly dependent on the hydrophobic/hydrophilic balance of the polymers and the chain conformation in solution. Recently, Sumaru et al. [221] synthesized a multiresponsive functional polymer by modification of PNIPAM with spirobenzopyran. This chromophore is believed to have four stable forms and the fraction of each form depends both on pH and irradiation with light. The authors studied the cooperative effects of irradiation, and temperature and pH changes on the PT behavior of the aqueous polymer solution. They found that the copolymer solution exhibits a logic-gate response to irradiation and that the temperature increases in three different modes depending on the pH of the solution. This behavior was attributed to the interaction between the thermoresponsive PNPAM main chain and the light- and pH-sensitive spirobenzopyran moieties. UV–visible measurements on an aqueous copolymer solution at different temperatures revealed that the dielectric envinronment of the copolymer was changing continuously with temperature, even far below the LCST [126]. This result suggested that the local weak orientation of the water molecules around the polymer was diminishing gradually during the early stage of the process leading to thermally induced phase separation. Various water-soluble diblock copolymers of DMAEMA and azoacrylate or azomethacrylate monomers were synthesized via ATRP [222]. The aqueous copolymer solutions showed LCST behavior. However, the photoinduced trans– cis isomerization had only an insignificant effect on the PT behavior of the azomethacrylate block copolymers owing to the formation of very compact core–shell micelles as a result of the high glass transition temperature Tg. Very recently, Lee et al. [223] reported the synthesis of well-defined, densely grafted molecular brushes containing trans-methacryloyloxyazobenzene (MOAB) and DMAEMA units in the side chains. The brushes were obtained by an ATRP ‘‘grafting from’’ approach. The temperatue dependence

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Fig. 71. Schematic presentation of the two-step approach for the synthesis of thermo- and photoresponsive polymers. Adapted from Desponds and Freitag [220] by permission of the American Chemical Society, USA.

Fig. 72. Schematic illustration of possible modes of aggregation behavior of statistical polymer brush in aqueous solution depending on the photochemical isomerization and temperature. Reproduced from Lee et al. [223] by permission of the American Chemical Society, USA.

of transmission spectra of an aqueous copolymer solution at 600 nm proved that the LCST was affected by the photoisomerization of the azobenzene units. The statistical copolymer brush with trans-MOAB units showed LCST behavior, presented schematically in Fig. 72. However, after isomerization to cis-azobenzene (less hydrophobic) upon UV-irradiation, the brush did not show the LCST within temperature range examined. This behavior indicates that dual-responsive polymer brushes can be prepared in this way. Living cationic copolymerization of 2-(2-ethoxy) ethoxyethyl vinyl ether (EOEOVE) and 4-[2-vinyloxy)ethoxy]azobenzene (AzoVE) was performed to obtain thermo- and photoresponsive poly(vinyl ethers) with azobenzene side groups (Fig. 73) [224]. The random copolymers of EOEOVE (exhibiting LCST behavior) and AzoVE showed different cloud temperatures under irradiation with UV or visible light due to cis– trans isomerization.

In this way it is possible to control the solubility of the polymer by irradiation at specific wavelengths at fixed temperature. For example, at 37 1C, the polymer with cis azo groups formed a clear solution while the trans-containing counterpart was water insoluble. Irradiation of the clear solution with visible light induced phase separation. Subsequent UV-irradiation returned the mixture to a clear solution and this process remained almost reversible, even after 100 cycles of photoinduced phase separation. Besides the random and the block copolymers, the photothermally modulated volume transitions in polymer hydrogels have shown a potential for applications in materials science [225,226] and in drug delivery systems [227,228]. Photoresponsive microgels consisting of lightly cross-linked PNIPAM copolymerized with an amine-containing comonomer were prepared by precipitation polymerization followed by covalent

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Fig. 73. Schematic structure of dual responsive poly(vinyl ether) and cis– trans isomerization upon visible or UV-irradiation. Adapted from Yoshida et al. [224] by permission of John Wiley & Sons Ltd., UK.

attachment of the temperature-jump dye malachite green (Fig. 74) [229]. Upon excitation with He–Ne laser the dye molecules undergo a nonradiative decay, resulting in an increase of the sample temperature, which in turn causes the microgel to undergo partial or complete deswelling. The deswelling of microgels can be manipulated by the amount of attached dye, the temperature, or the power of the pump laser. Another way of obtaining photo- and thermoresponsive hydrogel is the copolymerization of NIPAM, a vinyl monomer containing spirobenzopyran residue and a crosslinker (Fig. 75) [226]. Under acidic conditions the gel exhibited drastic, rapid volume shrinkage when irradiated with blue light. Furthermore, a photo- and thermoresponsive gate membrane was prepared by coating the gel onto the surface of a porous membrane. In this way reversible photocontrol of liquid permeation was demonstrated for the first time. Photo- and thermally switchable hydrogels were obtained by photochemical crosslinking of PNIPAM-co-AAc random copolymers modified with different chromophores: acridizinium [230], Nmethylstilbazolium, (propyloxy)N-methylstilbazolium and stilbene groups [230,231]. By cyclic changes of the wavelength of the irradiating light, the crosslinking reactions were reversed within certain limits. The temperature of volume PT of gels depended on the degree of crosslinking so the swelling/deswelling behavior of the networks was expected to be isothermally switched by exposure to light of an appropriate wavelength. Sershen et al. [227,232] prepared temperaturesensitive polymer nanoshell composites: nanoparticles with a dielectric core, coated with a metal shell.

Fig. 74. Structure of malachite green isothiocyanate.

Fig. 75. Chemical structure of cross-linked gel. Reproduced from Sumaru et al. [226] by permission of the American Chemical Society, USA.

In order to convert light to heat, gold nanoshells were embedded in a thermally responsive polymer PNIPAM-co-AAM. This copolymer cannot absorb strongly either visible or near infrared light. Hence the absorption of the composite was dictated by the nanoshells, which can be designed to maximize absorption in the spectral region of the light source.

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Drug molecules can be stored in a swollen composite hydrogel, which can be then implanted in the human body. By irradiating the implanted hydrogel the drug will be released, thus possibly allowing nanoshell–polymer composites to be used in photothermally modulated drug delivery. Another hybrid microgel that is photoresponsive in the near infrared spectral range, was prepared from PNIPAM-co-AAM and gold nanorods designed to absorb near IR-light [228]. Upon irradiation at 810 nm, the hybrid particles shrank by ca. 53%. These photothermally responsive microgels might also have potential application in drug delivery systems. 9. Solvent-sensitive PEO conjugates of thermoresponsive polymers PEO is one of the most studied water-soluble synthetic polymers. It remains unique in its macromolecular properties (availability with narrow MWD, a flexible polymer chain and end-functionality) and solubility both in water and organic solvents. PEO is characterized by hydrophilic interactions (hydrogen bonding of water molecules to the oxygen atoms on the polymer) and hydrophobic interactions because of the –CH2CH2– groups that repel water. PEO can dissolve in water only because water molecules form a layer around the macromolecule. This behavior is due to the fact that the oxygen–oxygen distance in the PEO chain matches the oxygen–oxygen distance in the structure of water. This is reminiscent of the hydration layer around proteins. The properties of this polymer are very complicated in that, although water-soluble, PEO chains fail to adsorb to most hydrophilic surfaces except at low pH. However, they adsorb from water if the surface is hydrophobic, a behavior well-known for amphiphilic molecules. These features make PEO an ideal candidate in designing stimuli-responsive block copolymers, particularly for application in medicine, and especially in the development of ‘‘stealth’’ long-circulating carriers in the human body. PEO is very sensitive to small changes in solvent properties (addition of salts and surfaceactive compounds in aqueous solution, addition of organic solvent, etc.) Biocompatibility is one of the most remarkable advantages of PEO. Typically, PEO with MW of 4000 is 98% excreted from the human body [233]. Hydrophilic PEO can also be used to modify the

surface properties of polymer particles [234]. The inclusion of PEO in copolymer systems imparts extremely beneficial surface properties within the body because of the ability to repel proteins in the aqueous environment. This repulsion prevents many polymer–cell interactions. For example, nanoparticles made from diblock poly(D,L-lactide-b-ethylene oxide) copolymer have increased blood circulation times (decreased clearance) in vivo above that of particles made from poly(D,L-lactide) alone [235]. Another advantage of PEO is that it can be prepared with a number of terminal functionalities, leading to its easy incorporation into copolymer systems. The biocompatibility of PEO, its effective prevention of the protein adsorption, its solubility in water, and in most organic solvents as well, and its easy functionalization have motivated syntheses of PEO-containing amphiphilic polymers as vehicles in drug delivery system [236–238]. The solution properties and self-assembling of amphiphilic block and graft copolymers containing PEO as a hydrophilic part is an essential topic in the polymer science not only from the theoretical but also from the practical point of view [239]. Such polymers have also been used to stabilize dispersions and emulsions. Since hydrophilic PEO provides steric stabilization of amphiphilic block- or graft-copolymer in aqueous solution, the combination of temperaturesensitive polymer and solvent-sensitive PEO should exhibit interesting thermosensitive aggregation behavior as at low temperature the interactions between PEO and water can effectively restrain the collapse of thermosensitive sequences. 9.1. Block copolymers comprising thermoresponsiveand hydrophilic-PEO blocks The unique properties of PEO–PNIPAM block copolymers in water have recently attracted much attention [51,53,55,56,240–244]. The combination of the temperature-sensitive PNIPAM and PEO blocks results in interesting thermosensitive aggregation behavior. In aqueous solutions below the LCST, these polymer structures are doubly hydrophilic and molecularly soluble. Above the LCST the PNIPAM blocks become hydrophobic, thus forming the inner core of the polymeric micelle, whereas the PEO blocks provide a steric stabilization because of the participation in the hydrophilic outer corona. Such micelles may dissolve owing to the loss of

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micellization capacity when the temperature is decreased below the LCST of the PNIPAM in the block copolymer. The block copolymers may be used as stimuli-sensitive drug delivery systems [237]. After administration and arrival of the micelles at the target in the body, for instance a tumor, a burst of a loaded drug could be achieved by local hypothermia. Therefore, many research groups have endeavored to synthesize well-defined block copolymers containing PEO and PNIPAM. Topp et al. [51,55] and Zhu and Napper [56,240] synthesized PNIPAM–PEO block copolymers from mono-hydroxy or bis-hydroxy end-functionalized PEO by radical polymerization of NIPAM using cerium(IV) redox initiation. The block copolymers have a narrow MWD leading also to a narrow size distribution of the micelles. The main drawback of the method is that Ce(IV) can directly initiate the polymerization of NIPAM to form homo-PNIPAM [53] and the Ce(III) ions produced can interact with PNIPAM-b-PEO to form complexes [240]. Another approach is to use PEO capped with an azobisisobutyronitrile derivative [241]. However, as in the case of Ce(IV)/OH redox system, homoPNIPAM contamination cannot be avoided during the block copolymerization. Recently, Hong et al. [242] successfully synthesized well-defined diblock and triblock copolymers composed of PNIPAM and PEO through RAFT

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polymerization of NIPAM initiated by PEO capped with one or two dithiobenzoyl groups (Fig. 76). PEO capped with DTBA groups can be easily prepared without specific purification because of the high capping efficiency of the maleic anhydride group (MAh) on PEO and the high addition reaction efficiency of MAh in MAh-PEO with DTBA. DTBA-terminated PEO is an effective transfer agent in the RAFT polymerization of PNIPAM. The chain length of the PNIPAM block in the diblock and triblock copolymers can be controlled by the initial molar ratio of NIPAM to the DTBA-terminated PEO as well as by NIPAM conversion. PEO-b-PNIPAM block copolymers were synthesized also by the ATRP of NIPAM using PEO macroinitiator [243]. When the polymerization temperature is 25 1C, the block copolymer is soluble in water, whereas it phase-separates to form micelles during polymerization as temperature is raised to 50 1C. In order to prepare stable hydrogel nanoparticles in water at room temperature, a small amount of N,N0 -ethylene bis-acrylamide was added as a cross-linker to the reaction system. The results of Zhu and Napper [56] showed that the PNIPAM-b-PEO microgel displays its unique aggregation behavior in aqueous solutions. The aggregate size and its distribution can be well controlled by fast heating. Aggregate particles with

Fig. 76. Synthetic scheme for preparation of PNIPAM-b-PEO copolymers via RAFT polymerization technique. Reproduced from Hong et al. [242] by permission of John Wiley & Sons Ltd., UK.

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monomodal size distribution can be obtained if the sample is quickly heated to temperatures above the critical aggregation temperature. The fast heating can result in smaller particle sizes at higher temperatures. The aggregate size obtained is almost independent of the microgel concentration if the temperature is high enough. This observation has been explained as a competition between intraparticle ‘‘coil-to-globule’’ transition and interparticle aggregation. On the basis of this finding, Zhu [244] studied the effects of the feed molar ratio (NIPAM to PEO) on the particle formation of PNIPAM-b-PEO in the presence of the cross-linker BIS and the aggregation-collapse behavior. He found that as the feed molar ratio of PNIPAM to PEO is increased, the morphology of PNIPAM-b-PEO can be developed from graft-like to a core–shell particle (Fig. 77). Smaller particle dimensions with a narrower size distribution can be obtained by the fast heating process. In all cases nanoparticles with a welldefined core–shell structure were obtained. The formation, and especially the shape of aggregates, was influenced by the length of the PNIPAM block, the mole ratio of the repeating units of PNIPAM and PEO, and the polymer concentration [241]. In general, the increased PEO block length affected critically the size and shape of the aggregates as well as the mass distribution within them above the LCST, owing to the enhanced solubilizing effect of PEO on the collapsing PNIPAM and the improved

steric stabilization of the aggregates induced by a PEO shell. Very recently, Zhang et al. [245] reported a lightscattering study of PEO-b-PNIPAM thermoresponsive micellization in water. The copolymer used was designed with low and narrowly distributed MW of PNIPAM block (PEO110-b-PNIPAM44). It was shown that the temperature-induced micellization depends strongly on the block copolymer concentration. The micellization of PEO110-b-PNIPAM44 at high copolymer concentration favors the formation of narrowly distributed, small dense micelles, unlike the gelation behavior of PEO-b-PNIPAM with a high molar mass PNIPAM block. On the other hand, large, loose micelles or micellar clusters are formed at low block-copolymer concentrations. Lin and Cheng [53] successfully used the Ce(IV)/ OH redox-initiated free-radical polymerization in water to synthesize block or star copolymers with a central hydrophilic PEO segment (A) and temperature-responsive PNIPAM terminal segments (B) (Fig. 78). Block and star copolymers of PEO and PNIPAM form liquid aqueous solutions at low temperature and transform to relatively strong elastic gels upon heating. Multiple-arm copolymers appear to form gels via a physical cross-linking mechanism, while diblock copolymers interact by a micellar aggregation mechanism. The rheological properties of the gels are dependent on the molecular architecture, with A(B)4 showing superior properties. The copolymers show low to moderate

Fig. 77. Schematic models for formation mechanism of aggregate particles and collapse transition for PNIPAM-b-PEO. Thin and bold curves represent PEO and PNIPAM respectively. Reproduced from Zhu [244] by permission of Springer Science+Business Media, Germany.

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injection viscosities, high gel strengths, low degrees of syneresis, and rapid gelation kinetics. Therefore, they are promising candidates for clinical uses such as in situ drug delivery, cell encapsulation, and anatomical barriers. Commercially available water-soluble triblock copolymers PEO–PPO–PEO and PPO–PEO–PPO, known under the trade names Pluronics and Synperonics are another combination of PEO with a thermoresponsive block (PPO). Pluronics are an important class of amphiphilic copolymers which display temperature-induced micellization. The aqueous solution properties of these materials have been thoroughly studied. Therefore, they are not an object of this review. Next we turn our attention to their analogs, the superhigh-MW (HMW) copolyethers, which are important industrial materials widely used in paper industry as flocculants, in pharmacy and cosmetics, and in the production of Li batteries and solar cells. In the last decade, a many of HMW amphiphilic copolyethers have been prepared by anionic suspension polymerization using a calcium–amide–alkoxide initiating system [54,246–250]. The materials produced by anionic suspension polymerization are typically not well defined: they are characterized by a broad MWD and compositional heterogeneity. On the other hand they are industrial products and have many useful applications. Recent results on aqueous solution properties of HMW PEO homopolymers [251] and novel poly(ethylene oxide-balkylglycidyl ether) diblock copolymers [250] establish that the coronas of the micelles formed by

Fig. 78. Schematic diagram of AB, A(B)2, A(B)4, and A(B)8 copolymers. Reproduced from Lin and Cheng [53] by permission of the American Chemical Society, USA.

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HMW amphiphiles can be considered as a single separate entity. Like the Pluronics copolymers, the HMW analog poly(propylene oxide-b-ethylene oxide) self-associates in a narrow concentration interval [252]. The aggregates exist at very low concentrations. In addition, they exhibit an enhanced kinetic stability towards dilution below the critical aggregation concentration (cac) and their disintegration takes weeks. In line with the extremely high MW of the polymer, the aggregates are characterized with low aggregation numbers in the range 2–3. 9.2. Graft copolymers comprising thermoresponsiveand hydrophilic PEO blocks The most studied copolymer architecture is the graft copolymer, with PNIPAM as a thermally sensitive backbone and PEO as hydrophilic grafts [253–259]. Usually the synthesis involves the freeradical copolymerization of NIPAM and PEO methacrylate [253,254]. The drawback of this approach is that the presence of long PEO chains in the copolymers gives a high probability for chain transfer to monomer during the polymerization [260]. The reaction is accompanied by gel formation due to the fact that the EO repeat unit in PEO and its derivatives has a chain transfer constant of the order of 103–104. However, Virtanen et al. [255,256] were successful in preventing cross-linking by employing another synthetic route to obtain well defined PEO-grafted PNIPAM. They started with the preparation of a functionalized backbone polymer by free-radical copolymerization of NIPAM with either N-acryloylsuccinimide (NASI) or glycidyl methacrylate. The second step was the attachment of various amounts of NH2-PEO (Mw 6000) to the functionalized backbones. According to Qiu and Wu [253] the formation of the PNIPAM-g-PEO nanoparticles with a ‘‘core–shell’’ structure involves two processes: an intrachain ‘‘coil-to-globule’’ transition and interchain aggregation (Fig. 79). For short PNIPAM-g-PEO chains, the interchain aggregation is dominant, but for a given copolymer concentration, fast heating can suppress it. Using longer copolymer chains, a dilute solution, and a fast temperature jump, the authors claimed successful preparation of a singlechain particle with a ‘‘core–shell’’ nanostructure. High-molar mass PNIPAM-g-PEO copolymers (Mn41  107 g/mol) with densely grafted PEO chains (one PEO chain per 30 repeating units of

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backbone chain) could undergo a very broad temperature-induced ‘‘coil-to-globule’’ transition [254]. At low temperature and in buffer solution, the long copolymer chains exist in random coil conformation with densely grafted PEO branches. At high concentrations (i.e. X10 wt%), these expanded copolymer chains can form a network with relatively stable pores by chain overlap. The densely grafted PEO chains play an important role in the high sieving ability for DNA separation in capillary electrophoresis. When the temperature is increased above the LCST of the copolymers, the copolymer chains collapse to nanoparticles with PNIPAM inside the core and the hydrophilic PEO chains on the shell. Such a conformation causes the copolymers to lose good sieving ability as a DNA separation medium. By studying almost the same polymer architecture Tenhu et al. [255,256] found that the LCST of the copolymers is highly influenced and increases with an increasing number of the PEO grafts. With an increasing amount of PEO, the density of aggregates formed at T4LCST decreases and their size distribution broadens. The collapsed aggregates most probably consist of a PNIPAM/PEO core sterically stabilized by a PEO shell. In dilute solutions of the graft copolymers, hydrophobic interactions compete with the solubilizing effect and the surface stabilization of PEO. At ToLCST the PNIPAM chains gradually shrink when the temperature approaches the critical value, and the flexible PEO chains with high hydrophilicity turn outward, pointing to the water phase and sustain the soluble polymer aggregates.

Fig. 79. Schematic illustration of two different nanoparticle formation mechanisms respectively related to short and long PNIPAM-g-PEO chains. Reproduced from Qiu and Wu [253] by permission of the American Chemical Society, USA.

It may be assumed that the conformation of the functionalized PNIPAM during the grafting (changes in hydrodynamic volume of the backbone and correspondingly also the accessibility of the functional groups of the main chain) affects also the localization of the side chains. Thus, a functional backbone copolymer with Mw 1.8  105 was grafted by amino-terminated PEO (Mw 6000) in water at two different temperatures, 15 and 29 1C respectively, in order to elucidate how the conformation of PNIPAM backbone affects the chemical composition and thermal properties of the final product [256]. The graft copolymers showed a remarkable difference in their thermal behavior. Fluorescence and ESR studies have revealed differences between the polymers, owing to the varying distribution of the PEO grafts along the PNIPAM main chain [257]. The polymer grafted in water at an elevated temperature (TLCST) differed clearly from the others, those synthesized either in cold water or in an organic solvent. This particular polymer form dense local hydrophobic domains inside the collapsed globule. The results strongly suggest that the distribution of the PEO grafts along the PNIPAM chains depends on the conformation of the functionalized PNIPAM during the grafting, and this affects the behavior of the graft copolymers. It is generally argued that at low temperature and in very dilute solutions, both PNIPAM and PEO are hydrophilic so that the whole copolymer chain exhibits an expanded random coil conformation [253,254]. However, as the polymer concentration increases, individual copolymer chains have a greater probability to associate with each other before they collapse and are stabilized by the grafted PEO chains. Indeed, Kjoniksen et al. [258] found that the size of the particles increases with increasing copolymer concentration and an appreciable temperature-induced contraction of the core–shell particles is evident. In spite of the high number of PEO grafts, the copolymer shows a strong tendency to aggregate, even at low temperature. Chen et al. [261] prepared linear PNIPAM chains grafted with short PEO chains (PNIPAM-g-PEO) by free-radical copolymerization in water of NIPAM and PEO macromonomers (Mw 5000) endcapped with methacrylate. They studied temperature effects on the solution viscosity of the thermally sensitive copolymer at different aqueous concentrations and observed a specific transition during the measurements of the copolymer reduced viscosities

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in semidilute aqueous solution at various temperatures. They attributed the viscosity increase at higher temperatures and higher concentration (43 g/L) to the formation of physical ‘‘crosslinking points’’ composed of collapsed PNIPAM cores and expanded PEO shells. The sharp decrease of the viscosities at higher temperatures and lower concentration (o3 g/L) could be attributed to the formation of independent globules (Fig. 80). PEG macromonomers bearing different terminal functional groups are useful tools for creating an intelligent graft-copolymer system because the functionality can be installed at the end of a comb chain in the graft copolymer after copolymerization with suitable comonomers [259,262]. Berlinova et al. [259] have broadened the properties of the PNIPAM-g-PEO graft copolymers by the synthesis of a PNIPAM backbone with a low level of endfunctionalized PEO side chains (Fig. 81). Novel associative graft copolymers consisting of a PNIPAM backbone of PEO side chains bearing

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terminal perfluoroalkyl, sulfobetaine or trimethylammonium groups have been prepared by the macromonomer approach. In aqueous solution the PEO terminal groups give rise to hydrophobic, dipole–dipole, or donor–acceptor interactions. The balance between intra- and inter-molecular sidegroup interactions can be controlled by varying the length of the side chains, the degree of grafting and the polymer concentration. In the dilute solution regime, copolymers bearing terminal perfluoroalkyl or sulfobetaine groups form aggregated species even at very low concentrations. Below the PT temperature semidilute solutions of the graft copolymers exhibit shear-dependent rheological properties. The highest viscosity enhancement at low shear rate shows PNIPAM grafted with 0.1 mol% PEO bearing perfluoroalkyl groups. Above the PT temperature the same copolymer gives a gel with an elastic modulus higher than the loss modulus. The results are consistent with the formation of transient networks of soluble or

Fig. 80. Formation of physical ‘‘cross-linking points’’ and independent globule of PNIPAM-g-PEO copolymer chains in semidilute aqueous solutions above and below a certain concentration; curve in green represents PNIPAM backbone and curve in red represents the PEO side chains. Reproduced from Chen et al. [261] by permission of Elsevier Science Ltd., UK.

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collapsed PNIPAM chains bridged by soluble PEO chains, as depicted in Fig. 82. Iijima and Nagasaki [262] reported the synthesis of PNIPAM-g-PEO graft copolymers with reactive groups at the PEO chain ends. The graft copolymers were obtained through a free-radical polymerization of NIPAM with a PEG macromonomer bearing an acetal group at one chain end and a methacryloyl group at the other end. The acetal end groups were easily converted to the aldehyde groups by acid treatment. The resulting graft copolymers having a PEG concentration lower than 30% formed nanoscale structures with a narrow size distribution above 40 1C, as confirmed by DLS analysis. 1H NMR measurements confirmed that the PNIPAM main chain became a solid core, retaining the nanosize shapes. Such temperature-induced nanospheres possessing peripheral reactive PEG tethered chains (Fig. 83) are promising as new nanobased biomedical materials. Vieira et al. [263] have combined the properties of thermosensitive, hydrophilic and hydrophobic

Fig. 81. Structures of associative water-soluble graft copolymers (x denotes mole percent of incorporated PEO macromonomer; n ¼ 22 or 45). Adapted from Berlinova et al. [259] by permission of Elsevier Science Ltd., Oxford, UK.

monomers to design potential thermosensitive drug carriers. They have found that the amphiphilic terpolymers of (NIPAM)x–(methoxy PEO methacrylate)y–(dodecyl methacrylate)z in aqueous solution form large aggregates. These polymers selfaggregate at low concentration forming stable micelle-like aggregates capable of hosting amphiphilic and hydrophobic molecules. As already mentioned, PVCL belongs to the category of thermosensitive polymers. This polymer is stable against hydrolysis; it is nonionic and biocompatible, and it has an LCST near body temperature. Among recent studies, Verbrugghe et al. [264] synthesized PVCL-g-PEO copolymers by a ‘‘grafting onto’’ method. A PVCL backbone with reactive functional groups (PVCL-co-NASI) was prepared by radical copolymerization of VCL and a small amount of NASI. These succinimide groups react easily with a primary amine, such as aminoterminated PEO (Mw 5000). At 20 1C, single copolymer molecules are present in the solution, but they aggregate above TCP (45 1C) forming stable aggregates. Further heating (60 1C) leads to shrinking of the aggregates. Virtanen et al [255] recently reported a similar phenomenon and ascribed it to shrinking of the thermosensitive core upon heating. This indicates that the collapsed macromolecules are still surrounded by water molecules, which can only be removed by further heating (Fig. 84). Microcalorimetry measurements revealed that the grafting of PVCL with the hydrophilic PEO chains does not influence the enthalpy change of PVCL during the PT, i.e. DH is directly proportional to the mole fraction of N-vinylcaprolactam in the copolymers. An essential drawback is that the transition range is

Fig. 82. Schematic illustration of associative behavior of PNIPAM grafted with 0.1 mol % perfluoroalkyl-ended PEO below and above the LCST. Adapted from Berlinova et al. [259] by permission of Elsevier Science Ltd., UK.

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Fig. 83. Schematic illustration of temperature-responsive PNIPAM-g-PEG with reactive groups at the PEG side chain ends. Reproduced from Iijima and Nagasaki [262] by permission of John Wiley & Sons Ltd., UK.

Fig. 85. Structure of hydrophobically modified PEO macromonomer. Adapted from Laukkanen et al. [265] by permission of the American Chemical Society, USA. Fig. 84. Model describing formation of aggregates and their shrinkage upon heating. Reproduced from Virtanen et al. [255] by permission of the American Chemical Society, USA.

remarkably broad, which implies that the dehydration continues after the first stage of the PT. Using emulsion polymerization, Laukkanen et al. [265] synthesized grafted temperature-sensitive PVCL microgel particles coated with short grafts containing a PEO segment. It is well known that when the macromonomer technique is used in emulsion polymerization, an important requirement is that the comonomer should be more hydrophobic than the macromonomer. Therefore, the grafting has been accomplished by using an amphiphilic macromonomer consisting of a hydrocarbon segment and a PEO segment (Fig. 85). Grafting the responsive particles with amphiphilic PEO derivatives considerably increases their stability toward added electrolytes, the effect being especially pronounced at high temperatures where the PVCL particles are shrunken [266]. PVCL grafted with amphiphilic PEO–alkyl chains (Fig. 86) forms intra- and inter-polymeric associates in water at room temperature depending on the concentration and the grafting density. The associates solubilize hydrophobic substances, such as pyrene, inside their nonpolar domains, which are composed of self-assembled C11EO42 grafts [267]. Upon heating, the PVCL backbone collapses, triggering a change in the hydration of the chain

and release of polymer-bound water molecules. The presence of C11EO42 grafts increases the aggregation temperature slightly, as compared to that of PVCL. Thermally induced aggregation leads to the formation of colloidally stable mesoglobules. Each particle is composed of several thousands of collapsed polymer chains, although the particles still contain much water at 50 1C. Turbidity measurements reveal that the CP is shifted toward lower temperature as the polymer concentration increases, and the depression is significantly stronger in the semidilute regime [268]. High polymer concentration and elevated temperature favor the growth of interchain aggregates. Jeong et al. [269] prepared thermogelling biodegradable polymers with hydrophilic backbones by grafting poly(lactic acid-co-glycolic acid) (PLGA) from PEO bearing pendant hydroxyl groups (PEOg-PLGA).The aqueous copolymer solutions exhibited a sol-to-gel transition in response to an increase in temperature. Micelle formation was confirmed by cryo-TEM and the dye solubilization method. The micellar diameter was about 9 nm, and the cmc was in the range 0.01–0.05 wt%. The critical gel concentration, above which a gel phase appears, was 16 wt%, and the sol-to-gel transition temperature was slightly affected by the concentration between 16 and 25 wt%. The hydrogel of PEG-g-PLGA with hydrophilic backbones was transparent during degradation and remained a gel for 1 week,

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Fig. 86. Structure of poly(N-vinylcaprolactam) grafted with amphiphilic PEO–alkyl chains. Reproduced from Laukkanen et al. [267] by permission of Elsevier Science Ltd., UK.

suggesting a potential application in short-term drug delivery systems. Hasan et al. [54] synthesized thermoassociating water-soluble graft copolymer systems based on HMW PEO. The idea was to imprint some ‘‘smart’’ properties into common PEO by introducing responsive components consisting of relatively short segments of PNIPAM grafts. The synthesis was performed in a two-step procedure: the synthesis of copolymer precursors of functional HMW PEO carrying OH groups by copolymerization of EO with glycidol followed by grafting of NIPAM onto the precursors using the Ce(IV) initiating system. In semidilute conditions, aqueous solutions of the PEO copolymers start to exhibit associative properties at temperatures slightly higher than the LCST of PNIPAM grafts. In this aggregation regime, PNIPAM side chains begin to self-assemble forming loose clusters which behave as physical cross-links.

network during deswelling (Fig. 87). The effect of PEO grafts on the fast deswelling changes is compared in Fig. 88 with the behavior of conventional PNIPAM gel (NG). Enhanced gel deswelling rates in response to temperature change were achieved by incorporating PEO graft chains in the PNIPAM network. The conventional PNIPAM gel shrinks slowly due to the formation of a surface ‘‘skin layer’’ restricting diffusuion of water from the gel. Rapid deswelling of the graft-type gel might find applications as a gel actuator or for regulation of mass transfer, as in artificial muscles or drug delivery. With PEO dimethacrylate (MW 400) crosslinker, a thermally initiated free-radical dispersion polymerization was used to prepare temperature-sensitive nanoparticles of PNIPAM-co-(PEO methacrylate) suitable for insulin loading [271]. The loading process was conducted at 4 1C for 24 h, and then the nanoparticles were collapsed at 37 1C. These temperatures provided the maximum volume swelling. The nanoparticles showed good insulin-protecting capability from high temperature and high shear stress and could be used as carriers for sensitive proteins and peptides during a fluidized bed coating process. Irradiation (g and UV) was used for the preparation of mixed networks based on HMW PEO and/ or NIPAM and PNIPAM [272]. These gels preserve the swelling transition temperature of pure PNIPAM but shrink faster above this temperature owing to the presence of hydrophilic PEO chains. In the collapsed state these gels absorb alkaline organic salts from aqueous solutions; 3–5% PNIPAM is sufficient to decrease the equilibrium degree of swelling by a factor of 2. The second component, PEO, prevents quick formation of a ‘‘skin layer’’.

9.3. Hydrogels comprising thermoresponsive- and hydrophilic PEO blocks To successfully implement new applications of hydrogels such as artificial muscles and rapidly acting actuators, the swelling–deswelling cycle of the bulk gel and its surface has to be accelerated. For this purpose, hydrophilic PEO graft chains can be introduced into PNIPAM by copolymerization of acryloxy-terminated PEO with NIPAM [270]. The graft chains have freely mobile ends and are designed to form channels for water molecules through the ‘‘skin layer’’ while maintaining strong hydrophobic attractions in the PNIPAM backbone

Fig. 87. Schematic structures of hydrogels comprising different types of PNIPAM-based copolymers: PNIPAM gel, PNIPAM-gPEO gel, and PNIPAM-co-PAAc gel. Reproduced from Kaneko et al. [270] by permission of the American Chemical Society, USA.

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Fig. 88. Swelling–deswelling kinetics of PNIPAM gel (NG) and PNIPAM-g-PEO gel in response to temperature changes. Reproduced from Kaneko et al. [270] by permission of the American Chemical Society, USA.

The reversible binding of ions suggests the possibility of applications in medicine and pharmacy. 10. Conclusions Stimuli-sensitive polymers have been known for over 40 years. However, they still remain a subject of vigorous investigations, both in academia and in industry, that can be expected to result in valuable applications in the near future. There are numerous reasons for this continuing interest. The development of devices based upon stimulisensitive polymers calls for a fine-tuning of their properties. The materials have to respond to the external stimuli in a way that precisely fits the need of the applications. In order to achieve this, a better understanding of the relations between the polymer properties (dependence of behavior at the transition point upon external conditions) and the structure of the macromolecules is necessary. Here, tailor-made polymers can be used as models that require the capabilities of controlled polymerizations. In the early years of studying stimuli-sensitive polymers anionic polymerization was the only method enabling good control; thus the majority of stimulisensitive polymers were obtained by free-radical polymerizations. The contemporary progress of controlled radical and cationic polymerizations has resulted in new, better-controlled structures of stimuli-sensitive polymers. Problems such as the dependence of the response function on the structural aspects of the macromolecules (molecular

weght, topology, distribution of chains units—block and random copolymers—and many more) can now be addressed with far better chances of success. Another important factor, which has received increasing attention in recent years is the supramolecular organization of the stimuli-sensitive macromolecules, especially those consisting of ‘‘modular structures’’ such as block copolymers, core–shell branched, or star macromolecules. In order to be able to control the properties of the associating systems at a nanoscale level we need to improve our understanding of colloid science and its methods. Nanoreactors, nanocarriers, nanosensors and other similar stimuli-responding nanosystems are expected to emerge from such studies. The need is well justified and reaches beyond a temporary fascination with nanotechnology. The self-assembly of macromolecules depends strongly on their stimuli-sensitive parts. This review clearly shows that one of the most important trends in modern polymer science is the synthesis of multistimuli-sensitive macromolecules containing blockor graft-sequences, that can provide different types of response. By combining the imprinted functions and by controlling changes in the environment, it becomes possible to develop copolymers that can self-organize in a great variety of multi-functional nano- and microstructures. It is difficult to foresee in detail the potential applications of systems that rely on stimuli-sensitive polymers. Certainly their application in biology, medicine and other related sciences is already

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