Soft Matter REVIEW

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This review describes the state-of the-art of nano-, micro- and macrogels, membranes, micro- and ...... brushes makes them a promising platform for designing ''smart'' polymer ..... 106 S. Xu, Z. Nie, M. Seo, P. Lewis, E. Kumacheva, H. A. Stone,.
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Soft Matter

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pHIEP

Random PDEA–PMAA PDEA core–PMAA shell PMAA core–PDEA shell

— 5.3 9.0

— 8.8 4.8

6.80 7.85 7.42

234 180 152

185 135 102

330 217 119

Amphoteric macromolecules of both linear or cross-linked structure exhibit similar properties that can be generalized as follows: 1. The existence of so-called isoelectric points (IEPs) where intra- and/or intermolecular attractions of opposite fixed charges lead to pseudoneutral character and have compact (or collapsed) structure of both linear and cross-linked amphoteric macromolecules. 2. Unfolding of linear and swelling of cross-linked amphoteric macromolecules at/or near the IEPs with increase in solution ionic strength (so-called ‘‘antipolyelectrolyte’’ effect). 3. Shifting of the IEPs due to the specific binding of lowmolecular-weight cations and/or anions compared to IEP values observed in ion-free environment. 4. Uptake and release of high- and low-molecular-weight compounds in response to environmental changes (pH, temperature, ionic strength, solvent quality, DC electric field, etc.). It should be noted that the driving force for the collapse of the particles at zero net charge is different for the core–shell and the random copolymer microgel particles. The random copolymer particles collapsed because of charge neutralization at their IEP when the number of positive and negative charges within the particle is equal, and hence their shrinkage is expected to depend on the ionic strength of the solution. However, the collapse of the core–shell particles occurred when both the core and the shell of the microgels became neutral, and thus it would not depend on the addition of salt. The reduction in particle size at extreme pH is attributed to the high ionic strength of the solution, which results in charge screening in the microgel particles. NIPAMbased amphoteric nano- and microgels show oscillatory swelling–deswelling properties depending on both pH and temperature (Fig. 1).40,46 Schulz,8 Harding9 and Homola10 studied spherical latex particles with functionalized zwitterionic (amphoteric) groups, displaying a range of different IEPs. PA microgels consisting of N-isopropylacrylamide (NIPAm), acrylic acid (AA), and N-(3-aminopropyl)methacrylamide exhibited zwitterionic behavior in a particular pH range.48 Volume transitions of microgels were significant in the zwitterionic range of pH since the oppositely charged groups formed attractive ion pairs which facilitated the expulsion of water from the microgel interior. Kumacheva and Das13 studied spherical polyampholyte microgels with different fractions of acrylic acid (AA) and 1-vinylimidazole (1-VI) monomers and compared to the microgels formed from their corresponding polyelectrolytes. The microgels showed significant swelling at both high and low pH values, but shrank between pH ¼ 4.0 and 7.0 due to electrostatic attraction between charged functional groups. The largest 9304 | Soft Matter, 2012, 8, 9302–9321

shrinkage took place at the IEP (zeta-potential ¼ 0). Since the pKa of AA and 1-VI are 4.25 and 6.99, respectively, the particles carried both positive and negative charges outside of the pKa value ranges. Tan et al. 6,11 studied pH-responsive polyampholyte microgels consisting of poly(methacrylic acid) and poly(2-(diethylamino)ethyl methacrylate) (PMAA–PDEA). These microgels exhibited better hydrophilic behavior at low and high pH values but become compact between pH 4.0 and 6.0, which is near the IEP. Dynamic-light scattering measurements showed that the hydrodynamic radius, Rh, of these microgels increases from 100 nm at pH 4.0–6.0 to around 200 nm (at pH 2.0 and 10.0). This indicates that the cross-linked PMAA–PDEA microgels exhibit polyampholyte properties in solutions (Fig. 2).11 The similarities between linear polyampholytes and amphoteric nanogels were remarkably demonstrated by Kokufuta and co-workers,49 who studied the electrophoretic behavior of linear ampholytic terpolymers (TP) and nanogels (NG). Fig. 3 shows some characteristics of NG and TP consisting of acrylic acid (AAc) and 1-vinylimidazole (1-VI) as anionic and cationic monomers, both of which were incorporated into the network of N-isopropylacrylamide cross-linked with N,N-methylenebisacrylamide (BAA).40 The electrophoretic mobilities of

Fig. 2 The hydrodynamic radius, Rh, and electrophoretic mobility of 0.1 wt% polyampholyte microgels with varying proportions of PMAA and PDEA microgel 60M-40D (circle symbols) and 40M-60D (square symbols) at different pH values at 25  C (these results were generated by conducting light scattering measurements). The filled symbol represents Rh, and the open symbol represents electrophoretic mobility. Photographs and TEM micrographs of 0.1 wt% 60M-40D microgel at three different pHs, i.e., pH of 2, 5, and 9 illustrate the change in solution transmittance and the morphology of the microgels. Reproduced from ref. 11 with permission of Wiley & Sons.

This journal is ª The Royal Society of Chemistry 2012

Fig. 3 Dependence of electrophoretic mobility (U) on pH for NG (C) and TP (B) in 0.01 N KCl at 25  C. Reproduced from ref. 40 with permission of ACS.

nanogel NG and terpolymer TP were measured as a function of pH at a fixed ionic strength (I) of 0.01. Despite a notable difference in Mw as well as in Rh between the NG and TP, their overall charges were found to be very close. Therefore, a comparison of electrophoretic mobilities between them is possible. A detailed comparison of experimental mobilities with theoretical calculations was made in terms of three different models: free draining model, charged surface model, and Henry’s model. It was concluded that the free draining model explains the electrophoretic behavior not only of amphoteric terpolymers, but also of polyampholyte nanogel networks. Multilayered microcapsules possessing amphoteric character composed of 4 layers of weak polyelectrolytes – poly(allylamine) (PAH) and poly(methacrylic acid) (PMAA) were developed by Mauser et al.50 The diameter of the capsules is plotted as a function of solution pH (Fig. 4). The reversible and repeatable capsule swelling is seen when they are cyclically exposed to pH 6 and pH 2.5. The mean capsule diameters are 3.5–5 mm at pH 2.5 and 6.5–7.5 mm at pH 6, respectively. Gentle stabilization of microcapsules made of PAH–PMAA by initiating the reaction between the primary amine groups of PAH and carboxylic groups of PMAA will

Fig. 4 The mean microcapsule diameter change as a function of alternative pH change. Reproduced from ref. 50 with permission of Wiley & Sons.

This journal is ª The Royal Society of Chemistry 2012

result in the formation of amide bonds and prevent their dissolution. Periodical changes of microcapsules offer the potential application as pH-responsive microsensor and micropump.51 In concentrated salt solutions,6 PA microgels demonstrate antipolyelectrolyte behavior and undergo additional swelling. Therefore, the amphoteric microgels shrink and precipitate in deionized water, however, they can expand and stabilize themselves in an electrolyte solution due to the screening of the electrostatic attraction within the particles. An ‘‘antipolyelectrolyte’’ phenomenon was observed for P((MAA-co-DMAEMA)-g-EG) polyampholyte nanogels (PANGs) at pH of 4.0, i.e., at their IEP.52 Equilibrium swelling degree of PANGs increases at the IEP as the ionic strength increases. This is due to the fact that the low-molecular-weight electrolyte screens the opposite charges on the gel chains unfolding the compact conformation. The effect of salt on stimuli-responsive microgels provides useful information and is a useful model in many complex biological systems for elucidating the macromolecular conformation. Kumacheva and Das studied the effect of ionic strength on the swelling and deswelling properties of polyampholyte microgels in KCl solutions of different concentrations.13 When salt concentrations were below 0.005 M, there was no significant change in microgel size. They demonstrated that a significant swelling peak occurred at higher salt concentrations for all polyampholyte microgels. This indicates that the polyampholyte microgel exhibits the antipolyelectrolyte behavior. The light scattering data proved that the large increase in microgel size was due to antipolyelectrolyte properties. There are relatively narrow size distributions and negligible changes in the scattering intensity (Fig. 5).13 Ogawa et al. reported the response of PA microgels to temperature, pH, and the salt concentration40,41 and found that the microgels with similar numbers of acidic and basic groups are stable in salt solutions, in contrast to their instability in deionized water. The authors correlated these results with intra- and interparticle interactions, which are not solely originated from electrostatic forces but are also from hydrogen bonding and hydrophobic association. As usual, at higher temperature,13,40 PA microgels contract in the same fashion as PE microgels when opposite groups are charged and hydrophilic. Ion pairing between the oppositely charged groups increases the extent of the temperature-induced deswelling (Fig. 1). The temperature changes of solution transmittance (T%) for G(1/4) and G(1/1) are shown in Fig. 6, from which the values of the LCST were estimated.40 The LCSTs for G(1/4) and G(1/1) are equal to 40  C and 50  C, respectively, and are in good agreement with the temperature at which the aggregation of gel particles takes place. Also, there was a good correlation between LCST values observed for the nanogel and terpolymer systems. The detailed studies of amphoteric nanogels have demonstrated that G(1/1) is prone to aggregate at pH ¼ pHIEP and at low ionic strengths. Under such conditions, nevertheless, the gel particles exhibit a high LCST. The reason is the presence of a large amount of hydrophilic segments consisting of ion-paired AA and 1-VI monomer units. Thus, it is assumed that hydrophobic association plays a key role in the LCST behavior observed not only in the terpolymer system but also in the nanogel system. Soft Matter, 2012, 8, 9302–9321 | 9305

Fig. 5 (a) Hydrodynamic radius (Rh/R0) as a function of KCl concentration: (A) poly(NIPAm-AA), pH ¼ 7.0, T ¼ 25  C, R0 ¼ 22.6 nm; (-) poly(NIPAm-VI), pH ¼ 4.0, T ¼ 25  C, R0 ¼ 91 nm. (b) Hydrodynamic radius (Rh/R0) as a function of KCl concentration for polyampholyte microgels: (A) PA-0.46, R0 ¼ 24.5 nm (-) PA-0.9, R0 ¼ 44.2 nm (:) PA-1.25, R0 ¼ 28.6 nm () PA-1.65, R0 ¼ 24.5 nm; pH ¼ pI, T ¼ 25  C. Reproduced from ref. 13 with permission of Springer.

temperatures was due to hydrophobic interactions between the particles. Symmetric PA microgels exhibited a broader temperature-dependent volume transition and more deswelling than asymmetric PA microgels due to the presence of a larger number of hydrophilic COO and ^NH+ ions in the zwitterionic window. The extent of the temperature-induced deswelling in PA microgels with symmetric composition was a result of the increase in ion pairing between the charged groups. The swelling and deswelling behaviour of amphoteric macrogels as a function of pH as well as their metal complexation ability with respect to Cu2+, Ni2+ and Co2+ ions was studied by Tatykhanova et al.53 Fig. 7 shows that the deswelling of amphoteric cryogels (ACG) synthesized at the molar ratios of allylamine : methacrylic acid : acrylamide [AAm] : [MAA] : [AA] ¼ 10 : 10 : 80; 20 : 20 : 60; 30 : 30 : 40; 40 : 40 : 20 and 50 : 50 : 0 mol%/mol%/mol% (abbreviated as ACG-118, ACG-226, ACG334, ACG-442 and ACG-550) is minimal at the IEPs. The pHIEP of amphoteric macrogels found from the swelling–deswelling measurements ranges between 3.5 and 4.3. Complexation of amphoteric macrogels with transition metal ions is accompanied by colourization of samples (Fig. 8). This is due to the formation of coordination and ionic bonds between metal ions and amine and/or carboxylic groups of macrogels, when aqueous solutions of metal salts pass through the gel specimen. The high absorption–desorption ability of amphoteric macrogels with respect to trace amounts of metal ions is promising for analytical applications and purification of wastewater. The reduction of macrogel–metal complexes by NaBH4 leads to the formation of nano- and micron-sized metal particles immobilized on the inner and surface parts of amphoteric macrogels (Fig. 9). It is expected that these amphoteric macrogels can serve as efficient heterogeneous supports for nano- and micron-sized zero-valent metal particles and as flow-through microreactors in catalysis. The nature of the medium may also affect the size of the microgel particles due to the dielectric constant of the solvent. The solvent plays a significant role in the following two aspects: (a) osmotic interactions between the repeating unit residues compete with or enhance their interactions with the solvent; (b)

Fig. 6 Temperature changes of transmittance (T%) of 0.1 M KCl solutions (pH ¼ pHIEP) containing nanogels G(1/4) and G(1/1). Polymer concentration: 1 mg mL1 for both samples. Reproduced from ref. 40 with permission of ACS.

The temperature effect on the stability of polyampholyte microgels was discussed by two different groups.13,40 Ogawa et al.40 first discussed and Kumacheva and Das13 later supported that the loss in colloidal stability of PA microgels at higher 9306 | Soft Matter, 2012, 8, 9302–9321

Fig. 7 Swelling–deswelling curves of amphoteric macroporous gels ACG-550 (curve 1), ACG-334 (curve 2), ACG-226 (curve 3), and ACG118 (curve 4) on pH. Arrows show the position of the IEPs. Abbreviations of ACG are given in Fig. 12. Reproduced from ref. 53 with permission of Wiley & Sons.

This journal is ª The Royal Society of Chemistry 2012

Fig. 8 Coloring of ACG-334 after absorption of copper, cobalt and nickel ions (bottom) and schematic representation of metal–polymer complexes in cryogel pores (top). Reproduced from ref. 53 with permission of Wiley & Sons.

Fig. 9 SEM pictures of ACG-334/Ni2+ (a) and ACG-334/Co2+ (b) complexes after reduction by NaBH4. Reproduced from ref. 53 with permission of Wiley & Sons.

the dielectric constant of the solvent and the extent of dissociation of ionic groups affect the strength of electrostatic forces in the microgels. Kumacheva and Das13 also reported the solvent effect on the swelling properties of polyampholyte microgels. It was noted that competing electrostatic and solvency interactions determine the polyampholyte microgel swelling response. The solvency effects dominated the swelling behavior of all PA microgels that exhibited a swelling maximum at 4 ¼ 0.5. To understand the temperature and solvent dependent volume changes of PA microgels better, it will be necessary to synthesize various polyampholyte microgels and further investigate various systems in relation to these parameters. Based on the changes in response or properties of polyampholyte microgel particles under the different conditions described above, nano/micro polyampholyte gel particles have been applied in many fields.

core–shell structured particles,23 the core can be made from any material: metal,58 metal oxide, non-metal oxide, salt, polymer, liquid, or gas (hollow structures). The shell is usually made of polymers. The stimuli-responsive properties of the particles may originate from the polymeric shell, core, or both the core and the shell. In this section, we focus on the synthesis of particles in the size range from nanometers to a few micrometers. To achieve the range of applications of microparticles, it is important to properly engineer the sensitivity of polymer properties to external stimuli for desired changes in the particles.59 Two major approaches2,28 have been commonly applied to fabricate nano/ micro polyampholyte particles: (1) fabrication of the particles from pre-synthesized polymers and (2) synthesis of nano/ microparticles by a heterogeneous polymerization method. These two methods include such assembly approaches as coacervation/precipitation, layer-by-layer assembly (LbL), grafting of the polymer to the particle surface methods, and various polymerization methods. Commonly accepted polymerization methods are such as controlled radical polymerization (CRP)60,61 atom-transfer radical polymerization (ATRP),62,63 reversible– addition fragmentation chain transfer (RAFT)64 and cryo-polymerization.65 The main requirement for carrying out the polymerization process is the presence of acid–base monomers, cross-linking agents and accelerators. Detailed information on the synthetic pathways towards nano- and microgels is given in ref. 23, 66 and 67. Various synthetic strategies for the preparation of microgels/nanogels including photolithographic and micromoulding methods, microfluidics, modification of biopolymers with various approaches, free radical heterogeneous polymerization in dispersion, precipitation, inverse (mini)emulsion, and inverse microemulsion were described. The following methods are used in the fabrication of amphoteric nano/micro-particles from pre-synthesized polymers. (1) Coacervation/precipitation technique.35,68,69 The coacervation indicates the formation of microscopic droplets of the coacervate phase between oppositely charged polymers. The colloidal dispersion tends to aggregate. The chemical crosslinking or physical gelation of the polymer in the coacervate phase are applied to create the amphoteric polymer particles (Fig. 10).70 For example, positively charged chitosan interacts with negatively charged biomacromolecules. Colloids based on electrostatic chitosan–DNA, chitosan–protein, and chitosan– polysaccharide complexes along with chitosan hydrogels crosslinked with polyion tripolyphosphate are among the most studied.71–73 Examples of the above described systems have the pH and ionic strength responsive colloidal particles including chitosan and carboxymethyl konjac glucomannan, and chitosan

2.2 Preparation of amphoteric nano-, micro- and macrogels The amphoteric particles discussed in this section are in two formats; (1) nano- and microspherical particles or latexes,54–56 and (2) particles with core–shell hybrid structure.47,57 In the This journal is ª The Royal Society of Chemistry 2012

Fig. 10 Scheme of the formation of PAA–gelatin complex coacervate particles and their pH triggered swelling transition. Reproduced from ref. 70 with permission of Elsevier.

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and dextran sulfate.74–77 Chitosan–carboxymethyl cellulose and chitosan-modified methyl cellulose exhibit both pH- and thermoresponsive characteristics.78 The advantages of these polyampholyte microgels are that they are biodegradable and biocompatible, non-toxic and non-allergenic, readily available and cheap as they are derived from renewable resources, suitable for biomedical and pharmacological applications. Yu et al.69 have developed a novel, ‘‘green’’, and convenient method to produce amphoteric chitosan–ovalbumin nanogels, combining the merits of chitosan nanoparticles and food protein nanogels together. Chitosan and ovalbumin solutions were mixed, the pH of the solution was adjusted to 5.4 and it was successively stirred and heated at 80  C for 20 min resulting in formation of nanospheres. The chitosan chains are supposed to be partly trapped in the nanosphere core upon heating because of the electrostatic attractions between chitosan and ovalbumin, while the rest of the chitosan chains should form the shell of these nanomaterials. The nanogels did not change the size distribution after long-time storage and did not dissociate in the pH range of 2.0–10.5. Protein nanogels were prepared from ovalbumin (OVA) and ovotransferrin (OT) by heat induced denaturation and gelation.68 The influence of the pH, weight ratio of OVA to OT, heating temperature and time, protein concentration, and stirring time on nanogel formation was studied. Covalently cross-linked whey protein microgels (WPM) were produced on a large scale from commercially available whey protein isolate without the use of a chemical cross-linking agent.79 Heat denaturation, aggregation, electrostatic repulsion, and formation of disulfide bonds are responsible for hierarchical structure of WPM. Mechanism of WPM formation may qualitatively be understood on the basis of the following synthetic procedure (Fig. 11). Upon heating of the whey protein solution close to the IEP, the proteins denaturate (characteristic size 5 nm) and rapidly form intermediate dense aggregates (characteristic size 9 nm) which further aggregate to WPM. Formation of intermolecular disulfide bonds leads to covalent cross-linking and generation of large

Fig. 11 Hierarchical structure of whey protein microgels (WPM). Reproduced from ref. 79 with permission of The Royal Society of Chemistry.

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aggregates. Deviation from the IEP causes electrostatic repulsion of similar charges and consequently stiffening and expanding of the network. The authors80 succeeded in controlling the particle diameters of gelatin nanogel in the range of 20–70 nm by gamma-ray irradiation. It was found that the prepared gelatin nanogel reversibly swelled and shrank by pH and temperature change. Volume-phase transition point and swelling ratio were found to change, depending on the absorbed dose and gelatin concentration. (2) Layer-by-layer (LBL) polymeric shell. Kunitake and coworkers81 and Mohwald and coworkers82,83 studied the fabrication of polymer shells around particulate cores and transformation of the core–shell particles into hollow spheres with LbL gel walls. As shown in Fig. 12, oppositely charged PEs were adsorbed alternatively onto melanin resin templates, then amphoteric polymer shells were obtained through dissolving the template. A click chemistry approach was reported to develop LbL assembly of ultrathin pH-responsive nanocapsules by Caruso and coworkers.84 The LbL approach was used to fabricate pHresponsive capsules from bovine serum albumin through glutaraldehyde-mediated covalent LbL assembly.85 The composition of the LbL shell determined responsive properties of LbLcoated nanoparticles. Changeable permeability of the LbL shell depended on the sensitivity of amphoteric complexes to pH and ionic strength. The sensitivity to ionic strength is due to the partial dissociation of the amphoteric polymer complex.86–89 For example, PAH–PMAA capsules are stable in the pH range from 2.5 to 11.5, a reversible swelling occurs in the pH interval from 2.7 to 2.6.50 Another example of design of responsive core–shell structures using the LbL method is a responsive core that is coated with a LbL shell. For example, thermoresponsive PNIPAm core–shell particles were made of the PNIPAm core and the PE LbL shell.90,91 ‘‘Core–shell’’ like microgels exhibiting amphoteric character were prepared by LbL method from an anionic microgel as a substrate (core) and consecutive polyelectrolyte adsorption treatment. Penetration of the microgel with poly(allylamine hydrochloride) and branched poly(ethyleneimine) led to the formation of a ‘‘complex shell’’ and the behavior analogous to that of an amphoteric microgel.92

Fig. 12 Schematic illustration of the PE assembly process and subsequent core removal. The process from (a) to (d) involves stepwise film formation. (e) Shows the dissolution of core and a formation of free PE hollow shells (f). (g) SEM image of nine-layer [(PSS/PAH)4/PSS] PE shells after solubilization of the core (g). Reproduced from ref. 83 with permission of Wiley & Sons.

This journal is ª The Royal Society of Chemistry 2012

(3) Heterogeneous polymerization.34,47 Polymerization in heterogeneous media provides important approaches used for the fabrication of nano/micro polyampholyte particles.93,94 The technique widely applied for the synthesis of monodisperse core– shell particles and for control of their surface properties. Emulsion, precipitation, and dispersion polymerizations95 are common synthetic approaches for fabrication of microspherical particles including core–shell structures. Emulsion polymerization employs radical chain polymerization to produce wellcontrolled spherical particles in the range of nanoscale to microscale. The approach includes monomers, water, watersoluble initiator, and surfactant. This process involves two phases; a dispersed phase, and a continuous phase. The monomers are in the dispersed phase. The initiation reaction occurs with either a water-soluble initiator (e.g. sodium persulfate) or an oil-soluble initiator (e.g. 2-20 -azoisobutyronitrile (AIBN)). Emulsion copolymerization of poly(methacrylic acid) and poly(2-(diethylamino)ethyl methacrylate) (PMAA–PDEA) yielded 200–300 nm pH-responsive polyampholyte microgels.12 The reverse micellar system of dioctyl-sulfosuccinate (AOT)/ octane and toluene was used as a template for preparation of acrylamide (AAm)/bisacrylamide(BAA)-based amphoteric nanogels with size ranged within 20–90 nm.96 Polyampholytic nanogels containing primary and secondary amino, carboxylic and sulfonic groups were also synthesized by the same way. Polyampholyte nanogels (PANGs) were prepared by distillation–dispersion copolymerization of poly(ethylene glycol) methyl ether methacrylate (MPEGMA), N,N-dimethylaminoethylmethacrylate (DMAEMA), and methacrylic acid (MAA) using acetonitrile (AN) as a dispersion medium.52 Polyampholyte gel particles were synthesized by aqueous redox polymerization in the presence of sodium dodecylbenzenesulfonate as a surfactant. Acrylic acid (AA) and 1-vinylimidazole (1-VI) were respectively used as anionic and cationic monomers, both of which were incorporated into the network of N-isopropylacrylamide (NIPAm) cross-linked with BAA.49 To determine the existence of un-crosslinked and dissolved polymers in nanogel dispersions, the authors employed an analytical method based on a combination of dialysis and colloid titration. It was found that amphoteric nanogel samples are free from un-crosslinked and dissolved terpolymers after the purification. Ionic and non-ionic surfactants and polymers (e.g. hydroxyl ethyl cellulose and polyvinylalcohol) prevent the interactive latex particles from coagulating via electrostatic stabilization, steric stabilization, or both, and they stabilize the particles.6,11 Surfactant-free emulsion polymerization has been developed. To achieve it, the continuous phase for this process must have a high dielectric constant (e.g. water) and ionic initiators have to be employed (e.g. K2S2O8) in the absence of an added surfactant. The charged polymer chains produced during polymerization stabilize the growing particles. This approach does not suffer from residual surfactant contamination.6 A polyampholyte microgel was prepared by successive quaternization (with trimethylamine) and hydrolysis (with p-toluenesulfonic acid) of the unfunctionalized precursor, e.g. semi-batch emulsion polymerized mixture of tert-butylmethacrylate, m- and p-vinylbenzyl chlorides, styrene, and divinylbenzene. The polyampholyte was immediately sampled and This journal is ª The Royal Society of Chemistry 2012

frozen after its removal from reflux, and then was characterized as dried microgels after lyophilisation.97 A macroporous amphoteric polymer based on N-[3-(dimethylamino)propyl]methacrylate and methacrylic acid was tailored in the presence of a pore-forming agent (CaCO3) and a template protein (bovine serum albumin or lysozyme).98 Template protein and CaCO3 were subsequently removed from the network, which leaves pore canals and recognition cavities complementary to protein shape and polar groups. The advantage of molecular imprinting is that the template molecules, in the course of interacting with acidic and basic groups of amphoteric macromolecules, adjust the size of pores and cavities to the configurational and conformational information over the template surface, thus allowing for efficient recognition and separation of the target protein. A series of macroporous amphoteric cryogels based on allylamine (AA), methacrylic acid (MAA) and acrylamide (AAm) cross-linked by BAA were synthesized by radical copolymerization of monomers under cryo-conditions.65 Amphoteric cryogels (ACG) synthesized at the molar ratios of [AA] : [MAA] : [AAm] ¼ 10 : 10 : 80; 20 : 20 : 60; 30 : 30 : 40; 40 : 40 : 20 and 50 : 50 : 0 mol%/mol%/mol% were abbreviated as ACG-118, ACG-226, ACG-334, ACG-442 and ACG-550 (Fig. 13). The morphology of macroporous cryogels which are formed in moderately frozen solutions of monomeric and polymeric precursors is determined by solvent crystallization when the temperature is kept below the freezing point of the solvent.4,99 According to the cryo-polymerization concept, the freezing of the initially homogeneous system results in crystallization of pure solvent (water) and accumulation of monomers and initiators in unfrozen micro-zones (so-called ‘‘cryo-concentration’’). The polymerization reaction proceeds in this non-frozen part of the reaction mixture. Water crystals grow in the course of freezing and inter-connections with other crystals take place until a continuous system of pores is formed. Thawing of the system leads to the formation of a monolithic gel matrix with continuous macroporous channels filled with liquid solvent. The gel has a sponge-like morphology and pore size of 50–200 mm (Fig. 14). A system of large interconnected pores is the main characteristic feature of these cryogels. The pore system in such sponge-like gels ensures unhindered

Fig. 13 Structural units of amphoteric cryogels derived from AA, MAA and AAm crosslinked by BAA.

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convectional transport of solutes within the cryogels, contrary to the diffusion of solutes in traditional homophase gels. In the synthesis of amphoteric core–shell microgels,47,58,100 two-step polymerization processes have been applied to produce particles with both cores and shells made of polymer. The first step is to synthesize the core of the particles that serve as the seed for the synthesis of the shell in the second step. Amphoteric core–shell microgel particles where the core comprised of a cross-linked poly(2-(diethylamino)ethyl methacrylate) (PDEA) or poly(methacrylic acid) (PMAA) network surrounded by a cross-linked PMAA or PDEA shell, respectively, were synthesized by emulsion copolymerization.47 Cationic core–anionic shell or anionic core–cationic shell microgels were synthesized as follows. First, the core was formed by emulsion copolymerization of the appropriate functional monomer with the cross-linker in the presence of an anionic stabilizer, sodium dodecylsulfate (SDS) or AOT. In the next step, the second monomer was copolymerized with the cross-linker in the presence of the core particles by seed polymerization to form the cross-linked shells. A polymerizable stabilizer, poly(ethylene glycol) methacrylate (PEGMA), was used in the second step of the synthesis, which conferred steric stabilization to the core– shell microgel particles. The use of a polymerizable steric stabilizer in the shell ensures that the amphoteric microgels obtained after deprotection of the tert-butylmethacrylate (t-BuMA) units will remain stable over the whole pH range, whereas an ionic stabilizer could cause particle flocculation near the IEP point as a result of overall charge neutralization. In this context amphoteric core–shell microgels can be considered as analogue of linear diblock polyampholytes which precipitate near the IEP point as a result of formation of intra- and/or interpolyelectrolyte complexes between acid and base blocks followed by hydrophobization and aggregation. A polyampholyte random copolymer microgel with the DEA and MAA units randomly distributed within the gel phase was also prepared. The TEM images of the polyampholyte PMAA core–PDEA shell microgel particles, stained with cadmium nitrate and potassium hexachloroplatinate are shown in Fig. 15a and b. Unique Janus type amphoteric microgels were synthesized using a Pickering emulsion based approach.101 At first poly[N-isopropylacrylamide-co-acrylic acid] (NIPAm-AA) microgels with uniform size were synthesized via precipitation polymerization then using NIPAm-AA microgels as stabilizers, a Pickering emulsion (oil-in-water type) was formed by stirring hexadecane (HD) and water with NIPAm-AA microgel. Amino groups were introduced by a carbodiimide coupling reaction using ethylenediamine and 1-ethyl-3-(3-dimethylaminopropyl)-

carbodiimide hydrochloride. In the microgel particles sitting at liquid interface, the carboxyl groups of hemisphere were dipped into hexadecane (HD) while the amine groups were in water (Fig. 16). It was demonstrated that these microgels exhibited the possibility of pH-responsive assembly and may potentially be used as micro-actuators. Application of microfluidic devices have recently become an important approach for producing monodisperse microparticles for synthetic102–105 and biopolymer polyampholyte microgels.106,107 The microemulsion system is thermodynamically stable, and also the size of the dispersed phase can be controlled by changing the ratio between the amount of surfactant and water. Therefore, the microemulsion method40,54,108 for synthesis of polyampholyte particles provides nanoscale particles.

Fig. 14 SEM images of cross (a) and longitudinal (b) sections of amphoteric cryogel ACG-118. Reproduced from ref. 65 with permission of BME-PT.

Fig. 15 The PMAA core–PDEA shell amphoteric microgel particles stained with cadmium nitrate (a) and potassium hexachloroplatinate (b). Reproduced from ref. 47 with permission of ACS.

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(4) Grafting methods.109 The grafting techniques use special techniques to chemically attach functional polymers to the surface of nanoparticles (NP). The nanoparticles usually are made of latexes, silica, magnetite particles, and noble metals. Therefore, a core particle can be of organic or inorganic nature. But the shell should be composed of an amphoteric polymer. The stimuli-responsive properties of these core–shell structures depend on the sensitivity of the grafted polymer chains to changes in thermodynamic solvent quality, pH, ionic strength, temperature, etc. 2.3 Amphoteric (co)networks Unique representatives of amphoteric nanostructured gels are polyampholytic (co)networks based on crosslinked ‘‘in–out’’ star (co)polymers of various structures (homopolymer, heteroarm, block and statistical) described by Patrickios and coworkers.110–113 Well-defined end-linked triblock polyampholyte co-networks composed of positively ionizable 2(dimethylamino)ethylmethacrylate (DMAEMA) repeating units and negatively ionizable methacrylic acid (MAA) (produced from tetrahydropyranyl methacrylate (THPMA) by acid hydrolysis after network formation) repeating units were synthesized using one-pot, sequential reversible addition–fragmentation chain transfer (RAFT) polymerization, by employing 1,4-bis(methoxytrimethylsiloxymethylene)cyclohexane (MTS) as initiator, 1,4-bis[2-(thiobenzoylthio)prop-2-yl]-benzene (1,4BTBTPB) as the chain transfer agent, and ethylene glycol dimethacrylate (EGDMA) as the cross-linker (Fig. 17 and 18). Amphoteric (co)networks based on ABA triblock polyampholytes with polyDMAEMA midblocks and equimolar BAB triblock polyampholyte with a polyMAA midblock, statistical

This journal is ª The Royal Society of Chemistry 2012

Fig. 16 Janus-type amphoteric microgels at the hexadecane–water interface. Reproduced from ref. 101 with permission of ACS.

and randomly cross-linked architectures as well as the linear precursors to the (co)networks were obtained. The degrees of swelling (DSs) of all the polyampholyte (co) networks determined in acidic, basic and isoelectric pH (pI) regions are presented in Fig. 19. A characteristic minimum of the DS is observed around the (co)network isoelectric point (pI), while they increased at acidic and basic pH values. The pI values of the polyampholyte (co)networks, estimated from the position of the swelling minimum, ranged from 5.3 to 6.8. At around the pI, the net repulsive forces are zero, while the van der Waals and hydrophobic attractive forces dominate, leading to a reduced extension of the polyampholyte chains. Fig. 20 schematically illustrates the conformations of the polyampholyte network at low, isoelectric, and high pHs. At high pH, the MAA blocks (in black) are ionized and expanded, while the DMAEMA blocks (in white) are neutral and rather shrunk. At low pH, the MAA blocks are neutral and rather collapsed and the DMAEMA blocks are ionized and expanded. At the isoelectric pH, both

Fig. 17 Chemical structures of the monomers, the cross-linker, and the initiator used for the preparation of the amphoteric (co)networks. Reproduced from ref. 110 with permission of ACS.

This journal is ª The Royal Society of Chemistry 2012

Fig. 18 Schematic representation of the synthetic procedure followed for the preparation of the end-linked co-network based on the gradient triblock copolymer THPMA25-grad-DMAEMA50-grad-THPMA25. The DMAEMA units are shown in light blue, the THPMA units are in purple and the MAA units are shown in light pink. Black dumbbells represent the EGDMA cross-linker units. Reproduced from (ref. 112) with permission of ACS.

blocks are rather collapsed and the lowest DS values are observed. Thus at the IEP, all (co)networks were in a semicollapsed state, with the DSs of most networks being composition and architecture independent. pKa values of typical anionic/ cationic monomers for their homopolymers are tabulated in Table 2.

2.4 Amphoteric nano/microgels and their applications In the past decade, there have been many studies focused on synthesis of polyampholyte microgels.8–11,13 Polyampholyte microgels are unique systems because of the multiple interactions acting simultaneously or competing against each other within their interior. The external stimuli-responsive properties of amphoteric nano/microgel particles have been investigated.6,11 Most of the above-discussed studies are based on their response to the ionic strength, pH, solvent, and temperature.13,41,48,56,114 As shown in Fig. 1, polyampholyte nano/microgel particles shrink in the pH range of the zwitteroionic region due to the neutralization of opposite charges inside the matrix. Outside the zwitteroionic region, the polyampholytes demonstrate polyelectrolyte behavior due to ionization of weak acid or base

Fig. 19 Degree of swelling the polyampholyte (co)networks in acidic, basic and isoelectric regions. Reproduced from ref. 112 with permission of ACS.

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pairing between the oppositely charged groups increases the extent of the temperature-induced deswelling. The polyampholyte nano- and microgels can be used in a broad range of applications since they have stimuli-responsive properties. Here, we will give several examples of their applications in different areas. Fig. 20 Schematic representation of the conformations adopted by the network based on the MAA20-b-DMAEMA20-b-MAA20 triblock polyampholyte at low, isoelectric, and high pH (the subscripts show the degree of polymerization). Reproduced from ref. 110 with permission of ACS.

groups in the particles. They will expand due to the electrostatic repulsion of unpaired ions. Inside the zwitteroionic region, ion pairing between the oppositely charged groups dominates over repulsion between unpaired like charges, leading to microgel shrinkage. Thus, the polyampholyte microgels attain their smallest size at the IEP which is in the zwitterionic region. Addition of inorganic salts increases the stability of microparticles in aqueous solutions due to screening the electrostatic attraction between the oppositely charged groups. This is called an antipolyelectrolyte effect. The dielectric constant of the solvent is a critical parameter that affects the performance of polyampholyte microgels in different media. At higher temperature, PA microgels contract similarly to polyelectrolyte microgels when both opposite groups are charged and hydrophilic. Ion

2.4.1 Amphoteric nano/microgels for sequestration of gold nanoparticles. One of the most popular applications of amphoteric nano/microgels involves sequestering gold nanoparticles.122 Polyampholyte poly(N-isopropylacrylamide-co-acrylic acid-covinylimidazole) (poly(NIPAm-AA-VI)) microgels were investigated on the sequestering of gold nanorods with varying the number of charged groups at different pH values and the effect of electrostatic forces on sequestering of the nanoparticles. Through observation of the affinity of gold nanorods for polyNIPAm-based microgels of cationic, anionic, and close-toneutral-state nature, it was shown that those electrostatic interactions alone are not the only governing force driving the loading of microgels with gold nanorods. The loading of gold nanoparticles into microgels is independent on the pH of the medium. Poly(NIPAm-AA-VI) microgels loaded with gold nanorods were studied at three pH values, namely, pH ¼ 4.5, pH ¼ 6.3, and pH ¼ 7.5 corresponding to the positively charged, almost neutral (close to the IEP), and negatively charged particles, respectively. 2.4.2 Amphoteric nano/microgels for drug delivery. Drug delivery is also one of the important applications of amphoteric

Table 2 Structures of typical anionic/cationic monomers and pKa values for their homopolymers14,115–121 Monomer

Structure

pKa

Reference

Acrylic acid

4.0 to 4.5

115

Methacrylic acid

6.0 to 7.0

116

2-(Diethylamino)ethylmethacrylate

7.0 to 7.3

14

2-(Diethylamino)ethylmethacrylate

7.2 to 7.4

117

2-Vinylpyridine

4.7

118

4-Vinylpyridine

5.4

119

Allylamine

9.0

120

1-Vinylimidazole

5.0 to 6.0

121

Acidic monomers

Basic monomers

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This journal is ª The Royal Society of Chemistry 2012

nano/microparticles.73 To mimic drug delivery, Bradley et al.38,123 demonstrated the uptake into, and in some cases, the release from, the amphoteric microgels of cationic and non-ionic surfactants. They employed pH-responsive core and temperature-sensitive shell microgels for the controlled uptake and release of active species. The uptake and release of an anionic surfactant from the microgels were investigated as a function of solution pH and temperature. These studies indicated that the electrostatic attraction between the anionic surfactant and the cationic core of the microgels dominated the absorption of the surfactant molecules. Hu et al.68 produced amphoteric ovalbumin–ovotransferrin nanogels using assembly methods and demonstrated their applicability as vehicles for drug delivery using benzoic acid as a model drug. They found that ovalbumin and ovotransferrin cannot bind with benzoic acid, whereas hydrophobic and electrostatic interactions are responsible for loading benzoic acid. The amphoteric nanogels are stable in the pH ranges of 2.0–4.0 and 7.0–11.0, carry net positive charges at pH lower than 5.5 and net negative charges at pH higher than 5.5, and form redispersible secondary aggregates at pH 5.0–6.0. Recently the Zhou group58 reported multifunctional core–shell nanocarriers with combined ability of both optical glucose detection and insulin delivery using amphoretic nanoshells (Fig. 21).58 The core–shell nanogels consisted of Ag nanoparticle (NP) cores covered by a copolymer gel shell of poly(4-vinylphenylboronic acid-co-2-(dimethylamino)ethyl acrylate) [P(VPBA-DMAEA)]. In this design, the small sized Ag cores (10 nm) provide fluorescence. However, the responsive polymer gel shell can convert the disruptions in homeostasis of glucose level into optical signals, and regulate release of preloaded insulin. Hoare and Pelton124 reported amphoteric, poly(N-isopropylacrylamide)-based microgels with glucose-dependent swelling response upon variation in physiological temperature, pH, and ionic strength. Deng et al.52 also investigated drug release behavior using polyampholyte nanogels consisting of P((MAA-co-DMAEMA)g-EG). Water-soluble chitosan (CS, Mn ¼ 5 kDa) was used as a model drug. They used pH-responsive properties of polyampholyte to release chitosan at physiological pH caused by the antipolyelectrolyte effect at the IEP. An increase in salt concentration causes the swelling of polyampholyte hydrogels.

Fig. 21 Schematic illustration of smart hybrid nanogels which show the possibility for optical glucose detection and self-regulated insulin delivery at physiological pH and temperature. Reproduced from ref. 58 with permission of ACS.

This journal is ª The Royal Society of Chemistry 2012

2.4.3 Amphoteric nano-assembly and microgels for gene delivery. Gene therapy can be defined as the treatment of human diseases by the transfer of genetic material into specific cells of the patient.125 It is a highly promising approach for the correction of genetic diseases such as haemophilia, muscular dystrophy or cystic fibrosis and also has the potential to treat some acquired conditions such as cardiovascular disorders, neurological disorders, cancer and AIDS.126 A major obstacle to the wide application of gene therapy is the difficulty in transporting intact plasmid DNA to target sites because of its vulnerability to enzymatic degradation in biological fluids.127 Therefore the development of efficient DNA delivery systems is highly desirable. Existing gene delivery strategies can be sub-divided into two categories: biological vectors such as viruses and non-viral vectors such as polymers or lipids. Although non-viral vectors are less efficient DNA transfection agents than viruses, they are characterised by better safety, lack of immunogenicity, very low frequency of integration, ease of large scale production and cost efficiency.128,129 Non-viral vectors such as cationic polymers can bind negatively charged DNA electrostatically and form compact particles known as polyplexes. Within the polyplex particles, DNA is protected from enzymatic degradation and can migrate into the cell nucleus (Fig. 22). The size of polyplex particles, their surface charge density and stability of polymer– DNA complexes are known to be the main factors determining their transfection efficiency (i.e. ability of introducing DNA into the cells).128 Polyethyleneimine (PEI) has been reported to be one of the most promising non-viral vectors for gene delivery.130,131 Since every third atom of PEI is a nitrogen atom, this polymer has a very high density of amines, and only 15–20% of which are protonated at physiological pH. These unique properties make PEI a very efficient proton sponge and ensures its effective DNA condensation ability and superior transfection efficiency both in vitro and in vivo.130 However, the in vivo applicability of PEI is limited because of its high cytotoxicity. Many attempts have been reported to derivatize PEI, aiming at the improvement of its transfection efficiency and toxicological profile, which included its partial acetylation,132–134 thiolation with subsequent disulphide cross-linking,135 quaternisation and attachment of alkyl groups136,137 and conjugation with various aminoacids.136 An interesting approach has recently been reported by Yao et al.,138 who synthesized PEI (25 kDa) conjugates with

Fig. 22 Scheme of DNA condensation by a polymeric vector and trafficking into the cell nucleus.

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hyaluronic acid (HA) of different molecular weights. HA is an anionic polysaccharide present in extracellular matrix and joint liquid of mammalians. This polysaccharide is non-toxic, biodegradable and biocompatible and therefore is suitable for injections.139 HA and its derivatives are also known to induce receptor-mediated intracellular signaling such as endocytosis, degradation and signal transduction. The authors138 have synthesized polyampholyte copolymers (HA-g-PEI) by the reaction between periodate–oxidized HA and PEI aiming to reduce the polymers’ cytotoxicity, improve their affinity to tumor cells and enhance their transfection efficiency. The ability of these polyampholyte conjugates to condense DNA was evaluated using agarose gel electrophoresis. It was established that the copolymers retard DNA migration when the N/P ratio of HA-gPEI–DNA mixtures reaches 2.5, 1.5 and 1.0 for copolymers with 60, 500 and 1500 kDa HA, respectively. The TEM examination of HA-g-PEI–DNA mixtures revealed that they form compact spherical complex nanoparticles (203–220 nm) at higher N/P ratios. These copolymers were found to provide a better protection of DNA from nuclease enzyme degradation compared to unmodified PEI; additionally they exhibited low cytotoxicity even at relatively high concentrations and the HA-g-PEI–DNA complexes were nearly non-toxic at optimal charge ratios. The copolymers with 500 and 1500 kDa HA have shown good in vitro transfection efficiency in HeoG2 cells, which was superior compared to the parent PEI. In vivo experiments in tumorbearing mice also have demonstrated that HA-g-PEI could facilitate DNA targeting. Asayama and co-workers140 have also reported the synthesis of polyampholyte comb-type copolymers with HA side chains and evaluated their interactions with DNA. These copolymers were synthesized by coupling the reducing end of HA and 3-amino groups of poly(L-lysine) by reductive amination. The 1H NMR investigation has revealed that these polyampholytes interact with DNA efficiently despite the presence of negatively charged HA side chains. Electrostatic deposition of anionic HA on the cationic surface of PEI–DNA complexes has been demonstrated to minimize non-specific interactions of these nano-assembly with serum proteins,141 also HA acted as a ligand to specific cells and helped to activate transcription. When HA was chemically modified by attaching cationic spermine side chains, this amphoteric HA–spermine conjugate was found to have improved transcription-enhancing activity and superior gene expression in cultured cells compared to its parent HA. Chitosan, a cationic polysaccharide, has previously been considered as a potential vector for gene delivery because of its biocompatibility, biodegradability and cationic nature.142,143 However, there are a number of drawbacks typical for application of chitosan in this area such as its limited solubility in water (it is soluble under acidic conditions and precipitates at pH > 6.5, ref. 144), and low gene transfection efficiency.142 Recently Shi et al.145 have reported the development of a novel polyampholyte based on N-imidazolyl-O-carboxymethyl chitosan and evaluated its suitability for application as non-viral vectors for gene delivery. The authors have demonstrated that the conversion of chitosan into amphoteric O-carboxymethyl chitosan resulted in a dramatic improvement of its solubility in water in a broad range of pH values (4–10), but unfortunately did not enhance its DNA binding ability. However, a further 9314 | Soft Matter, 2012, 8, 9302–9321

derivatization of O-carboxymethyl chitosan through its conjugation with 4-imidazolecarboxaldehyde has resulted in the formation of N-imidazolyl-O-carboxymethyl chitosan (ICMC), a polyampholyte with excellent toxicological profile, improved DNA binding and transfection efficiency. The nano-assembly formed by mixing ICMC with DNA plasmid had sizes in the range of 192–396 nm, with smaller particles resulting from higher ICMS/DNA ratios. Smaller nanoparticles also formed for ICMC with higher content of imidazole rings in its structure, which is related to stronger polymer–DNA interactions and better compaction of polyplexes. The cytotoxicity of ICMC with respect to HEK293T cells evaluated by the MTT assay was found to be significantly lower compared to commercial gene delivery vectors such as PEI and lipofectamine 2000. ICMC derivatives containing 13.2, 42.3 and 69.4% of imidazolyl rings gave DNA transfection efficiency of 3.5, 32.0 and 46.9%, respectively. This high transfection efficiency was related by the authors145 to the presence of primary, secondary and tertiary nitrogen atoms in ICMC and also to the proton sponge effect due to amphoteric nature of these polymers. Georgiou et al.146 have reported the synthesis of amphoteric star copolymers and their use as vectors for gene delivery. They prepared five star copolymers based on cationic 2-(dimethylamino)ethylmethacrylate (DMAEMA) and the hydrophobic tetrahydropyranyl methacrylate (THPMA) using group-transfer polymerization with ethylene glycol dimethacrylate as a coupling agent. Four isomeric star copolymers (one heteroarm, two star block, and the statistical star) with 3 : 1 DMAEMA/ THPMA molar ratio and one star DMAEMA homopolymer were synthesized. THPMA units in these copolymers were subsequently hydrolyzed into methacrylic acid (MAA) to give star polyampholytes. The authors146 have hypothesized that the negatively charged MAA units should weaken the electrostatic binding of these copolymers with DNA to facilitate its release from the polyplexes. The evaluation of DNA transfection efficiency mediated by these copolymers has shown the important role of their chemical architecture. The highest transfection efficiency was observed for DMAEMA15-starMAA5 (the subscripts show the degree of polymerization) compared to all other star copolymers. However, this transfection efficiency was still not as good as in the case of commercial vector SuperFect. All amphoteric star copolymers also had better toxicological profile compared to DMAEMA star homopolymer. Taira et al.108 investigated loading and releasing of ssDNA using amphoteric microgels. ssDNA is trapped at neutral pH in amphoteric microgels due to the formation of an ion complex between negatively charged protein and positively charged colloids. In alkaline pH, ssDNA is released due to the electrostatic repulsion forces caused by the change of the microgel charge as shown in Fig. 23. In summary, some enhancement in non-viral vector transfection efficiency and improvement in toxicity was reported in several studies, where polyampholytes were used in place of their cationic analogues. However, only few studies were reported so far to demonstrate the superior efficiency of polyampholytes. More research is needed in this area to evaluate the possibility of using amphoteric polymers of different chemical nature and structural architecture. This journal is ª The Royal Society of Chemistry 2012

Fig. 23 Schematic illustration of entrapment and release of ssDNA by pH-responsive amphoteric microgels. Reproduced from ref. 108 with permission of Wiley & Sons.

3. Amphoteric membranes Amphoteric membranes have been studied for various applications such as separation of low molecular weight organic molecules from inorganic salt mixtures,147–154 selective ion transport,155–157 drug delivery through membranes of biological interest,158,159 separation of ionic drugs and proteins,160,161 and separation of alcohol and water.162 They are considered to be ‘‘next generation membranes’’. In an amphoteric membrane,163 the following resulted from changes in ionization of functional groups in the membrane matrixes: (1) in the isoelectric region of the membrane it deswells in length and weight; (2) the electric resistance increases several orders of magnitude in this region; (3) under acidic conditions, the membrane becomes anion selective; however, it becomes cation selective under basic conditions; (4) under both acidic and basic conditions, the membrane is difficult to distinguish ion pairs such as Cl and SO42 or Na+ and K+; (5) at the IEP or high resistance region, however, the transport of Cl is 7–8 times easier than that of SO4. Therefore, the ionselectivity of the membrane is determined by the sign of fixed charge in the membrane matrix. If the charge of the membrane is positive, the membrane is anion-selective. If the charged groups of both signs are ionized, they neutralize each other. The distances between opposite charges are important. If the opposite charges are close enough, they neutralize through coulombic attractions. If they are far from each other, mobile anions and cations are allowed to penetrate into and across the membrane. The vast majority of both dense and porous commercially available polymeric membranes, as well as the porous supports of composite membranes, are produced by the phase-inversion process.164 In the phase inversion process, a viscous polymer solution is cast into a thin film or a hollow fiber and immersed into a homogeneous phase (non-solvent), which has a high affinity for the polymer solvent, but low or no affinity for the polymer. As both phases are brought into contact, a mass transfer process is initiated as solvent and non-solvent are exchanged, eventually resulting in the precipitation of a solid porous polymeric matrix that constitutes the membrane. In the fabrication of an amphoteric membrane, phase inversion methods are often applied. According to a literature study, the following fabrication approaches were applied either alone or together. The most common approach165 is to prepare the membrane directly from the amphoteric polymers produced from two monomers carrying different charged functional groups. The chemical grafting and radiation-induced graft approaches for the preparation of the membrane matrix157,166–168 were used to introduce the differently charged groups. Crosslinking chemistry using a cross-linker such as epichlorohydrin,169 This journal is ª The Royal Society of Chemistry 2012

glutaraldehyde,161,162,170,171 etc. was a common method for fabrication of membranes based on natural polymers such as chitosan. In 1932, Sollner172 first presented the idea that a mosaic membrane composed of cationic and anionic groups had special transport properties due to electrical interaction, and he pointed out that circulating electric currents should flow between the differently charged groups. Since then, amphoteric membranes have been of great interest and widely studied in separation of organic molecules from a mixture of salts. There has been remarkable progress in amphoteric membranes from both experimental147–149 and theoretical points of view.173 Weinstein and Caplan147,148 studied experimentally circulating currents which are a phenomena of piezodialysis. Piezodialysis174 is an important application of amphoteric membranes for desalination; it utilizes a mosaic membrane under a pressure gradient and enhances salt permeability. Leitz et al. described a ‘‘latex-polyelectrolyte’’ fabrication method of membranes with a large salt enrichment. Fujimoto et al.175 developed a mosaic membrane consisting of a penta-block copolymer of the BABCB type by selectively introducing anion and cation exchange groups into the microseparated phases. To increase the flux for possible industrial applications, Linder and Kedem176 recently prepared an ion exchange mosaic membrane from sulfonated polysulfone (SPSu) and bromomethylated poly(2,6-dimethyl phenylene oxide) (BrPPO). Mosaic membranes may be usefully applied to different separation problems, such as the separation of salts from water-soluble organic substances, treatment of waste streams from dye, food, dairy, fermentation, agriculture, pharmaceutical and mining industries.176 Recently, amphoteric polymer membranes received interest due to their pH-responsiveness, antifouling property, and flexibility in the design of charged structures. These polymers157,177 show potential applications not only in mimicking the behavior of biological membranes, but also in protein separations,171 waste metal treatment,178 and drug delivery systems.159,179,180 Saito and Tanioka181 prepared a polyamphoteric gel membrane from N-succinyl chitosan and polyvinylalcohol, and they investigated piezodialysis in the polyamphoteric membrane and the diffusive permeability of solutes with different charged conditions through the N-succinyl chitosan–polyvinylalcohol membranes. Nonaka et al.182 investigated the diffusive permeability of solutes with different charged conditions, and the changes in the membrane potential during the permeation of solutes through amphoteric polymer membranes. These amphoteric polymer membranes bearing both amino groups and carboxyl groups were prepared from 2,3-epithiopropyl methacrylate (ETMA)– butylmethacrylate (BMA)–N,N-dimethylaminopropyl acrylamide (DMAPAA)–methacrylic acid (MAc) copolymers. Matsuyama et al.183 studied the permeability of ionic solutes through a polyamphoteric membrane. Ramirez and Alcaraz158 theoretically studied the effects of pH on ion transport through amphoteric polymer membranes. Takagi and Nakagaki184 discussed the theoretical permeation of ions using the advanced amphoteric membrane model shown in Fig. 24. They determined the membrane charge by the dissociation of the amphoteric material as well as the selective adsorption of ions. Soft Matter, 2012, 8, 9302–9321 | 9315

Since the separation of biomacromolecules based on electrostatic interactions between their surface charges and the charged groups on the membranes is relatively simple and efficient, many ion-exchange materials have been prepared.161,168,169,171

4. Amphoteric thin films In this section, both grafted polyampholyte monolayers and amphoteric thin films on substrates are introduced because of their unique applications in the various fields185–187 such as colloidal stabilization,188 lubrication,189 ‘‘smart’’ surface coatings,190 protein adsorption,191 nano-actuators,192,193 and antifogging185,186 and antibacterial187 coatings. First, grafted polyampholytes on different substrates will be discussed. The stimuli-responsive behavior of weak block polyampholyte brushes makes them a promising platform for designing ‘‘smart’’ polymer films with tunable properties.194 Then, amphoteric layerby-layer assembled thin films will be introduced. The following reasons accounts for the limited amount of experimental work and the embryonic stage of studies on interfacial performance of polyampholytes. First is the rather complex behavior of polyampholytes at interfaces stemming from a large array of system parameters governing the interaction between the polymer and the substrate. So far, most of interfacial studies on polyampholytes have reported their adsorption on solid interfaces.195,196 For example, Mahltig et al.196–201 studied the adsorption of poly(methacrylic acid)block-poly(dimethyl aminoethyl methacrylate) (PMAA-bPDMAEMA) from aqueous solution on silicon substrates. It was found that the adsorbed amount of PMAA-b-PDMAEMA at the solution–substrate interface depended on the solution pH. Specifically, the adsorption increased at the IEP of the polyampholyte. At the IEP, virtually all copolymer precipitated in solution202 and almost no adsorption at the substrate was detected. Bhat et al.203 investigated the behavior of a grafted polyampholyte on a planar surface for the first time and observed a decrease in the thickness of the polymer brush around the IEP (Fig. 25). There are a lot of studies on grafted polyampholytes on planar surfaces from the theoretical point of view.204,205 The properties of block polyampholytes are quite different from those of random polyampholytes, as the localization of like charges within one segment increases the electrostatic interactions between oppositely charged blocks; therefore, only research on diblock polyampholytes is considered in this manuscript. Shusharina and Linse206 studied a diblock polyampholyte grafted

Fig. 24 Working principle of an amphoteric membrane. Reproduced from ref. 184 with permission of Elsevier.

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Fig. 25 Schematic illustration of the conformations of PDMAEMA-bPAA brushes grafted on a solid substrate as a function of pH. Reproduced from ref. 203 with permission of Springer.

onto an uncharged planar surface using mean-field lattice theory calculations and considered the effect of the polyelectrolyte charge, the polyelectrolyte length, and the amount of added low molecular weight electrolyte (salt) on the brush structure. Monte Carlo simulations207 have also been utilized to examine diblock polyampholytes grafted onto spherical particles with lattice mean-field theory. A strong dependence on the net charge of the diblock was found. If one of the blocks were charged, the chains extended from the surface with polyelectrolyte properties, however if the net charge was zero, the chains collapsed. Brittain et al.62 studied the stimuli-responsive behavior of poly(acrylic acid-block-4-vinylpyridine) (PAA-b-P4VP) prepared via ATRP on silicon substrate (Fig. 26). AB diblock polyampholytic polymer brushes PAA-b-P4VP were fabricated and a rich pH-responsive behavior was demonstrated from the grafted polyampholyte brushes. Both polyelectrolyte and polyampholyte effects were observed with the change in pH. Yu and Han208 extended Brittain’s work62 and reported stimuli-responsive behavior of the same polyampholyte brushes PAA-b-P4VP on a silicon substrate. Amphoteric thin films include coatings on the various substrates constructed with different methods such as spincasting and layer-by-layer dip coating. Most popular studies in this area focus on the multilayers formed via layer-by-layer dip coating method since the size, structure, and properties of each layer can be controlled at the nanoscale. Thin films can be constructed by physical44 and chemical forces.209,210 The properties of the film can be tuned by using different polymers, and varying other parameters such as the pH and ionic strength of the

Fig. 26 Scheme for preparation of PAA-b-P4VP brush using ATRP. Reproduced from ref. 62 with permission of ACS.

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solution. Most amphoteric films consist of multilayers that have electrostatic interactions between positive charges of polycations and negative charges of polyanions. In electrostatically formed multilayers, the substrate is immersed alternatively between oppositely charged polyelectrolytes for the desired film thickness.211 For example, in the case of the construction of chitosan and carboxymethyl cellulose multilayers on a glass substrate, chitosan is positively charged, and a carboxymethyl cellulose is negatively charged. A clean glass substrate is immersed alternately into the containers containing the two oppositely charged polymers. The film growth behavior of polysaccharide films is different from the films that are constructed from two oppositely charged synthetic polymers. The growth of synthetic polymer films is linear with dipping cycles. However, the film growth of natural polymers is exponential with dipping cycles. This kind of growth is the main reason for the existence of mobile free ions in the film, which compensate the charge of the outer layer of oppositely charged polyions.185,212,213 Chen et al.214 demonstrated layer-by-layer assembly of single-charged ions 1-butyl-3-methylimidazolium chloride ([BMIM]+) with a rigid polyampholyte sulfonated cardo poly(arylene ether sulfone) as shown in Fig. 27. The film growth was monitored by quartz crystal microgravimetry (QCM). Linear growth of the multilayers was observed. Lin and Su215 also investigated electrostatic assembly of only polyampholytes via the LBL method. Gelatin was used as the charged species in the layer-by-layer assembly process. Linear growth of gelatin multilayers was found by electrostatic interactions. The mechanical properties of thin film have been difficult to evaluate quantitatively in contrast to bulk polymer systems. There have been pioneering works in the evaluation of the Young’s modulus of thin films. MIT216 and NIST217 research groups developed the bucking instabilities technique for measurement of Young’s modulus of the thin films. The nanoindentation technique218,219 was also developed to measure the Young’s modulus of amphoteric thin films. To control the properties of amphoteric multilayers for various applications, it is important to not only consider the chemical compositions of polyampholytes, but also choose the right assembly conditions including pH and ionic strength.

Fig. 27 Layer-by-layer assembly of the sulfonated cardo poly(arylene ether sulfone) and ionic liquid[SPES–[BMIM]+ ] multilayers. Reproduced from ref. 214 with permission of The Royal Society of Chemistry.

This journal is ª The Royal Society of Chemistry 2012

Here we give several examples of amphoteric thin film applications. Kabishima et al.220 reported antifogging applications of polyampholyte on the glass surface. They synthesized polyamholytes, AAC-320 and AAC-610, which contain cationic monomers, anionic monomers, and hydrophobic monomers. The polymers were adsorbed on a glass surface as monolayers via electrostatic interaction. Cationic parts of polymer adsorbed on the negatively charged glass surface, and the anionic parts turned toward the side opposite from the glass surface. The polyampholyte monolayer on the glass showed good anti-fogging capabilities, and hydrophilicity. The antifogging applications of amphoteric thin films were studied using hydrophilic polysaccharides by Nuraje et al.185,186 In this study, hydroxyl rich polysaccharide film prevents water nucleation and condensation on its surface. A layer-by-layer assembly process was applied to construct antifogging coatings (Fig. 28). These coatings contain chitosan and carboxymethyl cellulose. The antifogging properties are a consequence of a strong interaction between the polar and H-bonding elements of the assembled polymers and water molecules and the formation of water thin films. After being chemically cross-linked, the hydrophilic polysaccharide films become porous and turn out to be superhydrophilic because of the capillarity of the porous films. Environmental scanning electron microscopy studies showed that the excellent antifogging capabilities of the polysaccharidecontaining multilayers were associated with the formation of water sheets as opposed to light-scattering water droplets observed in the fogging films. The mechanical stiffness and structure of the films are important parameters to create antibacterial films. According to some studies,187,221 it was found (Fig. 29) that the adhesion of viable, colony-forming S. epidermidis and E. coli correlates positively with increasing elastic modulus of weak polyelectrolyte multilayered substrates over the range 1 MPa < E < 100 MPa. These results show that substrate’s stiffness affects the adhesion of viable prokaryotes, such as bacteria, independently of other surface characteristics. These observations were not attributable

Fig. 28 Photos of 20 bilayers of chitosan (CHI)/carboxymethyl cellulose (CMC) coatings on glass and polycarbonate after exposure in a humidity chamber. (A) Glass, (B) polycarbonate, (C) left lens of a safety goggle. Yellow lined area indicates where coating was applied. Reproduced from ref. 185 with permission of ACS.

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to the differences in deposited physicochemical regulators of bacterial adhesion, including surface roughness, surface interaction energy, and surface charge density of the PEM thin films.

5. Summary This review considers the preparation, physicochemical properties and applications of amphoteric nano/microgels, selfassembly, membranes and thin films. It may be useful as a tutorial for non-experts and also provides valuable information for scientists in recent development of amphoteric materials. In spite of considerable achievements in nano-, micro- and macrostructured amphoteric gels surveyed from the literature analysis, several perspective directions, including the less developed and ‘‘white spot’’ parts, are outlined. The first task is the development of synthetic strategy of hydrophobically modified amphoteric gels because amphoteric macromolecules containing hydrophobic moieties due to strong tendency for self-organization in aqueous media can serve as simple model of biological membranes. The second task is to enhance research in the field of macroporous amphoteric gels. Pioneering works in this direction just started and their further development is the most challenging task. The third task is to design gel–metal conjugates composed of nano- and microsized amphoteric gels and metal nanoparticles (gold and silver) in order to apply them in nanomedicine, especially in treatment of cancer and infectious diseases. Moreover supporting of noble and transition metal ions in bulk of amphoteric nano-, micro-, macrogels followed by reduction to zero-valent state will open new perspectives for development of effective catalytic systems for decomposition, isomerization, hydrogenation, and oxidation of various organic substrates. In this context amphoteric macroporous gels can also play the role of efficient supports and flow-through microreactors in

Fig. 29 (a) Wild-type E. coli exhibit colony density varies directly with the stiffness (symbols) of the PEM substrata. (b) Viable, spherical DmreB E. coli adhere more readily to the stiffest substrata (E  100 MPa). Reproduced from ref. 221 with permission of ACS.

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heterogeneous catalysis. The next task is the immobilization of enzymes in the bulk of amphoteric nano-, micro-, macrogels to fabricate fine tunable biocatalysts demonstrating ‘‘on–off’’ behavior in response to the environment. Amphoteric nanosorbents (or nanoscavengers) might be useful for wastewater purification and analytical purposes. The main advantage of nanoscavengers is absence of external agitation because the particles move naturally through the sample by Brownian motion, convection and sedimentation. Finally crosslinked polymer systems based on dendrimeric polyampholytes and polymeric betaines are the next generation of amphoteric nano-, micro-, and macrogels with intelligent structure–properties– application relationships.

Acknowledgements SEK and NN are grateful to the Ministry of Education and Science of the Republic of Kazakhstan and World Bank for financial support (Grant no. 161).

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