Cationic Polymer Nanoparticles and Nanogels: From Synthesis to

Review pubs.acs.org/CR

Cationic Polymer Nanoparticles and Nanogels: From Synthesis to Biotechnological Applications Jose Ramos,† Jacqueline Forcada,*,† and Roque Hidalgo-Alvarez*,‡ †

POLYMAT, Bionanoparticles Group, Departamento de Química Aplicada, UFI 11/56, Facultad de Ciencias Químicas, Universidad del País Vasco UPV/EHU, Apdo. 1072, 20080 Donostia-San Sebastián, Spain ‡ Grupo de Física de Fluidos y Biocoloides, Departamento de Física Aplicada, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain 4.1.1. Conventional Production of Micro/ Nanogels 4.1.2. Nonconventional Production of Micro/ Nanogels 5. Conclusions and Future Perspectives Author Information Corresponding Authors Notes Biographies Acknowledgments Dedication References

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CONTENTS 1. Introduction 2. Designing the Cationic System 2.1. Cationic Monomers and Polymers 2.2. Cationic Initiators 2.3. Cationic Surfactants 3. Cationic Latexes 3.1. Synthesis Strategies To Produce Cationic Latexes 3.1.1. Unseeded Emulsion Polymerization Processes 3.1.2. Seeded Emulsion Polymerization Processes 3.1.3. Other Polymerization Processes in Dispersed Media 3.2. Characterization of Cationic Latexes 3.3. Applications of Cationic Latexes 3.3.1. Adsorption of Proteins on Cationic Latexes 3.3.2. Latex Immunoassay Aggregation 3.3.3. Adsorption of Polyelectrolytes and Surfactants on Cationic Latexes 3.3.4. Heteroaggregation of Colloidal Dispersions 3.3.5. Colloidal Monolayer Formed by Cationic Latex Particles at the Air−Water Interface 3.3.6. Deposition of Cationic Latexes 3.3.7. Cationic Latexes as Catalyst Supports 3.3.8. Film Formation with Cationic Latexes 4. Cationic Micro/Nanogels 4.1. Strategies To Produce Cationic Micro/Nanogels, Characterizations, and Applications

© 2013 American Chemical Society

1. INTRODUCTION In the past several decades, aqueous polymeric dispersions prepared by means of polymerization processes in dispersed media to produce polymeric particles having diameters in the colloidal range, have garnered increasing interest from both academic and industrial points of view.1 These nanoparticles are used in a large variety of applications, e.g., adhesives, waterbased coatings, textile, paper, additives, and flocculants. They are also suitable for use as fine or highly added value polymeric materials for medical diagnostic tests, antibody purifications, drug delivery systems, and material for calibrations. Monodisperse polymer colloids have proved to be very useful model systems for studying various colloidal phenomena and developing different technological applications. Most of the experiments reported have been performed with negatively charged particles, and relatively little attention has been paid to positively charged samples. It is usual in the literature of polymer colloids to use the expression “cationic latexes” to designate the cationic polymeric particles. In this review the synthesis of cationic polymer particles and nanogels by emulsion polymerization will be comprehensively revised. An in-depth study on the kinetics of cationic systems will be detailed and compared with that of well-known anionic systems. Then polymeric and colloidal features of the cationic particles/nanogels will be revised, and finally, some biotechnological applications of cationic particles/nanogels will be described in detail. Nowadays, in the field of cancer therapies, the idea of a carrier going to the specific target, passively or actively, is absolutely critical for the effective drug doses to reach the

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Received: July 2, 2012 Published: September 5, 2013 367

dx.doi.org/10.1021/cr3002643 | Chem. Rev. 2014, 114, 367−428

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Drug delivery systems have been designed to use pH as a mechanism to improve delivery of chemotherapeutics. Improved delivery mechanisms may reduce side effects and increase the quality of life of patients. Synthesized polymeric delivery vehicles based on particles/nanogels from conventional anionic pH-sensitive polymers exhibit swelling behavior at high pH. This mechanism is not useful for delivery to the acidic environments present in tumor tissues. Thus, the drug delivery vehicles must have a reverse acid swelling behavior, which is achieved with cationic monomers. The monodispersity of the particles/nanogels is one of the main requirements from the point of view of their biotechnological applications. For the objective of finding suitable experimental conditions for obtaining particles of a given size, having a narrow particle size distribution (PSD), the type of polymerization process is important. The most suitable processes found in the literature to obtain polymeric colloidal particles are those related to heterophase polymerization processes, mainly emulsion polymerization (seeded or unseeded, batch or semicontinuous). To the best of our knowledge,7 the emulsion polymerization technique is the most efficient and profitable polymerization method to produce polymeric nanoparticles (latex particles). As a result of the compartmentalization of the polymerization reaction in the nanoparticles dispersed in the continuous aqueous medium, reaction times are short and high conversions of monomer to polymer are obtained, and consequently, high reaction rates, good heat transfer (the continuous medium is water), and the possibility of controlling both particle size distributions (and therefore their monodispersity) and, if necessary, molecular weight distributions, comonomer compositions, and surface functionalization are achieved. Apart from these characteristics because it is a polymerization process in dispersed media, in emulsion polymerization nucleation processes, latex particles are formed and the monomer(s) needed for their growth is transported through the continuous phase. Another advantage in terms of versatility is that the monomer(s) can be fed continuously into the reactor either as a neat monomer or as an emulsion and the monomer to water ratio can be adjusted to obtain the desired solids content. Applications of latex particles made by emulsion polymerization in the biomedical field were concentrated initially in the area of in vitro immunoassays. Polymer particles have been extensively used in this field, starting in 1956 with the development of the latex agglutination test.8 After this, a significant number of applications of polymer particles in the biomedical field emerged in a combination of new biotechnological developments. Polymeric colloids synthesized by emulsion polymerization are currently finding new applications in the biomedical field. By controlling the experimental conditions of the emulsion polymerization process, one can obtain colloidal systems with particle sizes, monodispersities, and specific surface characteristics required for their use in biomedical applications. Moreover, colloidal systems comprise small polymeric particles suspended in aqueous medium, having a high surface area. For all these reasons, polymeric particles are being used as carriers of biomolecules, such as proteins, enzymes, etc. Among the variety of applications of supported biomolecules on the surface of polymeric particles, there are immunodiagnosis tests, labeling, identification, quantification, and separation of cells, and drug delivery systems.9

pathological region of interest without damaging the surrounding health cells or tissues. This is the idea of the “magic bullet”.2 This could consist of a delivery platform with nanometric size able to be specifically targeted to the tumor tissue, avoiding premature fragmentation and degradation3 and helping the transfer of a more concentrated drug load through the cellular membrane. This integral system could demonstrate a controlled delivery by activation by means of one or more stimuli such as temperature, pH, light, etc. It should be taken into account that, to release concentrated drug loads in nonhealthy tissues, it is necessary to have a robust delivery platform with the ability to control the release of the drug in a precise way with previous activation by an external stimulus. Another aspect to take into account is that particle sizes and their functional groups have a high impact on biodistribution and pharmacokinetics. As an example, nanoparticles with positive charge have a higher removal velocity than those with negative charge, and with respect to the size, particles with sizes between 100 and 200 nm, if unprotected, are quickly removed from the bloodstream by the mononuclear phagocyte system (MPS).4 However, the addition of biocompatible polymers such as polyethylene glycol (PEG) onto their surfaces (in the case of hard nanoparticles) avoids the actuation of the phagocytes as a result of the steric interferences provoked by the PEG chains on the nanoparticle surface and increases considerably the average circulation life in blood (from 1/2 to 5 h). The liver and spleen trap particles poorly or in a less covered manner. This type of surfacemodified nanoparticle can be considered as stealth for the immune system, and it is used to help in diminishing the removal velocity, inhibiting opsonization (labeling of nanoparticles with opsonin proteins which the macrophage recognizes, rejecting the foreign body).5 A longer circulation time, and therefore an increase in bioavailability, is very important because most of the nanocarriers operate by targeting tumors passively and taking advantage of their permeable vascularization and poor lymphatic drainage as a result of the rapid and active tumor angiogenesis. This phenomenon allows the nanocarriers to cross the endothelial barrier and accumulate in tumor tissues while they leave the surrounding healthy tissue intact.6 Cationic vectors facilitate cellular uptake. This has been proven in the case of the use of liposomes and cationic micelles in gene therapy. The use of cationic nanocarriers will facilitate endocytosis and allow loads that are nonpermeable to the cell membrane, such as hydrophobic drugs or DNA molecules, to be transported and released from the endosomes to travel (endosomal escape) to the chosen place. Nowadays, polymer particles and nanogels with cationic charge are being used in emerging biomedical technologies due to the strong interaction between DNA and cationic polymer colloids, the acid-swellable behavior of the nanoparticle/ nanogel, and the ability to form oriented bonds with proteins, among other aspects. On one hand, polycation−DNA complexes are called polyplexes. These polyplexes are very useful in gene therapy to improve the delivery of the new DNA into the cell. DNA must be protected from damage such as its rapid enzymatic degradation in serum conditions, and its entry into the cell must be facilitated. To this end, new polyplexes have the ability to protect DNA from undesirable degradation during the transfection process. On the other hand, tumor tissues exhibit a lower extracellular pH than normal tissues together with a slightly higher temperature. 368


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Scheme 1. Cationic Monomersa

2. DESIGNING THE CATIONIC SYSTEM Cationically charged nanoparticles and nanogels can be prepared by several polymerization processes, but always using cationic reagents able to be (i) covalently bonded to a nanoparticle or nanogel (monomers, polymers, and initiators) or (ii) physically adsorbed onto the nanoparticle surface (surfactants). It is impossible to revise, and even to mention, the huge amount of cationic compounds commercially available. However, the design of a cationic system with the right choice of cationic reagents is of paramount importance from all points of view (from synthesis to final application). Therefore, in this review the most remarkable cationic compounds, used in several polymerization processes described below, are classified as cationic monomers and polymers, cationic initiators, and cationic surfactants. 2.1. Cationic Monomers and Polymers

Scheme 1 shows the main cationic monomers used in the synthesis of cationic colloids by emulsion polymerization. As can be seen, different families of cationic monomers can be used depending on the type of cationic charge required. On one hand, cationic nanoparticles with pH-dependent surface charge densities are obtained if neutral forms of vinylpyridines [2vinylpyridine (2VP) or 4-vinylpyridine (4VP)] and (dialkylamino)ethyl methacrylates [2-(dimethylamino)ethyl methacrylate (DMAEMA) or 2-(diethylamino)ethyl methacrylate (DEAEMA)] are used. On the other hand, cationic nanoparticles with constant surface charge densities are obtained when quaternary ammonium cationic monomers are used. These cationic monomers are obtained by quarternization of neutral amine-containing monomers: (i) Quaternization of vinylpyridines such as 1-methyl-4vinylpyridinium bromide (MVPC), 1-methyl-4-vinylpyridinium iodine (MVPI), 1,2-dimethyl-5-vinylpyridinium methyl sulfate (DMVP), and 1-ethyl-2-methyl-5vinylpyridinium bromide (EMVP). (ii) Quaternization of (dialkylamino)ethyl methacrylates such as [2-(methacryloyloxy)ethyl]trimethylammonium chloride (MATMAC), [2-(methacryloyloxy)ethyl]trimethylammonium iodine (MATMAI), N,N-dimethylN-butyl-N-ethyl methacrylate ammonium bromide (DMBEMAB), and N,N-dimethyl-N-but yl-N(methacrylamidinopropyl)ammonium bromide (DMBMAPAB) (iii) Quaternization of other amine-containing monomers such as (vinylbenzyl)trimethylammonium chloride (VBTMAC), [3-(methacryloylamino)propyl]trimethylammonium chloride (MAPTMAC), and diallyldimethylammonium chloride (DADMAC). Other cationic monomers used in emulsion polymerization are (vinylbenzyl)isothiouronium chloride (VBIC) and (4vinylbenzyl)hydrazine (VBH). Special attention is focused on primary amino-functionalized monomers such as vinylbenzylamine hydrochloride (VBAH) and aminoethyl methacrylate hydrochloride (AEMH) because a primary amino functionality can react directly with a high variety of biomolecules, binding them onto the surface of cationic nanoparticles. The choice of an adequate cationic monomer will depend on the polymerization process used and the final application of the cationic system. As a general rule, the increase in the cationic monomer concentration leads to a faster polymerization rate, higher polymerization conversions, a smaller particle size, and

a

Vinylpyridines and their quaternary ammonium salts: 2VP = 2vinylpyridine; 4VP = 4-vinylpyridine; MVPC = 1-methyl-4-vinylpyridinium chloride; MVPI = 1-methyl-4-vinylpyridinium iodine; DMVP = 1,2-dimethyl-5-vinylpyridinium methyl sulfate; EMVP = 1ethyl-2-methyl-5-vinylpyridinium bromide. (Dialkylamino)ethyl methacrylates: DMAEMA = 2-(dimethylamino)ethyl methacrylate; DEAEMA = 2-(diethylamino)ethyl methacrylate. Quaternary ammonium cationic monomers (QACMs): VBTMAC = vinylbenzyl trimethylammonium chloride; MATMAC = [2-(methacryloyloxy)ethyl] trimethylammonium chloride; MATMAI = [2-(methacryloyloxy) ethyl] trimethylammonium iodine; MAPTMAC = [3-(methacryloyl-amino) propyl] trimethylammonium chloride; DADMAC = diallyldimethy-

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and nanogels, followed by ADIBA. However, the other bisamidines (VA-552, VA-067, and VA-060) have rarely been used. AIBA initiator contains primary amidines, while ADIBA contains cyclic disubstituted amidines. This difference in chemical structure makes ADIBA, which is the cyclic analogue of AIBA, more hydrolytically stable; no hydrolysis products were observed during its homolytic decomposition.14 However, as can be observed in Scheme 4, during the homolytic process of AIBA, hydrolysis of the primary amidine groups takes place, giving amide products such as 2,2′-azo-2-carbamyl-2′-amidinobispropane hydrochloride (ACAP) and 2,2′-azobis(2-carbamylpropane) (ACP). The amide products essentially do not undergo homolysis under the conditions that AIBA does. The study of the competitive rates of hydrolysis and thermal decomposition of AIBA in aqueous solution was published by Ito15 in 1973 and by Wahl et al.14 in 1998. They both concluded that the steady-state concentration of radicals formed by AIBA is relatively low because hydrolysis products are stable toward decomposition and do not contribute to radical formation. Furthermore, during the course of an emulsion polymerization using AIBA, the amidine hydrochloride function is partitioned between undissociated initiator, free radicals in water solution, byproducts from coupling reactions, and polymer/oligomer chain ends. With respect to the hydrolysis process, the first and the last of these sites (undissociated initiator and polymer/oligomer chain ends) are the most important, so it is on the polymer/oligomer chain ends where the hydrolysis affects the colloidal stability of the particles formed. The pH is the parameter which controls the relationship between the homolysis and the hydrolysis processes in the AIBA initiator. Increasing the pH increases the hydrolysis of the primary amidines because the hydroxyl ion acts as a catalyst. Conversely, the homolysis of AIBA decreases. At 60 °C Ito15 found that the ratio kh′/kd for AIBA goes from 17 at pH 10 to 1.11 at pH 7 and that hydrolysis at lower pH is much less important than homolysis. For that reason, an emulsion polymerization using AIBA as the cationic initiator must be carried out at pH lower than 7 to minimize the hydrolysis process. On the other hand, cationic initiators containing quaternized nitrogens, such as N,N′-dimethyl-4,4′-azobis(4-cyano-1-methylpiperidine) dinitrate (DACMP), have been used as an alternative to cationic bisamidines.16

Scheme 1. continued lammonium chloride; DMBEMAB = N,N-dimethyl-N-butyl-N-ethyl methacrylate ammonium bromide; DMBMAPAB = N,N-dimethyl-Nbutyl- N-methacrylamidino propyl ammonium bromide. Other cationic monomers: VBIC = vinylbenzyl isothiouronium chloride; VBH = 4-vinylbenzyl hydrazine. Primary amino-functionalized monomers: VBAH = vinylbenzylamine hydrochloride; AEMH = aminoethyl methacrylate hycrochloride.

higher water-soluble polymer (polyelectrolyte) formation in a batch emulsion polymerization process. To favor surface incorporation of a cationic monomer, reducing the formation of polyelectrolytes, other polymerization processes such as semicontinuous, seeded, or seeded shot-growth can be used.10 Related to monomer reactivity, differences will be given by the type of reactive double bond of the cationic monomer. However, it can be said without doubt that the pH of the reaction medium will be the key parameter for success of the polymerization process and the stability of the nanoparticles nucleated. To much less extent than cationic monomers, cationic polymers can also be used in the synthesis of cationic colloids by emulsion polymerization. Scheme 2 shows the main cationic Scheme 2. Cationic Synthetic Polymersa

a

PEI = polyethylenimine; PAAm = poly(allylamine); PVAm = poly(vinylamine).

polymers used. As can be seen, all the cationic polymers depicted are primary amino-functionalized polymers: polyethylenimine (PEI), poly(allylamine) (PAAm), and poly(vinylamine) (PVAm). 2.2. Cationic Initiators

Scheme 3 shows the cationic azo compounds, which can be used as thermal initiators in the synthesis of cationic polymeric colloids by emulsion polymerization. As can be seen, the most common cationic initiators are the family of azobisamidines:11,12 2,2′-azobisisobutyramidine dihydrochloride or 2,2′azobis(2-methylpropionamidine) dihydrochloride (AIBA or V50), 2,2′-azobis(N,N′-dimethyleneisobutyramidine) dihydrochloride or 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (ADIBA or VA-044), 2,2′-dimethyl-2,2′-azobis(Nbenzylpropionamidine) dihydrochloride (VA-552), 2,2′-azobis(1-imino-1-pyrrolidino-2-ethylpropane) dihydrochloride (VA067), and 2,2′-azobis[2-[1-(2-hydroxyethyl)-2-imidazolin-2-yl]propane] dihydrochloride (VA-060). Amidines are monoacid strong bases which hydrolyze in the presence of both acid and base catalysis.13 The hydrolysis of amidines is a two-step reaction. The first step is the most rapid and results in the formation of an amine (ammonia form unsubstitued amidines) and an amide. The second step is the hydrolysis of the amide to a carboxylic acid, and since amides are generally stable, the second step is slow. However, the sensitivity to hydrolysis is very dependent on the substituents. AIBA is the most common cationic initiator used in the synthesis of cationic nanoparticles

2.3. Cationic Surfactants

Scheme 5 shows the main cationic surfactants used in the synthesis of cationic polymer colloids by emulsion polymerization. The most common cationic surfactants used are quaternary ammonium salts such as hexadecyltrimethylammonium bromide or cetyltrimethylammonium bromide (HDTAB or CTAB), cetyltrimethylammonium chloride (CTAC), dodecyltrimethylammonium bromide (DTAB), and tetradecyldimethylbenzylammonium chloride (TBAC). However, in a few studies other types of cationic surfactants can be found, such as dodecylpyridinium chloride (DPC), octadecylpyridinium chloride (OPC), and Hyamine 1622 (HY). One of the most important roles that a surfactant has during the synthesis of latex particles by means of a conventional emulsion polymerization process is helping the solubilization of the monomer in the aqueous phase in the form of swollen micelles, increasing in this way the availability of the monomer in the continuous phase. Another function is to stabilize the new particles as they are formed. By increasing the amount of 370


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Scheme 3. Cationic Radical Initiatorsa

a

AIBA or V-50 = 2,2′-azobisisobutyramidine dihydrochloride or 2,2′-azobis(2-methylpropionamidine) dihydrochloride; ADIBA or VA-044 = 2,2′azobis(N,N′-dimethyleneisobutyramidine) dihydrochloride or 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride; VA-552 = 2,2′-dimethyl2,2′-azobis(N-benzylpropionamidine) dihydrochloride; VA-067 = 2,2′-azobis(1-imino-1-pyrrolidino-2-ethylpropane) dihydrochloride; VA-060 = 2,2′-azobis[2-[1-(2-hydroxyethyl)-2-imidazolin-2-yl]propane] dihydrochloride; DACMP = N,N′-dimethyl-4,4′-azobis(4-cyano-1-methylpiperidine) dinitrate.

Scheme 4. Homolysis and Hydrolysis of AIBA Initiatora

a

AIBA = 2,2′-azobisisobutyramidine dihydrochloride; ACAP = 2,2′-azo-2-carbamyl-2′-amidinobispropane hydrochloride; ACP = 2,2′-azobis(2carbamylpropane).

surfactant, the colloidal stability of the particles increases and coagulation decreases. The surfactant also has a strong influence on the particle size. It is well-known that both the type and amount of surfactant determine the nucleation stage of an emulsion polymerization. When the amount of surfactant is below its critical micellar concentration (CMC), the surfactant molecules are preferably in the aqueous phase rather than forming micelles, and in this way, only homogeneous nucleation takes place. On the other hand, when the amount of emulsifier is above its CMC, the surfactant forms micelles and is also present in the aqueous phase. In this case, micellar nucleation is the most important mechanism that takes place in an emulsion polymerization when slightly water-soluble monomers, such as styrene, are polymerized, and the

concentration or number of micelles determines the number of particles formed throughout interval I of the emulsion polymerization.17 The choice of an adequate cationic surfactant will be critical in synthesizing colloidally stable nanoparticles.

3. CATIONIC LATEXES Up to now the main and fundamental research in emulsion polymerization has been based on anionic systems, because in almost all the applications negatively charged particles are required. However, during the past decade the mechanisms governing cationic emulsion polymerization have been explored. It was found that the knowledge of well-studied anionic systems could not be extrapolated to cationic systems. In our work,18−20 the batch cationic emulsion polymerization of 371


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Scheme 5. Cationic Surfactantsa

a

HDTAB or CTAB = hexadecyltrimethylammonium bromide or cetyltrimethylammonium bromide; CTAC = cetyltrimethylammonium chloride; DTAB = dodecyltrimethylammonium bromide; TBAC = tetradecyldimethylbenzylammonium chloride; DPC = dodecylpyridinium chloride; OPC = octadecylpyridinium chloride; HY = Hyamine 1622.

theory,21,22 and particle growth stages, intervals II and III. In this kind of polymerization process, the particle nucleation period is short, thereby giving rise to distinct particle formation and growth periods. However, if the initiator concentration is low and the surfactant concentration is high, it is possible for particle nucleation and particle growth to proceed simultaneously for a significant period of the polymerization. In ab initio polymerizations, the particle nucleation stage often is a source of batch-to-batch variability. The limited control that can be exerted over polymer and latex properties greatly restricts the commercial utility of unseeded processes. Nevertheless, ab initio processes are of great importance to study and compare nucleation (interval I) and growth stages (intervals II and III) using different amounts and types of monomers, initiators, and surfactants. 3.1.1.1. Conventional Emulsion Polymerization Processes. The birth of emulsion polymerization can be dated to 1909, when the idea of mimicking the conditions used by Mother Nature to synthesize the natural latex of Hevea brasiliensis and Guyanensis rubber trees was attempted to improve the properties of synthetic rubbers produced by bulk polymerization.23 In 1912, a patented idea of using an aqueous emulsion of a monomer to carry out polymerization appeared for the first time.24 This was the birth of heterophase polymerization. For the next 20 years, the importance of emulsion polymerization increased due to the activities of companies in Germany and the United States and subsequent support and sponsoring by both governments.25 During these years a large number of patents accumulated, but in the same period (1930−1940) only very few papers were published in scientific journals. While the mechanism of emulsion polymer-

styrene was compared with the anionic one. The main difference found was that, under the experimental conditions studied, the kinetics of cationic systems were affected by the particle size, while in the anionic system, due to the lower particle size and lower initiation rates, the rate of polymerization was not dependent on the volume of the latex particles. Furthermore, in the cationic systems a dependence on the particle size of the rate of polymerization per particle together with the average number of radicals per particle was found. These differences were explained taking into account the limited particle coagulation observed with cationic surfactants and the high rate of radical formation of cationic initiators. 3.1. Synthesis Strategies To Produce Cationic Latexes

Cationic nanoparticles are obtained by using a combination of several cationic reagents such as cationic initiators, cationic monomers, cationic polymers, and/or cationic surfactants. To produce cationic nanoparticles, the most suitable processes found in the literature are those related to heterophase polymerization processes, mainly emulsion polymerization. This technique is observed as the most efficient and profitable polymerization process to produce polymeric nanoparticles. 3.1.1. Unseeded Emulsion Polymerization Processes. As commented in the Introduction, among the various types of heterophase polymerization techniques, there is emulsion polymerization, which is the most relevant to produce polymer nanoparticles or latexes in the colloidal range. One type of emulsion polymerization process is the unseeded or ab initio emulsion polymerization process, which is divided into three intervals encompassing the particle formation stage, called “interval I” according to Harkins’s 372


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polymerization system. However, the cationic azo initiator AIBA is very little affected by the presence of monomers, emulsifiers, and salts. The only restriction is that the cationic initiator should only be used with cationic emulsifiers. In this sense, they used a cationic system composed of AIBA as the cationic initiator and CTAC as the cationic surfactant. They found that at least in the beginning of the reaction serious discrepancies existed between the experimental data and Smith−Ewart theory.29 An electrostatic effect in cationic systems was found because with the addition of KBr or CaCl2 the rate of polymerization and the number of particles went through a maximum. Furthermore, the cationic latex particles formed were 1 order of magnitude larger than those obtained in the anionic emulsion polymerization and had a very narrow size distribution. There seemed to be a very short period of particle formation in the cationic system. The emulsion copolymerization of styrene with 4VP at different monomer ratios in the presence of poly(oxyethylene octylphenyl ether) with 19−20 oxyethylene units as the nonionic surfactant at pH 2 and 11 was reported by Ohtsuka et al.39 They studied the effect of 4VP on the kinetics of the emulsion polymerization of styrene and on the distribution of polymeric VP in the cationic latex. A bimodal distribution of the particle diameter was obtained in the polymerization under the conditions of low surfactant concentration and high 4VP fraction in the monomer feed. This was caused by insufficient stabilization of the resulting particles and by some changes in the character of growing radicals in the aqueous phase with conversion. Polymerization under acidic conditions was affected by the amphiphilicity of 4VP-rich radicals, which depended on the 4VP fraction in the monomer feed. In latex particles prepared at pH 2, the 4VP units were located preferentially on the surface, whereas the latex particles prepared at pH 11 had a nearly statistical distribution of 4VP on their surface. Wieboldt et al.40 studied the emulsion polymerization of styrene by using different cationic surfactants and ADIBA as the initiator. The cationic surfactants used were DPC, DTAB, HY, OPC, and TBAC. For all these surfactants, the authors proposed a coagulative mechanism. The surface activity and concentration of the emulsifier were rate-determining factors. At very low emulsifier concentration the particle surface charge mainly arose from initiator fragments and was independent of the emulsifier concentration. The coagulation rate was constant and also independent of the emulsifier concentration, so that a relatively small number of particles were formed. When the emulsifier concentration was increased, the surface charge density rose rapidly, the rate of coagulation decreased, and most of the small particles grew to larger ones. At still higher surfactant concentration, the particle surface became saturated and the surface charge density was independent of the emulsifier concentration. Consequently, the rate of coagulation and the number of particles were independent of the emulsifier concentration. However, heterocoagulation (i.e., coagulation between large and small particles) could occur during the growing period. Larger particles could capture small particles, and dispersions of particles with large polydispersity could be formed. At lower polymerization temperature, the adsorption of the emulsifier was enhanced, the period of seeding increased, a smaller number of primary seed particles coagulated, and the particle size distribution became broader. Ramos et al.18,19 studied the batch emulsion polymerization of styrene using different cationic surfactants (DTAB and HDTAB) and initiators (AIBA and ADIBA). First, the best

ization was briefly discussed in the scientific literature during this period, the large number of patents filed in many countries take into account the extensive work which was carried out during the same period in the research departments of various industrial companies.26 In 1945, Hohenstein et al.27 published a paper on the polymerization of styrene in agitated soap emulsions. In 1947, a group from Dow Chemical Corp. reported for the first time the synthesis of monodisperse polystyrene latexes.28 The same year, Harkins22 developed a general and qualitative description of emulsion polymerization having two main features: there are two loci for particle formation or nucleation, the monomer-swollen micelles and the aqueous phase, and the monomer-swollen polymer particles are the locus in which nearly all of the polymer is formed. Smith and Ewart29 published in 1948 the most important contribution to the emulsion polymerization theory, developing a quantitative theory of the radical polymerization kinetics in the monomerswollen polymer particles, considering that free radicals coming from the aqueous phase are supplied to the particles. They presented the equation for the calculation of the number of particles containing a given number of growing radicals and defined the different cases depending on the average number of radicals per particle. Since then, very well-known authors in the field have reported their interesting contributions to the knowledge of emulsion polymerization kinetics. Among them, there are fundamental contributions to the knowledge of emulsion polymerization kinetics, such as that of monomers of technical interest by Gerrens,30 the proposed mechanism on the precipitation of an insoluble growing radical forming a particle,31 and the quantitative theory of nonmicellar particle nucleation presented by Fitch and Tsai.32 These contributions together with the theoretical and experimental contributions on homogeneous particle nucleation in emulsion polymerization by Hansen and Ugelstad,33 nowadays called HUFT theory, for Hansen, Ugelstad, Fitch, and Tsai, were the basis for the development of this polymerization technique in dispersed media. Since 1976, the contributions have become more and more important for the understanding of emulsion polymerization kinetics, among them the calculation of the average number of radicals per particle taking into account radical entry, exit, initiation, and termination in the aqueous phase34 and the role of coagulation of primary particles during the nucleation period.35 Each year during the past 50 years, an extensive literature including books,36,37 reviews, papers, and patent applications on this field have been published. The main and fundamental research in conventional emulsion polymerization is based on anionic systems, and one can only find a few studies on cationic systems. There is some controversy about the first time the synthesis of cationic latexes was reported because several patents claimed their preparation during the 1960s. However, in the open literature the first studies were published in the 1970s. In 1970, Breitenbach et al.38 compared the kinetics of the cationic emulsion polymerization of styrene with that of the homologous anionic emulsion polymerization. They suggested that one of the important parameters for the kinetics of emulsion polymerization was the rate of formation of free radicals in the emulsion system. The persulfate ion generally used as a source of radicals is strongly influenced in its rate of decomposition by different additives present in an emulsion 373


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Scheme 6. Kinetics of the Batch Cationic Emulsion Polymerization of Styrene18,19

surfactant. The rate of surfactant adsorption on primary particles relative to the coagulation rate of these particles must be important, and surfactants that adsorb fast will give higher particle numbers than surfactants that adsorb at a slower rate. At low surfactant concentration, SDS has a faster rate of adsorption than its cationic homologue DTAB, nucleating more particles. However, at high surfactant levels DTAB adsorption is competitive with particle growth, so a larger number of particles can be stabilized, achieving a higher number of particles than with its anionic homologue. In addition, cationic initiators (ADIBA and AIBA) have a higher decomposition rate with respect to KPS. In this way, cationic systems have a faster initial rate of radical formation (26 and 5 times higher for ADIBA and AIBA, respectively), so the number of nucleated particles suffers slight changes with increasing concentration of the cationic initiator because the amount of initial radicals needed to promote the nucleation has been exceeded. Therefore, the main difference found between anionic and cationic emulsion polymerization of styrene was that the kinetics of cationic systems were affected by the particle size. Furthermore, a dependence of the particle size on the rate of polymerization per particle together with the average number of radicals per particle was found in cationic systems. As can be seen in Scheme 6, this dependence was stronger with variation of the cationic initiator concentration (ADIBA or AIBA) than with variation of the cationic surfactant DTAB. On the other hand, regarding cationic systems in which HDTAB was used as the cationic surfactant,19 lower dependences of the rate of polymerization and the number of particles on the HDTAB surfactant concentration were found than by using DTAB (see Scheme 6), but a higher effect of the size of the particles on the rate of polymerization per particle and on the average number of particles was observed. Furthermore, different kinetic behaviors were observed with the two cationic initiators used (ADIBA and AIBA), and they were due to the lower stabilizing effect of the cationic radicals provided by AIBA, which means that a lower amount of particles were nucleated. Using ADIBA, the same number of particles was obtained by increasing the initiator concentration, but a faster polymerization rate was observed. This was due to the strong dependence of the average number of radicals per particle on the initiator concentration at the same particle size. Using AIBA, higher dependences of the rate of polymerization and number of particles were obtained, and a double effect on the average number of particles was observed: the effect of the particle size and the effect of the amount of initiator added.

conditions to obtain stable cationic latexes at high conversions were identified. When the surfactant concentration was above its CMC, latexes with high conversions were achieved for the two surfactants studied (DTAB and HDTAB). Cationic latexes with less coagulum were obtained using ADIBA as the cationic initiator due to its superior resistance to hydrolysis. AIBA is hydrolyzed to amide at basic pH values, and in this way, the concentration of radicals formed in the aqueous phase decreases. Subsequently, the kinetics of the batch cationic emulsion polymerization of styrene was studied in-depth and compared with its homologous anionic case. Scheme 6 shows the dependences of the surfactant and initiator concentrations on the rate of polymerization (Rp) and the number of polymer particles (Np) for the different systems. As can be seen, the exponents obtained for both the rate of polymerization and the number of particles with respect to the sodium dodecyl sulfate (SDS) and potassium persulfate (KPS) concentrations in the anionic system were similar to those obtained for Smith− Ewart’s case II29 (Rp ≈ Np ≈ [SDS]0.6[KPS]0.4). These results were also in agreement with those proposed by Gardon41 for low particle size systems at low initiation rates and corroborate the linear dependence of the rate of polymerization on the number of particles, which means that for a conventional anionic emulsion polymerization of styrene the rate of polymerization is not dependent on the volume of the latex particles. However, the kinetics of the cationic systems was very different mainly due to the different properties of cationic initiators and surfactants. Regarding cationic systems in which DTAB was used as the cationic surfactant,18 the exponents obtained by fitting the experimental data with respect to both the cationic surfactant (DTAB) and initiators (ADIBA or AIBA) were much higher for the number of particles than those obtained for the rate of polymerization (see Scheme 6). These cationic systems represent a typical case of the so-called “limited particle coagulation” that is said to control the particle population in the nucleation step.42 When the primary particles are formed, they may start to coagulate with each other. The stability of the particles will be dependent on their surface charge and size and the electrolyte concentration (and valency). When the particles coagulate, the surface charge will increase, as most of the surface-active groups stay on the surface. When the particles become sufficiently large, they will have enough charged groups to prevent further coagulation. This is due to the simple picture of the limited particle coagulation. Under these conditions, the number of particles formed will be a function of the surfactant concentration and also the type of 374


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Table 1. Cationic Latexes Obtained by Surfactant-Free Emulsion Polymerizationa main monomer S S VBC, DVB MS S S S S S, S-BD S S S S, DVB S S, DVB S-BA S-BA S, AAm

S S, DVB S a b

cationic comonomer

DMVP EMVP 4VP MVPB, MVPI DMAEMA DEAEMA DEAEMA DEAEMA, MAAc DMAEMA DMAEMA MATMAI MAPTMAC VBIC VBTMAC DMBEMAB DMBMAPAB DADMAC MAPTMAC MATMAC VBTMAC MATMAC VBAH VBAH AEMH

initiator

reaction conditions °C, °C, °C, °C,

AIBA, ADIBA DACMP AIBA AIBA AIBA

50−95 70−80 50−65 60−80 65 °C

350 rpm 250 rpm 350 rpm 250−350 rpm

KPS AIBA AIBA

70 °C, 300 rpm 60 °C, 300 rpm 60−80 °C

H2O2 + Fe(NO3)3 KPS AIBA AIBA

60 70 70 70

°C, °C, °C, °C,

∼50 rpmb ∼50 rpmb 350 rpm 300 rpm

AIBA AIBA AIBA AIBA AIBA AIBA, KPS

60 70 70 70 70 70

°C, °C, °C, °C °C °C,

300 rpm 350 rpm 200 rpm

AIBA AIBA AIBA

70 °C, 400 rpm, EtOHd 70−80 °C, 350 rpm 70 °C, 300 rpm

400 rpm

particle diameter (nm)

conversion (%)

191−1059 771−834 348−1154 476−683 180−570 210−570 97 (pH 2), 450 (pH 11) 105−285 73−134 77−212 120−160 185 572−699 148−184 119−170 151−317 102−362 100−114 207−242 211−312 426 149 92−234 87−215 86−620 200−1000 126−285 100−560

16−94 97−98 45−88

ref 44 45 46 47 48

60−99 70−99 20−99

49 50 43

99

51, 52 53 54 55

40−90 10−99 40−96 90−99 80−99 60−99

56 57 58 59 60 61

78−99 47−97 88−96 90−100

62 63 64, 65

S = styrene; VBC = vinylbenzyl chloride; DVB = divinylbenzene; BD = butadiene; BA = butyl acrylate; MS = methylstyrene; AAm = acrylamide. Tumbled end-over-end (∼50 rpm). cMAA = methacrylic acid (anionic comonomer). dEtOH = ethanol as cosolvent.

Ramos and Forcada20 also studied the kinetics of cationic emulsion polymerization of styrene in the presence of small amounts of cationic monomers (VBTMAC and MATMAC) using HDTAB as the surfactant and AIBA as the initiator. Polymerizations using the more hydrophobic cationic monomer (VBTMAC) showed higher conversions due to the in situ creation of an amphiphilic copolymer with styrene, improving particle stability, and faster rates of polymerization were observed by increasing the cationic comonomer concentration. With the more hydrophilic cationic comonomer (MATMAC), the same behavior was observed up to 0.012 M MATMAC. At higher concentrations most of the MATMAC homopolymerized in the water phase, and therefore, the ionic strength controlled the colloidal stability of the system occurring coagulation. 3.1.1.2. Surfactant-Free Emulsion Polymerization Processes. The majority of the syntheses of cationic nanoparticles found in the literature were carried out by means of surfactantfree emulsion polymerization processes. From the point of view of using cationic nanoparticles in biotechnological applications, the main advantage of these processes is the lack of surfactant in the final latex. Table 1 shows the most representative works found in the literature dealing with surfactant-free cationic emulsion polymerization. As can be seen, both cationic initiators and cationic comonomers are responsible for conferring cationic charge on nanoparticles. By Using Cationic Initiators. In a first simple approach, the cationic initiator is the only component providing cationic charge onto the nanoparticle surface. In this way, Sakota and

Okaya43 obtained a stable cationic polystyrene latex in the absence of surfactants using AIBA as the initiator. The formation of the particles was attributed to the precipitation of growing radicals produced in water, similar to that proposed for the polymerization of styrene initiated with KPS. However, the cationic latex was stabilized with the fragments of AIBA chemically bound to the surface of the particles. Later on, Goodwin et al.44 also reported the synthesis of monodisperse cationic polystyrene latexes by surfactant-free emulsion polymerization of styrene using, as cationic initiators, AIBA and ADIBA. In this case, the particle diameters of the latexes covered the range from ca. 83 nm to 1.0 μm, a useful range for experiments in the colloidal domain. In addition, a dimensional analysis of the variables involved gave the following equation, which represents the experimental data over a wide range of preparative conditions: ⎧ [M]1.099 [IS] 2563 ⎫ ⎬ − 0.19 log(d p) = 0.384⎨log + 0.833 T ⎭ ⎩ [In]

(1)

where dp is the final diameter of the particles (nm), [M] is the initial monomer (styrene) concentration, [IS] is the initial ionic strength (including the initiator), [In] is the initial initiator (AIBA) concentration, and T is the absolute temperature (K). As can be observed, similar to anionic systems, the particle size increased with an increase of the ionic strength and monomer concentration and with a decrease of the temperature and initiator concentration. 375


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the medium, but being considerably swollen by water, they form a microgel. (ii) In the case of a lower cross-linking degree, the aqueous solutions of polycationic chains have a better transparency, but a higher viscosity; their sedimentation ability upon centrifugation strongly decreases. They behave as true solutes, and the particle structure has totally disappeared. Highly monodisperse cationic poly(methylstyrene) (PMS) latex particles were also prepared via surfactant-free emulsion polymerization in the presence of AIBA as the cationic initiator.47 Because methylstyrene exhibits reactivity analogous to that of styrene, the surfactant-free emulsion polymerization of methylstyrene also proceeds through a similar nucleation mechanism of styrene. However, in comparison with the styrene system, a bigger particle size and a lower conversion were observed using methylstyrene under the same initiator concentration. The conversion increased with an increase of the initiator concentration, and 88% conversion was achieved when the methylstyrene to AIBA ratio was 20/1. This ratio was much higher than the styrene to AIBA ratio reported by Goodwin et al.,44 only 300/1 being required. This effect was attributed to the presence of the methyl group, which stabilized the benzylic radical. Furthermore, the particle size was found to decrease with an increase of the initiator concentration and reaction temperature. On the other hand, the increase of the ionic strength of the aqueous phase led to the formation of larger particles, but had little effect on the particle size distribution and conversion. The agitation speed was found to have a remarkable influence on the particle size distribution. A low agitation speed ( CCC(pH 7) > CCC(pH 9), which cannot be explained by the mobility values at those pH values. Hence, the stability of the F(ab′)2−latex complexes is not controlled by the electrostatic interaction energy since the highest mobility values are found at pH 9 whereas the CCC is almost zero at this basic pH. This suggests that the stability at pH 5 is probably due to a steric effect between the adsorbed F(ab′)2 molecules. The adsorption and electrophoresis experiments carried out with F(ab′)2 coming from monoclonal antibodies144 on positively charged latex particles demonstrated that the affinity of F(ab′)2 molecules for the latex particles was barely influenced by electrostatic interactions. At the saturation level, however, the adsorbed amounts were dependent on the overall electrostatic interaction, resulting in a maximum amount adsorbed when the charge of the protein fragment is partly compensated by the sorbent surface charge. The trends in the adsorption of the monoclonal antibodies (IgG) and the

3.3.1.2. Strategies To Improve the Colloidal Stability of Sentitized Latex Particles. To increase the colloidal stability of the IgG−cationic latex particles, the coadsorption of albumin molecules149,150 or nonionic surfactants is proposed by different authors. The first option is adequate for physically adsorbed IgG, and the second strategy requires the protein molecules to be chemically bound to the cationic latex surface. Elgersma et al.149 completed a very interesting study on the competitive adsorption between bovine serum albumin (BSA) and monoclonal immune γ-globulins (IgG’s) by sequential and simultaneous addition of the proteins to differently charged polystyrene (PS) latexes as the adsorbates. These authors paid special attention to the role played by the electrostatic interactions in the adsorption process and performed experiments with (i) IgG’s of different isoelectric points, (ii) positively and negatively charged latexes, and (iii) different pH values. Furthermore, they studied the displacement of the preadsorbed protein by the second added protein in sequential adsorption experiments. It was observed that BSA more easily displaces the preadsorbed IgG than the converse. In this case, the electrostatic interactions did not play a major role, and even more, under certain conditions their effect was absent. Concerning competitive adsorption, the displacement of the first protein is not always a prerequisite for the adsorption of the second protein. However, in simultaneous adsorption experiments from binary and ternary mixtures of BSA (iep = 4.7−5.0) and four monoclonal IgG’s (iep from 4.9−5.2 to 7.9− 8.1), the enrichment of one of the proteins at the expense of the other(s) was studied by these authors as a function of the supply from the solution and the electrostatic interaction between the proteins and latex. The most important conclusion is that under electrostatically repulsive conditions competitive adsorption is strongly influenced by the electrostatic interaction between the adsorbent surface and the respective proteins. The preference for one protein or another became less pronounced with increasing adsorption time. However, when the proteins were electrostatically attracted to the adsorbent, the influence of electrostatics on preferential adsorption was hardly discernible. Perhaps, the most relevant conclusion of this work is that with both sequential and simultaneous (competitive) addition of the proteins the results indicated that the conformational rearrangements in adsorbates of BSA are faster than in those of the IgG’s. Elgersema et al.151 confirmed this important discovery in a work on the kinetics of single and competitive protein adsorption studied by reflectometry and streaming potential measurements. 3.3.1.3. Adsorption of F(ab′)2. It is well-known144,152,153 that the use of an F(ab′)2 fragment instead of the whole IgG antibody for antigen−antibody sites eliminates false positives due to the presence of the rheumatoid factor, when antiantibody is used as the final reagent,154 and that protein binds to the Fc portion of the whole IgG antibody. The adsorption of an F(ab′)2 fragment on cationic latexes was experimentally studied by Ortega-Vinuesa et al.155 and Buijs et al.144 The F(ab′)2 fragment was obtained by pepsin digestion of rabbit polyclonal IgG and two monoclonals, both mouse anti-hCG (human chorionic gonadotropin) from isotype IgG-1, followed by different purification chromatography processes to remove undigested IgG. In the first case, the iep values obtained for this fragment were in the 4.6−6.0 range. The molecular weight was 102 000. The cationic latex particles were prepared using ADIBA initiator as previously described.116 The particle diameter and surface charge density (amidine groups) were 391


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fraction of F(ab′)2 displaced is significant: 23%, 29%, and 31% at the three pH values studied (5, 7, and 9), which could be explained by taking into account the electrostatic interaction between the positively charged polymer surface and the net negative charge on the albumin molecules. This effect was also observed by Elgersma et al.141 in single BSA adsorption on cationic latex. As the amount of preadsorbed F(ab′)2 increases, the protein fragment is progressively easier to displace by mBSA and the amount of the latter that can reach the surface decreases. The results seem to indicate that single F(ab′)2 adsorption on cationic latex takes place with the formation of at least one bilayer, which is broken by the BSA molecules in the second step of the sequential adsorption. The displacement of F(ab′)2 occurs only when the preadsorbed amounts are larger than a certain critical value, which depends on the adsorption/ desorption pH. The main factor in the desorption of F(ab′)2 on the cationic latex is an increase of the ionic strength and the presence of BSA. However, the colloidal stability of the F(ab′)2−cationic latex complex was significantly improved by BSA adsorption. Also, F(ab′)2 molecules were coadsorbed with a cationic commercial lipid, namely, distearoyldimethylammonium bromide (DSDMA),164 on a cationic latex sample. The cationic lipid was adsorbed (≅0.4 μmol m−2) on the cationic latex only when the content of ethanol in the media was very low (1%, v/ v) at pH 7. However, in a sequential adsorption the amount of the cationic lipid adsorbed on a previously F(ab′)2 coated cationic latex slightly increased. In any case, the electrophoretic mobility and CCC of the F(ab′)2−DSDMA−cationic latex complexes decreased with increasing amount of adsorbed F(ab′)2. Therefore, it was not possible to stabilize cationic latex−F(ab′)2 complexes under physiological conditions adsorbing a cationic lipid, and this is why there are not developed immunodiagnostic tests based on latex immunoassay aggregation (LIA) reactions with these systems. 3.3.2. Latex Immunoassay Aggregation. LIA procedures use submicrometer polymer particles as substrates for antigen−antibody reactions to measure certain analytes. This type of immunoassay offers a double advantage, since it combines high sensitivity with simplicity and inexpensive nonhazardous reagents (in comparison with any radioimmunoassay method). To improve the detection limit of the latexbased immunoassays, an optical instrumental method is required. As discussed by Newman et al.,165 LIA is based on the formation of a particle-enhanced immune complex and, subsequently, detection using transmitted light, which depends on the following: (1) The diameter, concentration, and refractive index of the polymer carriers and surface charge density. (2) The concentration and surface density of protein. (3) The wavelength and intensity of the light source. (4) The pH, ionic strength, and temperature. (5) The presence of additives in the reaction medium. (6) The colloidal stability of the protein−latex complexes. Cationic latexes are being used in the development of immunoassays based on the antigen−antibody reaction. However, basic studies of the method are not as numerous in terms of the effects on the sensitivity of factors such as the size of the latex particles, the wavelength used in light absorption measurements, the pH and ionic strength of the reaction medium, and the amount of protein bound to the latex nanoparticle surface. An immunoturbidimetric quantitation by

corresponding F(ab′)2 molecules were similar, although there was some evidence that hydrophobic interactions and/or conformational changes were less important for F(ab′)2 adsorption. Also, it was shown that the orientation (end-on or side-on) of the F(ab′)2 molecules at the solid−liquid interface can be determined by the sorbent surface charge. To ensure the correct orientation of the Fab fragments, Delair et al.57 synthesized cationic latex particles bearing sulfhydryl groups, which permit a covalent coupling between the protein fragment and the functionalized latex particles. Nakamura et al.159 have questioned the use of the ζ-potential as a parameter for predicting the colloidal stability of sensitized latex particles. In the same sense, the studies of Ohshima and Kondo160−162 revealed that the ζ-potential loses its meaning for soft colloidal particles with a structured interface, since the electrophoretic mobility is insensitive to the precise position of the slipping plane; thus, a different approach must be used for describing the electrokinetic behavior of F(ab′)2 molecules adsorbed onto cationic polymer surfaces. The theoretical model developed by the above-mentioned authors gives the electrophoretic mobility for structured solid−liquid interfaces as a function of three parameters: N (charged group density in the protein layer, assuming a homogeneous charge distribution); λ, which gives an idea about the frictional force that the protein layer exerts on the surrounding liquid; d (depth of the protein layer from the latex surface). In the case of latex particles coated with increasing amounts of F(ab′)2 molecules, the best fitting between experimental and theoretical electrophoretic mobility data is obtained when λ is 0.3 nm−1 and N is 0.025 mol−1. The depth of the bound protein layer, d, is 8 nm. The value of d for F(ab′)2 bound to the latex surface obtained by these authors seems to be reasonable because it falls in the 4.4−14.3 nm range reported by several authors.153,163 The density of charged groups (N) in the surface region of the F(ab′)2−latex complex obtained in that work is identical to that obtained by Nakamura et al.159 for human serum albumin (HSA)−latex complexes, which reinforces the great resemblance between the electrokinetic behavior of albumin and F(ab′)2 molecules adsorbed on latex particles. The depth of the bound protein fragment F(ab′)2 layer (8 nm) is, however, between the values obtained by those authors for the IgG−latex (10 nm) and HSA−latex (6 nm) complexes, which are in agreement with the molecular sizes of IgG, F(ab′)2, and HAS. To increase the colloidal stability of F(ab′)2−cationic latex particles, the coadsorption of albumin molecules was completed by Ortega-Vinuesa et al.156 This coadsorption process of F(ab′)2 and monomeric bovine serum albumin (m-BSA) is usually carried out by means of a sequential process. Sequential protein adsorption is a two-step process. First, one type of protein (F(ab′)2) is adsorbed on the latex particles. It is left there for a certain time, after which a second protein (BSA) is added to this protein−adsorbent complex. Adsorption of the second protein may involve partial or complete displacement of the preadsorbed protein. Besides, the adsorption of this second protein could be desirable to increase the colloidal stability of the immunolatex, because BSA is a highly charged protein at neutral pH. The ability of adsorbed protein to be displaced was monitored as a possible indicator of adsorbed protein−surface interactions. F(ab′)2 was adsorbed on cationic latex for 4 h. The latex-bound F(ab′)2 was then incubated with m-BSA for 20 h. Besides, the sequential F(ab′)2 and m-BSA adsorption was performed at two different degrees of coverage of F(ab′)2. The 392


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latex agglutination requires that consideration be given to the following: (1) The characteristics of the polymer colloids in terms of ionic properties, hydrophilicity, functional groups reacting with proteins, etc. (2) The conditions for sensitization, which determine the amount and mode of attachment of antibody or antigen. (3) The conditions for agglutination tests, which influence the efficiency of the reaction between antigen and antibody, regardless of which is attached to the particle surface. (4) The characteristics of the apparatus used for the turbidimetric assay. The first two aspects were analyzed by Ortega-Vinuesa and Hidalgo-Alvarez.156 Ortega-Vinuesa et al.166 studied the third and fourth aspects. In this case, F(ab′)2 antibody fragments from anti-C-reactive protein (CRP) rabbit polyclonal IgG were used. These fragments were obtained by pepsin digestion of IgG and purified by gel filtration chromatography followed by protein A chromatography to remove undigested IgG. Purity was checked by SDS−PAGE (SDS−PAGE stands for sodium dodecyl sulfate−polyacrylamide gel electrophoresis and is a method used to separate proteins according to their size), and the molecular weight was found to be 102 000. No IgG contamination was detected. The isoelectric points of F(ab′)2 were in the 4.7−6.0 range. To suppress nonspecific interactions of the complementary antigen and to increase the colloidal stability of the sensitized particles (immunolatex) in the reaction medium, nonoccupied sites on the cationic latex particles were coated with BSA. The procedure used was similar to that employed with IgG molecules.167 In brief, the reactivity of the immunolatex was measured by turbidimetry after 5 min of immunoaggregation with human CRP in a spectrophotometer. As a general rule, the sensitized cationic latexes had a relatively higher colloidal stability than the sensitized anionic latexes, and hence, they provided reagents with a better optical response. Less than 0.025 μg/mL C-reactive protein was detected using cationic latex particle enhanced optical immunoassay. The sensitivity, reproducibility, and detection limit of these latex agglutination immunoassays depend on the technique used to detect the aggregated product. There are a number of instruments that permit full quantification of the extent of colloidal particle aggregation, thus avoiding the subjectiveness of manual detection. These instrumental methods are far more sensitive than visual detection methods. Moreover, such instruments are commercially available. The following optical methods are the most used: (1) Turbidimetry, which relies on the absorbance of a cationic latex suspension before and after sample is added. (2) Nephelometry, a method based on the intensity of the scattered light at a determined angle. The readings of agglutinated samples are compared with the results of a blank test. (3) Angular anisotropy, in which scattered light is measured at two angles, usually one above and one below 90°. (4) Photon correlation spectroscopy or dynamic light scattering, an assay method based on the principle that when laser light is directed onto a particle, the frequency change of the scattered light will be related to the speed

of the particle. A single particle will move (diffusion) relatively faster than two adhering particles. Ortega-Vinuesa et al.168 carried out a comparative study of these optical techniques applied to particle-enhanced assays of C-reactive protein using cationic (amidine groups) latexes. For each optical technique the following aspects were studied: sensitivity, detection limit, reaction time, amount of sample used, and availability of the required detection device. The results obtained by these authors showed that both angular anisotropy and photon correlation spectroscopy offered lower detection limits (near 1 ng/mL CRP) and used little reagent, but had longer assay times than the classical optical techniques of turbidimetry and nephelometry. In the previously mentioned latex aggregation immunoassays the antibodies or fragments of IgG molecules were physically adsorbed onto cationic (amidine group) latexes. However, antibodies can be covalently bound to the cationic latex with amino groups, which must be positioned on the surface of the latex particles (see Figures 19 and 20).

Figure 19. Angular anisotropy. Ratio between the intensity of light scattered to 30° and 70° (open symbols) and 90° (solid symbols) and the CRP concentration. Triplicate experiments are shown (first, squares; second, circles; third, tilted squares). Reprinted with permission from ref 168. Copyright 1997 Elsevier Ltd.

Figure 20. Photon correlation spectroscopy. Average sizes of the aggregates as a function of the antigen concentration. Triplicate experiments are shown: first (■); second (●); third (⧫). The dashed line represents the average diffusion coefficient of these aggregates. Reprinted with permission from ref 168. Copyright 1997 Elsevier Ltd. 393


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Several reports7,169,170 have indicated that immunoreagents are more stable if functionalized latexes bind antibodies covalently because the chemical attachment is very stable over time. The use of amino-functionalized latexes has several advantages over that of other functionalities (the binding agent, glutaraldehyde, is more stable than carbodiimide, and it can be used to form spacer arms and allows a good antibody orientation).171 Ramos et al.79 have prepared amino-functionalized latexes using a multistep method with the purpose of developing a new immunoreagent. Since the synthesis of these amino latexes has already been described in section 3.1.2.2 of this review, in this part the focus is on the application of this type of cationic latex in the development of a new immunoreagent to measure the serum ferritin concentration. The antihuman ferritin IgG was covalently coupled to the amino-modified latexes with a procedure consisting of three steps. The first one was the activation of particle amino groups with glutaraldehyde. Latex particles at a final concentration of 5 mg of latex/mL of 10−2 mol/dm3 (pH 6.8) phosphate buffer were incubated with glutaraldehyde solutions at different concentrations for 4 h at room temperature with continuous mixing. The residual aldehyde groups of the latex particles could then be used for covalent binding of amino ligands. After removal of unreacted glutaraldehyde by repeated centrifugation and washing with the starting buffer, the particles were resuspended in 0.1 mol/dm3 (pH 9.5) carbonate buffer, and antibody solutions were added and incubated overnight at 4 °C. The imine bond formed was unstable because it had the tendency to hydrolyze with time, again giving amine and aldehyde groups.172 To overcome this inconvenience, the particles were incubated with sodium borohydride in different solutions for 1 h at room temperature with continuous mixing. After removal of the reducing agent, the particles were washed with 0.1 mol/dm3 (pH 7.4) phosphate-buffered saline (PBS), 1% Tween 20 solution, to elute antibodies not covalently attached to the particles. Finally, the coated particles were resuspended (0.2 g/dm3) in glycine-buffered saline−BSA containing 0.17 mol/dm3 NaCl, 0.1 mol/dm3 glycine, 1 g/ dm3 BSA, 1% Tween 20, and 40 mg/dm3 N3Na (at pH 7.4), kept at 4 °C, and sonicated briefly to provide a working latex reagent. To optimize the coupling procedure, different parameters were varied: concentration of glutaraldehyde (1−0.125%), concentration of antibody added (2.5−0.15 mg/m2), and concentration of reducing agent (10−0.1 g/dm3). The immunoaggregation reaction was carried out in a CobasMira Plus clinical chemistry analyzer by turbidimetric assay. The following parameters were studied: (1) Concentration of glutaraldehyde (the best reactivity was obtained with the lowest concentration (0.125%)). (2) Particle size and surface charge density (the immunoreactivity decreases with the size and the particle electrical charge). (3) Antibody concentration in the activation step (at an IgG concentration of 0.9 mg/m2, the best analytical measurement and a high covalent coupling efficiency were obtained). (4) Sodium borohydride concentration. The effect of borohydride was assayed to reduce the imine bond, and an excess of reducing agent improved the

immunoreactivity of the reagent prepared by these authors. (5) Detection limit (the detection limit for ferritin was 3.5 ng/mL). It should be noted that in a comparison study by Sanz-Izquierdo et al.173 between latex particles with different functionalized surface groups (amino, acetal, and chloromethyl) the lowest detection limit was found in the case of the amino-modified particles. 3.3.3. Adsorption of Polyelectrolytes and Surfactants on Cationic Latexes. In the past few decades, synthetic monodisperse colloids, such as cationic latexes, have been widely employed as a solid substrate in polyelectrolyte113,174−185 and surfactant164,184,186−188 adsorption experiments. In general, surface-adsorbed polyelectrolytes increase particle coagulation rates by two distinct mechanisms: charge neutralization and/or polymer bridging. In the first case, the adsorption of polyelectrolyte segments to oppositely charged sites on the particle surface results in a decrease in the repulsive electrostatic interactions between approaching particles and subsequently an increase in particle coagulation rates. Charge neutralization has been documented in the coagulation of positively charged particles by anionic polyelectrolytes.189 Polymer binding occurs when polymer molecules simultaneously attach to two or more molecules, leading to particle destabilization at intermediate surface coverage. In other cases, depending on the conformation adopted by the polymer at the solid−liquid interface, polyelectrolytes can improve the stability or rheological properties of colloidal dispersions by means of a steric hindrance mechanism.175,181 In that context, there are several studies on the adsorption of nucleic acid probes (deoxyribonucleic acid (DNA), singlestranded DNA (ssDNA) fragments, oligodeoxyribonucleotides (ODNs) or, more simply, oligonucleotides) on cationic latexes.176,190−193 In general, they have the goal of elucidating the adsorption/desorption mechanism of ssDNA molecules on aminated latex particles or biodegradable polymer-based particles.194 Perhaps it is opportune now to remember that DNA is made up by two single strands, which are in turn composed of a chain of nucleotides. Each nucleotide consists of a phosphate group, a desoxyribose sugar, and one of the four following nucleic bases: thymine (T), cytosine (C), adenine (A), and guanine (G). The phosphate and deoxyribose groups constitute a skeleton common to all DNA. On the contrary, the order of bases along the chain is specific to each DNA molecule and constitutes the genetic code of each organism. ODNs are fragments of small ssDNA (generally less than 200 nucleotides) that can be considered as small polyelectrolytes. Automatic synthesis of ODNs permits their chemical modification, and they can be matched with an ssDNA fragment, so they are of interest for different biological applications. It is quite difficult to set up a general rule on the adsorption mechanism of ssDNA molecules on cationic latex particles because the chain length is instrumental in the role played by the hydrophobic interactions and the structural changes suffered by ssDNA molecules at the solid−liquid interface. Nevertheless, in general, the attractive electrostatic interaction is the predominant force in the adsorption of acidic ssDNA on cationic latex particles. Morevover, a linear correlation was found between the amount of an oligonucleotide, poly(TGC), adsorbed onto a cationic (amine) latex and the ζ-potential of the latex particles.190 This is experimental evidence that the 394


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enhanced sensitivity. Also, cationic latex particles have been employed to detect nucleic acids (dsDNA fragments) by means of an affinity sensor based on surface plasmon resonance (SPR).201 As a model anionic polyelectrolyte, ssDNA molecules have been used to elucidate the factors that influence the aggregation of cationic latex particles by negatively charged polyelectrolytes.178,179,177 These authors studied the destabilization of cationic latex with amidine groups caused by the adsorption of ssDNA of different chain lengths (from 3 to 1400 nucleotides) with a thymine base composition. The goal of this study was to explain how polymer flexibility and polymer−surface interactions affected the coagulation process. Under the neutral pH conditions employed, ssDNA molecules are acidic polyelectrolytes with a negative charge per nucleotide (DNA monomer). The following effects were experimentally studied: (i) polymer chain length on adsorption; (ii) DNA coatings on coagulation rates; (iii) aggregate structure; (iv) polymer surface conformation. In relation to the chain length effect of the ssDNA molecules on their adsorption on a cationic latex (480 nm in size, 131 mC/m2 surface charge density due to amidine groups, 1.19 nm mean distance between charges), in general, the adsorption isotherms exhibited a high-affinity character in which the adsorbed amount rapidly approaches saturation with increasing ssDNA concentration in solution.177,191 Importantly, the mass of ssDNA adsorbed at saturation coverage appears to be independent of the chain length for molecules at least 10 nucleotides in length. This phenomenon is commonly observed for fully charged polyelectrolytes adsorbed to oppositely charged particles and is typically interpreted to mean that the polyelectrolyte in question is adsorbing in a flat conformation.202,203 For saturating levels of the different samples of ssDNA used, the average area occupied by each ssDNA segment was approximately 0.84 nm2, and there are 1.5 times as many polyelectrolyte charges as particle charges. The measurements of the thickness of the adsorbed ssDNA layer by PCS at low ionic strength (0.005 M NaCl) established that these polyelectrolytes are adsorbed on the latex with all segments in trains. Concerning the effect of ssDNA coatings on the coagulation rates of a cationic latex (120 nm in size, 81 mC/m2 surface charge density due to amidine groups, 1.5 nm mean distance between charges), Walker and Grant177 found that the particles are stable at low and high polyelectrolyte doses and rapidly coagulate at an intermediate dose. These experiments were carried out with an ssDNA sample 40 nucleotides in length, but similar results were obtained with other samples. The particles were destabilized at some critical polyelectrolyte concentration (CPC) and were stable at polyelectrolyte doses above and below the CPC. Moreover, coagulation of ssDNA-coated cationic particles at the CPC is diffusion-limited. Also, in this case, coagulation is due to charge neutralization since particle destabilization occurs when precisely the right amount of ssDNA is added to completely neutralize the surface charge. At a higher ssDNA dose, the net charge on the latex particles was reversed and the particle suspension was stable. Polymer bridging did not occur in these systems, even when ssDNA molecules employed to destabilize the suspension were about the same size as the particles.177 Götting et al.204 observed similar behaviors with a model ODN (phosphorothioate oligonucleotide, PTO 16-mer) with the sequence 5′-ACG

adsorption behavior of ODNs on cationic latex particles can be explained using the following equation related to the adsorption of polyelectrolytes:195 NS = KCf exp( −nE)

(2)

where n is the number of nucleotides, E the average adsorption energy per base, Cf the equilibrium ODN concentration, and K a particular constant depending on the nature of the system being investigated and experimental conditions. The adsorption energy E is usually assumed as the sum of two contributing factors (electrostatic and nonelectrostatic interactions): nE ≈ Eelectrostatic + Enonelectrostatic

(3)

The electrostatic contribution can be determined from the ODN charge (σODN) and the net surface charge of the latex (σlatex) and expressed as the product of these two charges, i.e.

Eelectrostatic ≈ σlatexσODN

(4)

This electrostatic energy is thus expected to vary linearly with respect to the surface charge density (or the ζ-potential). As mentioned above, different authors experimentally found this linear dependency.190,191 The nonelectrostatic contribution to the overall energy (E) might be caused by the interactions between the aromatic bases of the ODNs and hydrophobic patches on the latex particles (hydrophobic forces) and/or hydrogen binding between the amine groups of the latex particles (at basic pH) and the oxygen groups of the ODNs. In general, this contribution is small, but in some cases seems to not be negligible.191 The hydrophobic interactions and the conformation changes of the ssDNA molecules become more important as the chain length increases. For instance, the driving force for the adsorption of a double-stranded DNA (dsDNA) (2000 base pairs) on a supposed cationic latex (with negative electrophoretic mobility!) is not of electrostatic origin but rather due to a hydrophobic effect.196 The maximal adsorbed amount (Ns,max) of ODNs adsorbed as a function of the surface charge density of the latex particles can be quantitatively predicted using the general approach of Hesselink197,198 proposed for the adsorption of polyelectrolytes and expressed according to the following equation: Ns,max =

εkBTκ ln(u) 4πα 2e 2

−

σlatex αe

(5)

where αe is the charge per ODN chain, e is the elementary charge, α > 0.5 for a highly charged polyelectrolyte, ε is the dielectric constant, κ is the reciprocal Debye length, T is the absolute temperature, kB is the Boltzmann constant, and ln(u) is the nonelectrical free energy gain. Ganachaud et al.,191 when adsorbing an ODN (dC12G5T10) on an aminated latex, found reasonable agreement between the calculated and the experimental values of Ns,max. As a general trend, ODN desorption from the surface of cationic latexes is easier at pH values where the attractive electrostatic interactions between both components are weaker, i.e, pH 9.0.176 Furthermore, ODN release can be induced by the addition of an anionic surfactant (SDS) or by increasing the pH of the dispersion medium.199 To avoid the desorption of the ODN caused, e.g., by an increase in the ionic strength or pH changes, Delair et al.200 developed a covalent procedure of ODN immobilization onto amino-containing hydrophobic polystyrene cationic and hydrophilic PNIPAM latexes. The obtained conjugates were used as diagnostic tests with 395


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size of ∼78 nm and a positive ζ-potential in a very broad range of pH values. Special attention was paid to the pH effect on DNA adsorption; it was found that below pH 8 the adsorbed amount was quite large (about 204−215 mg of DNA/g of latex nanoparticles). However, at pH 9 and 10 the adsorbed amount decreased dramatically to about 100 mg of DNA/g of latex. Once again, the electrostatic interaction between acidic DNA molecules and positively charged latex particles is the keystone accounting for this behavior. The adsorption of polypeptides on cationic latexes has been used as a test to explore different electrokinetic theories to convert electrophoretic mobilities into ζ-potentials182 or to explain the electrokinetic data in terms of conformational changes of the adsorbed polypeptides chains.183 In other cases, to avoid desorption of the adsorbed molecules from the solid phase, covalent grafting was long investigated, leading to an irreversible binding of peptide onto functional latex particles.209 There are very few studies on the adsorption of positively charged polyelectrolytes on cationic latex particles. Rustemeir and Killmann180 have studied the adsorption isotherms of the pH-dependent positively charged polyelectrolyte polylysine (PLL) on negatively and positively charged polystyrene latexes. Obviously, we are particularly interested in reviewing the findings obtained with the cationic latex. In this case, the results obtained were very clear; there is no adsorption of the PLL (molecular weight ∼557 000) on the cationic latex at pH 6−7 and an ionic strength of 0 or 0.5 M NaBr. The repulsive electrostatic force is enough to avoid the adsorption of PLL on a positively charged interface. To date, there have been relatively few studies reported113,174,175,181,210 on the adsorption/desorption of a negatively charged polyelectrolyte on a positively charged solid−liquid interface. Such studies have determined systematically the effect of the adsorption procedure and pH values,113 ionic strength,174 and degree of ionization and molecular weight181 on polyelectrolyte adsorption characteristics. In these studies, Meadows et al. demonstrated using electron spin resonance (ESR) spectroscopy how the equilibrium adsorbed layer concentration and configuration of the hydrolyzed polyacrylamide (PAA) on a cationic latex (amidine) can be significantly manipulated by control of the adsorption procedure. For example, while adsorption from a low electrolyte concentration (direct adsorption) results in predominantly flat adsorbed layer configurations, adsorption from a high electrolyte concentration followed by redispersion into the low electrolyte medium (indirect adsorption) gives rise to enhanced levels of adsorption and more extended (thicker) adsorbed layer configurations. The same authors175 analyzed the colloidal stability of the above-mentioned dispersions through observation of the interparticle repulsive forces using a surface balance technique and examined the stability/ redispersibility of the dispersions in the presence of added electrolyte. Briefly, these authors found that the dispersion prepared by an indirect adsorption procedure exhibited markedly increased interparticle repulsions compared to those of its directly prepared counterpart. In addition, the indirectly prepared dispersion was considerably more stable (steric contribution) toward the addition of 1/1 electrolyte, with the concentration of added NaCl necessary to produce aggregation of the dispersion being over 10 times that required for aggregation of the directly prepared counterpart. In conclusion, these works reveal the instrumental role played by the conformation (trains, loops, and tails) of the anionic

GAA ACC GTA GCT G-3′ adsorbed onto a cationic latex with imidazolinium end groups. The aggregate structure was obtained by examining how the average hydrodynamic radius changes over long time scales using dynamic scaling theory, and the fractal dimension df = 1.61 is solely dictated by the nature of the coagulation kinetics, in this case diffusion-limited cluster aggregation (DLCA). With respect to the polymer−surface conformation, as Walker and Grant178,179 demonstrated the conformation of modified ssDNA molecules (these molecules contain ethylphosphonate linkages in which the negative charge on the phosphorus was turned off and replaced with a hydrophobic ethyl group) at the solid−liquid interface can be determined using a biochemical technique called hydroxyl radical footprinting (HRF). This consists of using OH radical to cleave the ODN part not in contact with the surface. ssDNA molecules are adsorbed on the surface of latex particles, and then hydroxyl radicals are generated by the Fenton reaction.205 These results provide important new insight into the relationship between the structure of adsorbed polyelectrolyte layers and the stability of aqueous colloidal dispersions. The ssDNA molecules adsorbed on a positively charged latex are highly protected from hydroxyl radical attachment, suggesting that the sugar moieties in the ssDNA molecules interact directly with the latex surface. Because ssDNA adsorbs close to the cationic latex surface, this molecule influences colloid stability by altering the electrostatic character of the cationic latex surface. In this case, steric and bridging forces are of secondary importance. It should be noted that with anionic latex particles the results are completely different.179 An experimental study carried out by Charreyre et al.206 succeeded in determining the conformation of the ODN chemically bound by its 5′-end on a cationic latex by fluorescence energy transfer (FET). This method consists of using a couple of fluorescent molecules, the fluorescein (as a donor) bound to the 3′-end of the ODN and tetramethylrhodamine (as an acceptor) immobilized on the latex surface. The efficiency of this method varies as a function of the mean distance between the two fluorophores (i.e., between the ODN and the surface).193 Fluorescence energy transfer studies of ODNs bound to the surface of an amine-containing latex in the presence of a nonionic surfactant (Triton X-405) provided interesting information about the interfacial conformation of immobilized ODNs under different experimental conditions. A “brush”-type structure was observed at pH 10, whereas at neutral or weakly acidic pH the conformation was mostly flat.206 Using a completely different technique (small-angle ̈ neutron scattering), Elaissari et al.192 tried to find the structure of adsorbed and covalently bound ssDNA fragments (polythymidylic acid, dT35) on aminated latex particles. Also, in this case, the adsorbed molecules lie close in a flat conformation on the surface of the cationic latex particles, irrespective of the pH and ionic strength. Again, this can be attributed to strong attractive electrostatic interactions between the negatively charged oligonucleotides and the positively charged latex particles. The covalently bound dT35 molecules, however, at basic pH (9.2) and high surface coverage (0.8 mg/m2) extend more radially into the solvent, giving rise to a thicker layer (from 6 to 8 nm) in comparison to the case of physical adsorption (from 3 to 6 nm). To optimize the adsorption of genomic DNA (250−300 base pairs) molecules on cationic latexes, Güven et al.207,208 have recently prepared monodisperse cationic nanoparticles by emulsifier-free microemulsion polymerization with a minimum 396


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molecules on the cationic latex particles involves mainly hydrophobic interactions between both components, although the attractive Coulomb interaction might also play a certain role (see Figure 21). The plateau value of 10.1 μmol/m2 obtained

polyelectrolyte adsorbed onto cationic latex particles. The smallest amount of polyelectrolyte adsorbed (0.18 mg/m2, direct adsorption) is a good fit with the fact that the polymer segments are adsorbed almost entirely in trains close to the latex surface, whereas the biggest one (0.32 mg/m2, indirect adsorption) agrees with a high proportion (75%) of adsorbed polymer segments present in the form of loops and tails. Nevertheless, in the case of strongly charged polyelectrolytes (poly(styrenesulfonate), PSS), the repulsive steric forces between the adsorbed polyelectrolyte layers remain unimportant in stabilizing these systems.211 The most important weak anionic polyelectrolyte in industry is poly(acrylic acid) (PAAc). However, little is known on how PAAc influences the stability of cationic latexes. To fill this gap and clarify how the degree of ionization and the molecular mass of PAAc influence the stability of (amidine) cationic latexes, Sadeghpour et al.181 have recently studied both effects. In general, the results obtained are in agreement with the wellknown correlation that exists between the polyelectrolyte conformation and colloidal stability of polyelectrolyte-coated latexes. The stabilization of bubbles and foams by adsorbed particles has been known for over a century.212 However, currently there is a growing interest in the use of cationic or modified cationic latex particles as stabilizers of aqueous foams because recent studies suggest that the air−water interface exhibits anionic character.213,214 Fujii et al.215 have prepared PS particles carrying pH-responsive poly(2-(diethylamino)ethyl methacrylate) (PDEA), which is covalently bound to the particle core. These hairy cationic latex particles can act as pH-responsive stabilizers of aqueous foams by adsorption at the air−water surface. A similar procedure was previously employed by Kettlewell et al.216 and Hunter et al.217 but using in these cases a poly(ethylene glycol) monomethacrylate macromonomer (PEGMA) and cationic polystyrene latexes prepared with an azo initiator (AIBA). The PEGMA−AIBA−PS latex proved to be the best foam stabilizer even at relatively low latex concentrations (3.0 wt %), with long-term foam stabilities being obtained after drying. In this context, Yang and Pelton218,219 have very recently developed a new technology to facilitate the froth flotation of hydrophilic glass beads using a cationic PS latex with controlled hydrophobicity. In the case of the surfactant adsorption, experiments on cationic latexes could also supply some interesting information about the surface characteristics. In fact, Vijayendran220 have shown that polymer polarity exerts a considerable influence on the Gibbs energy of adsorption of SDS at latex−water interfaces and developed an adsorption model that relates the saturation adsorption of the surfactant molecules to the polarity of the polymer surface. Surfactants are used as adsorbates at the solid−liquid interface to control the surface charge and/or the hydrophobic−hydrophilic character of the surface. Also, in this case, most of the experiments reported on surfactant adsorption were performed with anionic latexes, and relatively little attention was paid to cationic latexes. Galisteo-Gonzalez et al.186 studied experimentally the effect of the alkyl chain length of some anionic surfactants such as docecanesulfonate (SDSo), tetradecanesulfonate (STSo), and hexadecanesulfonate (SHSo) on cationic latexes with amidine ionic superficial groups (712 ± 12 nm in diameter and 327 mC/m2 surface charge density). The adsorption isotherms indicate that the adsorption mechanism of alkanesulfonate

Figure 21. Isotherms for the adsorption of SDSo, STSo, and SHSo at pH 6.0 in 10−3 M KBr solution on cationic polystyrene particles. Reprinted with permission from ref 186. Copyright 1990 Springer.

by these authors for the adsorption of SDSo corresponds to a charge density of 890 mC/m2, reflecting the formation of multilayers of surfactant on the latex surface, because the surface charge density is 327 mC/m2. This seems to again support the idea of an adsorption mainly due to the hydrophobic interactions between the n-alkyl chains and the positively charged latex surfaces, which are strongly hydrophobic. The high value of the surface charge density of some cationic latexes, unlike that of the surfactant, may induce the formation of clusters of vertically oriented surfactant molecules held together in part by hydrophobic interactions between their long chains. Such clusters can occur at surfactant concentrations well below the bulk CMC (SDSo, 9.8 × 10−3 M; STSo, 2.6 × 10−3 M; HSTo, 7.0 × 10−4 M),221 and this phenomenon is usually called “hemimicelle formation”.222 The adsorbed amounts of n-alkanesulfonate anions on amidine polystyrene particles are much larger than those reported by Connor and Ottewill223 for the adsorption of n-alkyltrimethylammonium cations on carboxylate polystyrene particles. The variation trends, however, are in both cases very similar. The adsorption process occurs in two main steps. First, a well-defined jump is found, which corresponds to the adsorption of the surfaceactive anions onto the cationic groups of the surface with the alkyl chains lying flat on the surface. Second, a more gradual adsorption occurs with the alkyl chains adsorbing onto a surface with a net negative charge. The hydrophobic character of the charge-determining groups on the positively charged polystyrene surface also favors this second step. Different authors188,224−227 examined the single and sequential adsorption of an anionic surfactant (e.g., SDS) and a nonionic surfactant (e.g., Triton X-100 (p-(1,1,3,3tetramethylbutyl)phenyl polyethylene glycol)) on cationic latexes. Romero-Cano et al.224 accomplished some years ago a complete adsorption study on Triton X-100 onto cationic latexes having amidine ionic superficial groups and a surface charge density of 92 mC/m2. The pH of the aqueous solution 397


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outward over a distance corresponding to the thickness (Δ) of the Stern layer. The final expression is

controls the surface charge, and hence, this factor is considered an important variable in that study. The adsorption isotherms showed that an increase in the surface charge yielded a decrease in the amount of the adsorbed nonionic surfactant. The experimental results were explained using a descriptive mechanism of the adsorption process, which considers the presence of holes in the layer of adsorbed surfactant. The adsorption isotherms were analyzed with two classical adsorption theories, those of Langmuir228,229 and Kronberg et al.230−232 Both theories gave a good description of the results, but the latter offered more information on the adsorption phenomena. In a subsequent work, the same authors studied the desorption of Triton X-100 from cationic latexes due to a discontinuous method based on the wash step (centrifugation− removal−redispersion) or a continuous method based on the replacement of the dispersed media. The desorption results showed that under all the experimental conditions utilized a residual amount of the nonionic surfactant (∼1.3 μmol/m2) remains adsorbed, indicating irreversibility of the nonionic surfactant adsorption. The addition of a nonionic surfactant to colloidal dispersions is widely employed to modify the colloidal stability. Once the surfactant molecules are adsorbed onto the particle surface, three different types of stabilization can be distinguished as a consequence of the relation between the van der Waals attraction energy (VA) and the steric interaction energy (VS). The colloidal stability of cationic latexes before and after adsorption of Triton X-100 were studied by Romero-Cano et al.226 using optical methods to determine the stability factor, W, previously defined. Whatever the theoretical expression of W, it depends on the interaction potential between the interacting particles (V(H), where H is the surface to surface distance of the two approaching particles).233−236 The interaction potential V(H) can be separated into three contributions: electrostatic repulsion (V R ), attractive interaction (V A ), and steric interaction (VS): V (H ) = VR (H ) + VA(H ) + VS(H )

VR (H ) =

64πankBT κ

2

γ 2 exp( −κH )

(10)

(11)

If there are polymeric chains covering the external surface of a nanoparticle and δ is the average thickness of such coils, then an osmotic effect will appear when the two particles are nearer than a distance equal to 2δ. The osmotic pressure of the solvent in the overlap zone will be less than that in the regions external to it, leading to a driving force for the spontaneous flow of solvent into the overlap zone, which pushes the particles apart: Vosm(H ) =

⎞⎛ 4πa 2⎛⎜ 1 H ⎞2 ϕ2 − χ ⎟⎜δ − ⎟ ⎝2 ⎠⎝ v1 2⎠

(12)

where v1 is the molecular volume of the solvent, ϕ2 is the effective volume fraction of segments in the adsorbed layer, and χ is the Flory−Huggins solvency parameter. However, if the two particles are closer than a distance equal to δ, at least some of the polymer molecules will be forced to undergo elastic compression. Thermodynamically, this compression corresponds to a net loss in configurational entropy. This effect gives rise to a new repulsion potential, Velas(H), related to the restriction of the movement of the hydrophilic coils extended toward the solvent. ⎛ 2πa ⎞⎛ H ⎡ H ⎛ 3 − H / δ ⎞ 2 ⎤⎞ ⎟ ⎥⎟ ϕ2δ 2ρ2 ⎟⎜⎜ ln⎢ ⎜ Velas(H ) = ⎜ ⎠ ⎦⎟⎠ 2 ⎝ Mw ⎠⎝ δ ⎣ δ ⎝

(6)

⎡ 3 + H /δ ⎤ ⎛ H⎞ − 6 ln⎢ ⎥⎦ + 3⎜⎝1 + ⎟⎠ ⎣ δ 2

(13)

where Δ2 and Mw are the density and the molecular weight of the adsorbed polymer. This effect modifies the osmotic potential, which is now given by

(7)

Vosm(H ) =

⎛ H ⎞⎤ ⎞ ⎡H 4πa 2⎛⎜ 1 1 ϕ2 − χ ⎟δ 2 ⎢ − − ln⎜ ⎟⎥ ⎝ ⎠ ⎝ δ ⎠⎦ ⎣ v1 2 2δ 4 (14)

For the electrosteric stabilization mechanism, both effects (electrostatic repulsion and steric stabilization) must be combined. Normally, the total interaction energy is assumed to be the sum of all attractive and repulsive potentials (eq 6) (see Figure 22).226,241 Experimental log W versus log(electrolyte concentration) plots for the bare cationic latex were fitted using the DLVO theory, and values of the diffuse-layer potential (ψδ ≈ 18 mV) and the Hamaker constant (A ≈ 7 × 10−21 J) were obtained. It should be noted that ψδ and A are related to VR and VA (the London−van der Waals interaction), respectively (see Figure 23). These values of ψδ and A are in agreement with typical values of both parameters for polystyrene latex particles. In the same way, log W versus log(electrolyte concentration) plots for cationic latex particles covered with the abovementioned nonionic surfactant were fitted using the extended

and the nonsimplified expressions for the attractive Hamaker239 interaction is 2a 2 2a 2 A⎛ VA(H ) = − ⎜ 2 + 6 ⎝ H + 4aH (H + 2a)2 H2 + 4aH ⎞ ⎟ (H + 2a)2 ⎠

γ 2 exp(−κ(H − 2Δ))

VS(H ) = Vosm(H ) + Velas(H )

where a is the particle radius, n is the number of ions per unit volume, κ is the Debye reciprocal length, kB is the Boltzmann constant, and T is the absolute temperature. The factor γ is related to the diffuse-layer potential, ψδ, through zeψδ zeψδ γ = tanh ≈ (when ψδ → 0) 4kBT 4kBT (8)

+ ln

κ2

The steric repulsion due to a layer of polymer adsorbed onto a cationic latex can be calculated using the expressions obtained by Vincent et al.240 According to this DLVO extended theory, the steric stabilization effect is usually due to two contributions, osmotic and elastic:

VR(H) and VA(H) can be calculated using the classical expressions of the Derjaguin−Landau−Verwey−Overbeek (DLVO) theory:237,238 VR (H ) =

64π (a + Δ)nkBT

(9)

where A is the Hamaker constant. If the Stern layer thickness is considered, eq 9 must be modified by shifting the reference plane for repulsive energy 398


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Figure 24. Theoretical dependence of W on [NaCl]: experimental data for bare particles (□) and 2.0 μmol/m2 PS-CAT/TX100 complex (*) at pH 6. Reprinted from ref 226. Copyright 2001 American Chemical Society.

Figure 22. Net interaction energy as a function of distance for the PSHEMA latex: (◆) Velas; (+) Vosm; (□) VR; (×) VA; (Δ) V. Reprinted with permission from ref 241. Copyright 1996 Elsevier Ltd.

headgroup of the surface-active agent and hydrophobic sites on which the alkyl chains adsorb. Concerning the sequential adsorption of nonionic and anionic surfactants, Porcel et al.188 accomplished an experimental study on the sequential adsorption of SDS and Triton X-100 onto cationic latexes. A comparison between the two surfactants showed that SDS was more easily replaced than Triton X-100 when sequential adsorption on the cationic latex was studied. The electrical state (electrophoretic mobility) of the solid−liquid interface depends on the addition sequence order of both surfactants. In relation to colloidal stability, when a layer of nonionic surfactant is adsorbed on the surface of the cationic latex, the electrosteric mechanism explains the experimental results. If SDS is adsorbed, the stabilization or coagulation of the coated cationic latex particles is a consequence of the changes in the electrical repulsion between particles. However, when both surfactants are adsorbed, the assumption of additivity is not correct; that is, the electrostatic repulsion and the steric stabilization (osmotic and elastic compression) are not totally independent. 3.3.4. Heteroaggregation of Colloidal Dispersions. Heteroaggregation is the aggregation of mixed particle systems where the colloidal particles may differ in charge, size, and chemical composition. The phenomenon of heteroaggregation is shown to be important in applications such as mineral flotation, cell recovery, stability of emulsions, paper and cement additives, or retention aids, and synthesis of engineering ceramics, among others.242−247 Heteroaggregation, however, is not as extensively studied as homoaggregation, i.e., the aggregation of monocomponent colloidal dispersions. This may be mainly due to the relatively complex interactions between dissimilar particles that the classical Derjaguin−Landau−Verwey−Overbeek theory cannot account for.129,248 While the overlapping of the electrical double layers surrounding two like particles is always unfavorable, this is not necessarily the case when unlike particles approach each other. At low electrolyte concentrations, attractive interactions between oppositely charged particles can even increase the aggregation rate to values above the diffusion limit.249,250 The Hogg−Healy−Fuerstenau (HHF) theory for two dissimilar spheres is based on two assumptions:

Figure 23. Stability of cationic latex PS-CAT at pH 6 (□), 8 (Δ), 9 (○), and 10 (*). The line represents the theoretical fitting curve. Reprinted from ref 226. Copyright 2001 American Chemical Society.

DLVO theory, and reasonable agreement was found assuming a thickness of ∼1.0 nm for the surfactant layer around latex particles (see Figure 24). Although Triton X-100 (TX100) is a nonionic surfactant, the electrical state of the cationic latex particle−electrolyte solution changes slightly when surfactant molecules are present at that interface.227 Also, the adsorption of Triton X-100 is used to estimate the hydrophobic character of the cationic latex−solution interface. Typically the maximum amount of nonionic surfactant adsorbed on cationic latexes with amidine groups on the external surface is around 2.24 μmol/m2,155,164 which is equivalent to an area per molecule of Triton X-100 on a latex surface of 74 Å2. These values are quite different from those obtained with an anionic latex with sulfate anionic groups on the surface, 1.25 μmol/m2 and 135 Å2, respectively. This result indicates that the cationic latex with amidine groups on the external surface is more hydrophobic than the anionic latex having sulfate groups. The cationic latex has two types of sites for adsorption, charge sites that interact with the anionic 399


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interest. The formulas derived by these authors are very simple, but accurate, analytic expressions for the electrical double layer and interaction free energy between two spherical colloidal particles valid up to the moderate- to high-potential regime and all κh values. There are many interesting phenomena in electrostatic heteroaggregation which were discovered in the past decade using simulation methods257−262 and single-cluster detection techniques263 for monitoring the time evolution of the cluster size distribution. Puertas et al.264 reported an interesting effect arising at very low electrolyte concentration in simulated 1/1 mixtures of equally sized particles with opposite electric surface charge. They found that the cluster concentration profiles exhibit a noncontinuous behavior at relatively long aggregation times. In other words, clusters differing by only one constituent particle behave quite differently. They named this effect cluster discrimination. The first experimental support for this hypothesis was reported a few years ago. 265 Cluster discrimination was found experimentally in heteroaggregation processes arising in 1/1 mixtures of positive and negative polymer colloids at low and very low ionic concentrations. Monomer discrimination could be detected already at 10−2 mol/dm3 KBr, while dimer discrimination started to appear only for electrolyte concentration smaller than 10−3 mol/dm3 (see Figure 25). This shows that cluster discrimination is not an

(i) the linear Debye−Hückel (D−H) approximation in which the electrostatic potential is assumed to obey the linearized form of the Poisson−Boltzmann (P−B) equation and (ii) the Derjaguin approximation237 in which the sphere−sphere interaction energy is obtained from a knowledge of the distance dependence of the energy per unit area for corresponding parallel plates by an integration over the surface of one sphere. The D−H approximation yields the interaction energy to quadratic order in the surface potential, and therefore, the HHF formula can only be applied for sufficiently low surface potentials. The expressions derived by Hogg, Healy, and Fuerstenau for the London−van der Waals and electrostatic interaction between two dissimilar particles are 2a1a 2 2a1a 2 A⎛ VA(r ) = − ⎜ 2 + 2 6 ⎝ r − (a1 + a 2)2 r − (a1 − a 2)2 + ln VE(r ) = επ

r 2 − (a1 + a 2)2 ⎞ ⎟ r 2 − (a1 − a 2)2 ⎠

(15)

a1a 2 {(ψ01 + ψ02)2 ln(1 + e−κ(r − a1− a2)) a1 + a 2

+ (ψ01 − ψ02)2 ln(1 − e−κ(r − a1− a2))}

(16)

a1 and a2 are the particle radii, ψ01 and ψ02 are the surface potentials, r is the center to center distance, and κ is the Debye reciprocal length, which depends on the solvent ionic concentration. Ohshima et al.251 have extended the HHF results to moderate potentials by first obtaining an expression for the interaction between plates correct to the sixth power in the surface potentials and then using Derjaguin’s method to give the result for the interaction between spheres. Derjaguin’s method, however, is applicable only for large particle radii and for small particle separations. Using an integral equation method devised by McCartney and Levine252 for the interaction between two similar spheres, Bell et al.253 derived an improved expression for the interaction between dissimilar spheres, which tends to the HHF formula at small separations and has the correct asymptotic behavior at large separations. The utility of the improvement of Bell et al. is that it is uniformly valid for both small and large separations provided the surface potential is low. Although curvature corrections are included to some extent in their treatment, Ohshima et al.254 have derived the exact expression for correction terms due to curvature effects, without using Derjaguin’s method, but considering that the surface potentials on the particles remain constant during interaction and are small enough to apply the linear D−H approximations to the P−B equation. Nevertheless, the differences between the exact and approximated (HHF) solutions are habitually within the experimental errors of the measurements involved in any heteroaggregation experiment. Probably, it is due to the fact that between interacting spheres the real interaction potentials are the “effective” and not the surface potentials. However, there are some doubts about the validity of the HHF theory when the sphere radii are very different in magnitude.255 The HHF approximation is accurate for large κa (κ is the Debye screening parameter, and a is the sphere radius) and small κh (h is the distance of closest approach between the spheres), but Sader et al.256 have presented a modified HHF approximation which is accurate even for moderated κa values and for all κh ranges of practical

Figure 25. Cluster concentration profiles at fixed time (t0 ≈ 2 × 104s) for different KBr concentrations: 1.0 M (left-pointing triangle) 10 mM (◇); 1.0 mM (▽); 0.1 mM (Δ); 0.01 mM (○); no added KBr (□). Reprinted with permission from ref 265. Copyright 2004 American Physical Society.

intrinsic property of pure heteroaggregation processes since it is not fully developed as soon as homoaggregation processes are completely absent. Furthermore, it is observed that for decreasing ionic concentrations dimer discrimination is becoming more pronounced. This finding implies that cluster discrimination is most likely related to the range of the attractive electrostatic interactions between the oppositely charged colloids. The experimental results were also compared with the Brownian dynamics simulations (BDSs) performed by Puertas et al.264 Not only qualitative but also quantitative agreement was observed when the adequate normalizations were performed. Especially, the onset and the increasing strength of dimer discrimination were predicted quite satisfactorily by the BDS. In their simulations, Puertas et al. found that cluster discrimination gives rise to an odd−even behavior in the cluster concentration profiles; i.e., odd size 400


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clusters become dominant in the cluster size distributions (CSDs). Experimental data confirmed this prediction for monomers and dimers. Hence, the good agreement between experiments and simulations supports the hypothesis that the cluster discrimination phenomenon originates mainly from the long-range electrostatic interactions. Other interesting phenomena are predicted to occur in electrostatic heteroaggregation processes as a function of the relative concentration of the two reacting species. For instance, López-López et al.266 have studied by means of off-lattice simulations the binary diffusion-limited cluster−cluster aggregation (BDLCA) processes. The fundamental role played by the relative concentration, x, was investigated for both short and long aggregation times. At short aggregation times, the predominant reaction is dimer formation due to bond formation between two unlike particles. In this region, the effective dimer formation rate constant, kS(x), follows the parabolic behavior predicted by the HHF theory. At long aggregation times, the aggregation behavior is highly dependent on x. For x > xc ≈ 0.15, aggregation continues until a single cluster is formed. In this region, the time evolution of the CSD is somewhat similar to the well-known diffusionlimited cluster aggregation (DLCA) processes. The main difference was found to be an excess of monomers that is observed even for x = 1/2. This monomer excess seems to be identical to the monomer discrimination mentioned above. In other words, these BDLCA simulations show that monomer discrimination may occur even in the absence of any particle− particle interaction (see Figure 26). At x values close to xc, these authors found an atypical time evolution for oligomers composed of 8−10 particles. Their number reached two maxima corresponding to two different compositions: several minority particles per cluster at short times and just one minority particle per cluster at long times (see Figure 27). This behavior was not reported for on-lattice BDLCA simulations.257,267,268 At relative concentrations below xc, stable aggregates continue to diffuse in the system and a single cluster is never formed. In summary, the proposed scheme for BDLCA processes for relative concentrations below xc comprises the following five stages: (1) HHF stage. Fast reactions between unlike monomers form dimers.

Figure 26. Cluster size distribution up to 10-mers, ni(t) (thin dashed lines for odd i and thin solid lines for even i), and the overall number of aggregates, M1(t) (thick solid line), at initial relative concentrations of (a) x = 0.50, (b) x = 0.15, and (c) x = 0.05. The numbers indicate the number of constituent particles of the clusters. Reprinted with permission from ref 266. Copyright 2005 American Physical Society.

(2) Seed formation stage. Dimers continue to be formed. They also grow by adding further majority particles and therefore become first-order seeds. This stage ends when all free minority monomers have disappeared. (3) Seed aggregation stage. Some first-order seeds react among them, forming higher order seeds. These seeds keep growing by adding majority monomers. (4) Seed completion stage, The seeds are so highly covered that they cannot react any longer among themselves. Nevertheless, they still can grow by adding majority monomers. (5) Stable aggregate stage. All clusters are completely coated by majority particles. Aggregation comes to an end. This aggregation scheme is representative of all the simulated BDLCA processes for relative concentrations clearly below xc. However, the moments at which these stages start and end depend on the initial relative concentrations.

Figure 27. Time evolution of the composition detailed cluster size distribution for octamers, n8l(t), at x = 0.15 and l = 1 (thin solid line), l = 2 (dashed line), and l = 3 (dotted line). The number of octamers, n8(t), is also plotted (thick solid line). Reprinted with permission from ref 266. Copyright 2005 American Physical Society.

Theoretical models based on Smoluchowski’s theory269 were demonstrated again to be an important tool to rationalize the kinetic properties in the heteroaggregation of equimolar mixtures.270 The situation changes completely if the binary charged colloidal system possesses large asymmetries between the numbers of positive and negative particles. Recent studies on the heteroaggregation of these type of systems reveal the existence of novel, interesting phenomena, such as the formation of clusters with a high stability and the appearance of two peaks in the time evolution of the concentration of certain sorts of clusters (two-hump effect).271 The appearance 401


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aggregation of cationic latex particles (R2) by the addition of smaller anionic latex particles (R1) the size ratios (R2/R1) can determine the monomodal or bimodal (two peaks in the aggregation rate) aggregation rate response. The expected monomodal response is only found for smaller particle size ratios (R2/R1 ≤ 0.13), whereas the bimodal response is most notable for intermediate particle size ratios, R2/R1= 0.36 and 0.49 being the clearest. Probably, the explanation of this curious behavior is given by the different weights of the collision rate constant and collision efficiency in the rate of aggregate growth depending on the particle size ratios. Concerning heteroaggregation processes due to differences in the chemical composition, we can distinguish three different types of studies: (1) Heteroaggregation between hard and soft particles.278,279 An interesting case of heteroaggregation between hard and soft particles was studied by Islam et al.,280 where a variation of temperature is the cause of the heteroaggregation between a cationic PNIPAM microgel and an anionic polystyrene latex. The mixed dispersions are colloidally stable at 20 °C, whereas at elevated temperatures (50 °C) a heteroaggregation of the dispersion takes place within certain concentration ranges of microgel particles. By using a surface-masking technique, based on the heteroaggregation of small (thermosensitive microgel) and large colloidal (latex) particles, Bradley and Rowe281 have prepared Janus (two faces with different surface properties) microgels. (2) Heteroaggregation between hard and hard particles.282,283 The attractive interaction between hard particles with opposite charges is used for monolayer formation upon self-assembly of monodisperse anionic latex particles and multilayer formation upon alternating self-assembly of cationic and anionic latex particles at positive glass supports.284 The selfassembled multilayers were highly porous and exhibited a very large surface area, which makes them attractive as separation layers, filters, and supports for catalysis. With growth of the polyelectrolyte and adsorbance of neutral polymer on latex particles, the hard behavior of the colloidal particles can be changed; this is the way to systematically prepare hairy colloids. The most interesting aspect of the heteroaggregation of hairy colloids is their fully reversible assembly in aqueous solutions.285 (3) Heteroaggregation between soft and soft particles.286,287 Probably, microgels are the best model soft particles given that they show soft repulsive interactions arising from repulsion between hydrated polymer hairy chains located at the exterior of the particles. In comparison with the heteroaggregation between hard particles, binary mixtures of soft particles have possibilities of exhibiting phase behaviors that have never been observed before using hard particles. In this sense, Suzuki and Horigome288 have very recently reported the phase behaviors of binary mixtures composed of temperature-sensitive cationic and anionic gels. Both microgels were synthesized by aqueous free radical precipitation polymerization using N-isopropylacrylamide and N,N′-methylenebisacrylamide but using different types of water-soluble initiators and comonomers. The most interesting result found by these authors is that the presence of a small amount of electrolyte altered the dispersing behavior of the binary mixture when each microgel was in its hydrated swollen state. Furthermore, the addition of a small amount of salt prevented the binary mixtures from flocculating, resulting in non-close-packed structures on a planar substrate in the dry state, which is similar to single-species microgels. Adding a

of the two-hump effect in the cluster size distribution is observed in electrostatic heteroaggregation processes at low electrolyte concentration with large asymmetries in the relative particle concentration (but similar sizes and surface potentials) by means of Brownian dynamics computer simulations and experimental measurements. The study of the time evolution of this type of aggregating system demonstrates that several cluster formation mechanisms with different characteristics time scales are involved.272 The results obtained by these authors show that the internal composition of the clusters is the main aspect determining the time evolution of the process. The heteroaggregation of binary charged colloidal systems at high particle concentration asymmetry leads to new, fascinating phenomena with no analogues in the homoaggregation processes: the formation of clusters of high stability and the appearance of multiple peaks in the cluster size distribution. The heteroaggregation between particles with different particle sizes and chemical compositions is also possible. Different authors using thermodynamics and kinetic approaches have studied the colloidal stability of binary latex dispersions of similar chemistry but varying size. Shenoy et al.273 derived a formally correct expression for the effective doublet stability ratio (Weff) of a bimodal system 100 and 200 nm in diameter. It accounts for the difference in particle size and extends the HHF theory. Others authors, such as Borkovec et al.,274−276 studied the early stages of heteroaggregation of latexes with different sizes experimentally. A novel multiangle static and dynamic light scattering device was used as a powerful tool to probe the particle aggregation process in situ. These authors were able to discriminate the rate constants for A−A, B−B, and A−B particle aggregation.274 In the first stage of their study, the more general situation, where homoaggregation and heteroaggregation occur simultaneously, was excluded, but a little later Borkovec et al.276 also addressed this situation. The values of the apparent and absolute heteroaggregation rate constants, kAB, obtained by static light scattering (SLS) and DLS were equal within experimental error for the three types of binary samples used.274 The mixing ratio of the particle radii ranged from 0.5 to 0.8, the cationic latexes being of smaller size. In their experiments, the ionic strength was 10−4 mol/dm3 and the pH was adjusted to 4 by adding HCl. Under these experimental conditions, only heteroaggregates were formed, and no homoaggregation took place. The values of the absolute heteroaggregation rate constants obtained by multiangle DLS are within the range of 5.28 × 10−18 and 6.01 × 10−18 m3 s−1. These values can be considered as independent of the mixing ratio. Subsequent technical improvements in the optical treatments of the experimental data did not significantly change the values of kAB obtained by the same authors.276 Time-resolved multiangle SLS and DLS are able to measure the heteroaggregation rate despite the simultaneous formation of homoaggregates. Yu and Borkovec277 measured the early-stage aggregation process between positively charged amidine particles 67 nm in radius (particle A) and negatively charged sulfate particles 84 nm in radius (particle B) dispersed in KCl electrolyte solutions at pH 4. This means that kAA, kBB, and kAB were simultaneously determined. At 10−4 mol/dm3 KCl the homoaggregation rate constants were negligible, whereas kAB became 5.42 × 10−18 m3 s−1. At 0.3 mol/dm3, however, kAA and kBB were 4.90 × 10−18 and 3.80 × 10−18 m3 s−1, respectively, and kAB became 3.21 × 10−18 m3 s−1. In a very interesting experimental work, Olsen et al.277 observed that in the 402


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fluorescent and highly magnetic core−shell polymer particles.293 Obviously, this technique relies on electrostatic interactions to induce the coating of small particles onto large ones. In the same direction, Han et al.294 have recently studied the effect of the surface charge density and particle size of both opposite latex particles on the formation of heteroaggregates which are used as anionic ion exchange resins. On one hand, Vincent et al.295 and Goodwin and Ottewill et al.296 were the pioneers in the study of the adsorption of small cationic polystyrene particles onto large anionic polystyrene ones. On the other hand, Furusawa et al.297,298 were the first researchers to apply this procedure to the elaboration of silica−latex composites and magnetic particles. An alternative strategy to insert mutual interactions among the colloidal components was used by Bayer et al.299 This strategy is based on the coverage of colloidal particles with complementary H-bond patterns. The simplest complementary H-bonding motif in this sense is to cover one colloidal component with an H-bond donor and the other colloidal component with a H-bond acceptor. They synthesized 4hydroxylstyrene-functionalized cross-linked colloids as one component and 4-vinylpyridine-functionalized cross-linked polystyrene colloids as the second component. Polymerization was carried out by means of surfactant-free emulsion polymerization. If both latexes are directly combined as a suspension in CHCl3, a fast heteroaggregation is observed. In heteroaggregation of binary particle systems an exciting challenge is the determination of the cluster composition. This can be achieved if particle populations are marked (e.g., fluorescently labeled). Rollié and Sundmacher300 determined dynamically by flow cytometry the cluster composition of a binary particle mixture of oppositely charged polystryrene particles and rhodamine B-labeled melamine−formaldehyde particles. The cluster composition is mainly dependent on the ionic strength and particle number ratios. Studies on heteroaggregation processes in two-dimensional systems are very scarce301 in comparison with the number of works published on this topic for three-dimensional systems. Only a few simulations have been done regarding the effect of different particle sizes (binary colloidal monolayers) on twodimensional heteroaggregation.302−304 There are practically no experimental studies on this topic; only Ristenpart et al.305 used an ac electric field to assemble planar superlattices of binary colloidal suspensions on an electrode. They observed triangular or square-packed arrays depending on the field frequency and relative particle concentrations. The structure formation in binary colloids observed by Ristenpart et al. was studied theoretically by Varga et al.306 These authors found that the total concentration of particles, the relative concentration, and the relative dipole moment of the components determine the structure of the colloid. At a low concentration of particles, aggregation leads to fractal structures. For increasing concentrations, a crossover to lattice structures was observed. The results obtained by these authors at high concentration are in good agreement with those found experimentally. It is worth pointing out that heteroaggregation is an emerging scientific topic, and much work still remains to be done in this field. Some important subjects involving the aggregation of binary colloidal systems are, for instance, the heteroaggregation of nonspherical particles, the aggregation of patchy colloids, and the exploration of the phase diagrams of binary colloidal systems with opposite charges at different number ratios, x. The experimental observation of the BDLCA

small amount of salt and gently stirring could redisperse the slow flocculation of microgels. These tunable properties are ascribed to the existence of electrostatic interactions and steric hindrance of hydrated polymer chains at the exterior of the microgels. Also, Hou et al.289 have investigated the effects of cations on the sorting of oppositely charged microgels. They used thermally sensitive anionic microgels of poly(N-isopropylacrylamide-co-sodium acrylate) and cationic microgels of poly(Nisopropylacrylamide-co-(vinylbenzyl)trimethylammonium chloride) as a simple model to understand the role of ions on cell-sorting. The most relevant conclusion of this study on the heteroaggregation of those microgels in the presence of different cations is that the adhesive property plays an important role in the sorting of oppositely charged microgels. Microgels can be considered as stimulus-responsive, or smart, materials. According to Bradley et al.,290 a smart material is one that can sense a stimulus from its surroundings, e.g., temperature or light, and react to it in a useful, reliable, reproducible manner. Smart materials therefore respond to changes in the environment in a rather predictable manner, and some have a memory as they revert back to their original state once the stimulus is removed. The dispersion behavior of smart particles can be manipulated by external stimuli such as temperature, pH, electric/magnetic fields, or light. The abovementioned authors have recently reviewed the studies on heteroaggregation where at least one of the particles is a stimulus-responsive smart colloid. A new challenge in the use of oppositely charged microgels is the preparation of pH-triggered physical gels. McParlane et al.291 were the first to investigate the formation of dual pHtriggered physical gel (soft particle glass) using concentrated mixed dispersions of heteroaggregated pH-responsive microgels (poly(ethyl acrylate−methacrylic acid−1,4-butanediol diacrylate) (PEAMAA) and poly(2-nonylpyridine−divinylbenzene (PVP)). The phase diagram for the mixed PEAMAA/PVP heteroaggregates showed that glasses were obtained at both high and low pH values. From pH 4.0 to pH 6.4, the heteroaggregated microgels flowed after tube inversion and were weak gels. As these authors emphasize, the experimental differences between these particle gels and glasses were the ability of the particle gels to flow and low elasticities. It should be noted that the phase diagram of the heterodispersion is the sum of the individual phase diagrams for each microgel. This implies that it is the pH-triggered swelling of the microgel particles that is responsible for the onset of gel formation for the mixed systems. In the first case of heteroaggregation between hard and soft particles, negatively charged polystyrene latex and positively charged microgel particles of similar size and surface charge were used. The structures of the aggregates as well as the aggregation kinetics were investigated.278 Perhaps the most interesting aspect of this investigation is that the differences in the homoaggregation rates of both types of particles permit the formation of large clusters formed by microgel particles (or microgel−polystyrene particles), while the smaller clusters are composed of polystyrene particles. In the second case, the structure of the heteroaggregates was studied as a function of the mixing ratio. For the third case, the use of thermosensitive microgels287 adds temperature as a new variable in the formation of heteroaggregates. Some authors have prepared, using the stepwise heterocoagulation concept, nanocomposites292 and 403


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regime and the heteroaggregation of charge-asymmetric colloidal mixtures in two dimensions (particles trapped at the liquid−fluid interface or confined between walls) are also of great interest.271 On the other hand, the heteroaggregation with or the deposition onto natural colloids (inorganic solids, small organic compounds, and larger rigid biopolymers), followed by their sedimentation from the water phase, is the main removal mechanism of nanoparticles (CeO2, for example) in natural water.307 3.3.5. Colloidal Monolayer Formed by Cationic Latex Particles at the Air−Water Interface. Recently, the behavior of colloidal dispersions confined in 2-D geometry has drawn wide interest. From an experimental point of view, there are different forms of 2-D systems. For example, a dispersion of charged particles bound by two charged plates of the same sign constitutes a 2-D system since the electrostatic repulsion makes the particles remain confined at the intermediate plane between two walls.308 Also, a system consisting of particles trapped at the air−liquid or liquid 1−liquid 2 interface can be considered to be a 2-D system.309−311 The formation of colloidal monolayers is especially interesting because of the ability of particles to affect the stability of emulsions, foams, and interfacial properties. Also, in this case, the number of works with cationic latex particles is much less than that with anionic latex particles.312,313 Once cationic latex particles are dispersed at the interface (air−water, usually), they remain trapped because of the surface tension effect and electrostatic forces. In two-dimensional aggregation, additional theoretical and experimental complexities appear in comparison with coagulation of bulk colloidal suspensions (see Figure 28).314 On one hand, since the

Moreover, from an experimental point of view, the deposition procedure of colloidal particles at the interface is a delicate process due to the difficulty of avoiding initial heterogeneities and fluctuations in the particle surface dispersion. In some works, the kinetic and morphological behavior of colloidal aggregation for cationic latex particles confined at the air−water interface is studied as a function of the salt concentration (KBr, Na2SO4, and Na3PO4).312,313 The socalled CCC, i.e., the salt concentration at the transition from slow coagulation (many collisions are necessary for two aggregates to stick together; this is the reaction-limited cluster aggregation (RLCA) regime) to rapid coagulation (aggregation controlled only by the diffusion time of the aggregates, the DLCA regime), was determined experimentally by MonchoJordá et al.313 from both kinetic and structural properties, and a good accordance between both results was achieved. These experiments showed that the valence of the counterions did not affect the qualitative behavior of the aggregation properties, but it already changed the CCC inversely to the value of the valence (see Figure 29). Although similar aggregation behavior for the CCC is expected in the two-dimensional case, actually there is a big difference in relation to three dimensions. In two dimensions, a large amount of salt is necessary for inducing particle coagulation (1 mol/dm3 vs 0.15 mol/dm3 KBr, for instance).313 To explain the large stability of colloidal monolayers observed even for very high salt concentrations, Robinson and Earnshaw315 proposed the existence of dipole−dipole repulsive interactions. According to them, the dipoles are surface charges at the top of the particle that have trapped a counterion from the solvent during the initial turbulent spreading. Following these authors, this interaction is responsible for the nonisotropic forces between clusters formed in aggregation processes in 2-D. However, other experimental results311 showed that 2-D structured colloidal monolayers formed at the air−water and oil−water interfaces cannot be explained only considering dipolar repulsive interactions; therefore, a longer range interaction potential is necessary. Quesada-Pérez et al.316 carried out experiments on stable colloidal monolayers at the air−water interface, and they showed that the particle interaction potential manifests a long-range repulsive barrier (close to 7 times the particle diameter). In that study, they also suggested the possibility of Coulombic electrostatic forces (i.e., monopolar forces) as well as dipolar forces. This suggestion was confirmed317 using molecular dynamics to show that the longrange repulsive interaction between particles at the oil−water interface is principally caused by monopole−monopole Coulombic interactions. In a theoretical model developed by Moncho-Jordá et al.,312 long-range interactions are accounted for by means of two different interactions: (i) dipole−dipole forces that control the aggregation at high ionic strength and (ii) monopole−monopole Coulombic interactions that govern stability at salt concentrations lower than the CCC. Moreover, the results showed that the fraction of monopoles ( f mon) is the main parameter controlling kinetics in 2-D aggregation, and hence, a CCC can be defined from the salt concentration at which f mon becomes zero. 3.3.6. Deposition of Cationic Latexes. In general, deposition318 plays a vital role in many technological and natural processes, such as thoses involving drugs, cosmetics, detergents, paper making,319 bacterial adhesion, carrier flotation, colloidal contaminant transport, filtration, and semiconductors. The initial deposition process is generally

Figure 28. Sketch of the colloidal particle arrangement at the interface between phases 2 and 3. Calculations of the fraction included in each phase are different for the θ < π/2 (A) and θ > π/2 (B) cases. The fat black line (C) indicates the wetted part of the particle when r > l. Reprinted with permission from ref 314. Copyright 2000 Elsevier Ltd.

particles are trapped at the interface, the interaction force between them depends on their degree of wetting.315 Consequently, the interaction between the wet parts of the colloidal particles is quite different from the interaction between the external parts, and the theoretical treatment for determining the energy requires numerical computation.314 404


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been widely reviewed.320 However, the role of some important factors, such as discreteness of the charges and their possible rearrangement, in deposition has been scarcely considered. Only Somasundaran et al.318 studied the influence of the surface heterogeneous nature of the latex particles and substrates (frosted glass slides) and the dynamics involved in deposition under free settling conditions using different types of latex particles (including cationic and zwitterionic latexes) and discussed the results in terms of relevant colloidal forces (electrical double layer and van der Waals interactions, gravitational force). Conventional deposition was found for amidine latex particles, with electrostatic forces playing a dominant role. This means that the presence of an attractive electrostatic force led to a favorable deposition of amidine latex particles, whereas that of a repulsive electrostatic force led to the absence of deposition. Nevertheless, a good deposition of zwitterionic particles was observed in spite of the presence of an apparent electrostatic repulsion. The authors explain this anomalous deposition as due to the reconformation of the mixed hairy charged groups. Aizenberg et al.321 have used substrates chemically micropatterned with anionic and cationic regions to govern the deposition of charged colloidal particles (negatively and positively charged latex particles of around 1 μm). This method of self-assembly of colloidal particles onto a patterned (e.g., lithographically modified) substrate is named “colloidal epitaxy”. According to these authors, the direct observation of the colloidal assembly suggests that this process includes two steps: an initial patterned attachment of colloids to the substrate and an additional ordering of the structure upon drying. This approach to the colloidal epitaxy makes it possible to fabricate complex, high-resolution two-dimensional arrays of colloidal particles. Revut and Us’yarov322 have studied the role played by different electrolytes in the deposition of cationic latex particles on flat surfaces; divalent counterions were found to have a stronger influence on this process than univalent counterions. The results indicated that the duration of the adhesion bond is determined by the concentration and nature of the ions in the solution. AFM can be used to investigate the adsorption behavior of cationic latex particles on mica.323 Particularly, this technique permits useful information on the initial kinetics of the adsorption and microstructure of adsorbed particles to be obtained. Alince et al.324 studied the deposition of cationic latex particles on cellulose fibers. This process may be described as mutual interaction of unlike particles (heterocoagulation) in terms of the HHF theory for sphere−plate interaction. The rate of deposition of colloidal particles on a solid substrate in the absence of a potential barrier (i.e., when particles are of opposite sign or uncharged) is closely controlled by diffusion. However, differences are noticed in the colloidal behavior of hard, nonfilming (polystyrene) and soft, film-forming (polystyrene−butadiene) latexes. The hard latex deposits as individual particles at a rate that is apparently diffusion controlled. The deposition of the sof t latex indicates two concurrent mechanisms. The initial deposition of individual particles is accompanied by aggregation of the depositing latex. The rate is likely affected by the latex’s tendency to coagulate, and full deposition of the homocoagulating latex is observed. The explanation of this different behavior is sought in interplay of attraction forces acting on deposited latexes. The hard latex is apparently not in intimate contact with the fiber surface, and

Figure 29. Kinetic exponent, z, as a function of the salt concentration for (a) KBr, (b) Na2SO4, and (c) Na3PO4. The CCC is obtained from these plots as the salt concentration at which z reaches its maximum value, close to 0.6. Reprinted with permission from ref 313. Copyright 2002 Elsevier Ltd.

described by a set of transport equations, also known as Fokker−Planck equations, which take into account particle− substrate surface interactions. During this stage a constant rate of particle deposition is generally observed. In contrast, the later stages of deposition are thought to be governed by desorption, surface heterogeneity, blocking of deposition sites, and excluded area effects. Colloidal forces dominating deposition processes and kinetic processes involved have 405


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Furthermore, the cationic latex-bound cobalt(II) complex of N,N′-ethylenebis(salicylaldimine-5-sodium sulfonate) showed high catalytic activity in the autoxidation of 2,6-dibutylphenol in water in comparison with the conventional polymer-free system.327 Furthermore, the complex was useful in the promotion of nucleophilic displacements of carboxylate anion on alkyl halides in aqueous medium.327 Nevertheless, the colloidal catalyst showed some loss of activity after successive runs, which is probably associated with the coagulation of the latexes used. 3.3.8. Film Formation with Cationic Latexes. The process of transforming a stable dispersion of colloidal particles into a continuous film with the same cohesive strength of the bulk material is complex and is usually described in three sequential steps: drying, particle deformation, and diffusion. Particle coalescence and film formation occur if the drying temperature is above the polymer glass transition (Tg) or if a small amount of coalescing solvent is present.336 Therefore, the physical properties of the film develop after dehydration forces the particles into contact. The particle compaction or deformation step in latex polymer film formation during drying has received continuous theoretical and experimental attention since the seminal work of Bradford and co-workers337,338 in the early 1950s that modeled film formation as a Frenkel viscous flow of contacting polymer spheres under polymer−air and/or polymer−aqueous-phase interfacial tension. Shortly thereafter, Brown339 made compelling arguments that the role of liquid water was not only contributory but also central to the deformation process. The principal force was proposed to be capillary compression (which is proportional to the water−air interfacial tension and inversely proportional to the radius of the spheres) of the particle assemblage with water evaporation, controlled by the latex serum−air surface tension, against the deformation resistance of the polymer characterized by its viscoelasticity. Virtually all work since has comprised attempts to variously refine, extend, verify, or refute Brown’s theory and premises and to propose alternatives, but forces arising from surface energies involving aqueous latex serum persist in the models.340 Vanderhoff et al.,341,342 however, consider that the driving force for coalescence under the limit conditions for film formation is the particle−water interfacial tension. Laplace’s equation is used to show that a pressure gradient exists, which pushes matter from the central part of the particle to the interparticle contact area. This is due to the very small radius of curvature at the edges of the contact zone. The third important theory is one proposed by Sheetz.343 According to this author, a thin layer of coalesced particles is formed closer to the surface of the drying latex. The remaining water evaporates after diffusion through this polymer layer, and the packing of particles is compressed as if by a piston. Capillary forces ensure the coalescence of the surface layer. The results obtained by Dobler et al.344 support Sheetz’s theory of coalescence where deformation of particles is due to compression of the packing of spheres by evaporation of water through a continuous polymer surface layer permeable only to water vapor. In the particle deformation and compaction stage of latex polymer film formation, the principal variables are (i) the polymer composition, (ii) the particle size, (iii) time, and (iv) the water content of the deposited film and in the drying environment. The literature on polymer film formation is extensive, and a recent review summarizes the works on this.345 Also, in this case, the use of cationic latexes is relatively novel. The

when the attractive double layer interaction is diminished due to the salt effect, the attraction is outbalanced by thermal motion and fluid shear. The soft latex, however, can establish a better contact with fibers, and the attraction force over a shorter separation distance resists the hydrodynamic forces. 3.3.7. Cationic Latexes as Catalyst Supports. Catalysts play a major role in many biochemical reactions and industrial processes. To allow continuous operation, an important requirement for industrial processes, many catalysts have been immobilized onto insoluble, often porous, supporting particles. In addition, economics and environmental legislation favor such immobilization. However, the catalytic activity often decreases on immobilization as a result of mass transport limitations. Recently, much attention has been paid to the immobilization of catalysts without the loss of reactivity.325 Polymer colloids (latexes) offer interesting possibilities of combining these two requirements. Obviously, our attention is focused on the use of cationic latexes as catalyst supports. Catalysis can be carried out in or on cationic latexes. In the first case, cationic latexes promote hydrolyses and oxidation of organic compounds in aqueous dispersions by concentrating reactants and catalysis into the small volume of the latex phase and by increasing the intrinsic rate constants.326 However, in the second case, cationic latexes are used as simple supports, which exhibit a high surface area due to the small particle size.104,325,327−329 Polymer colloids were used as catalyst supports for the air oxidations of phenols, mercaptans, and alkyl aromatic hydrocarbons, for various oxidations of alkenes, and for the decarboxylation of 6-nitrobenzisoxazole-1-carboxylate.330,331 Polymer colloids substituted with quaternary ammonium ions are highly active supports for catalysis of reaction of organic compounds when one of the reactants or a catalyst is an anion that binds strongly to the particles.332,333 These swollen cationic latexes are used in aqueous dispersions as supports for o-iodosobenzoate (IBA)-catalyzed hydrolysis of p-nitrophenyl diphenyl phosphate (PNP-DPP), and the highest second-order rate constant exceeded by a factor of about 2 the maximum value reported for IBA in CTAC micelles.334,332,335 All the results obtained in these studies are qualitatively consistent with an ion exchange model of catalysis in which IBA competes with chloride ion and buffer anion for polymer binding sites and the catalysis reaction rates depend primarily on the intrapolymer concentrations of PNP-DPP and IBA catalyst. Also, cationic latexes prepared by emulsifier-free polymerization of styrene and 1-methyl-4-vinylpyridinium bromide (qVPBr) have been used as cocatalysts in the autoxidation of 2mercaptoethanol in the presence of cobalt(II) phthalocyanine tetrasodium sulfonate (CoTSPc). It was found that all systems studied enhanced the catalytic activity compared with the polymer-free CoTSPc-containing system.325 To improve the catalyst activities of CoTSPc on cationic latexes, Twigt et al.104 prepared them by the shot-growth method and using the ionic copolymer poly(styrene-co-1-methyl-4-vinylpyridinium bromide) (PS−qVPBr) as the emulsifier. Effectively, an increase in the cocatalytic activity of these hairy latexes in the CoTSPccatalyzed oxidative coupling of 2-mercaptoethanol was found compared with that of the latex prepared batchwise. Schipper et al.329 found an improved method for the mercaptoethanol autoxidation using cationic latexes with short ionene blocks with seven quaternary ammonium groups at their particle surface. 406


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minimum film formation temperature (MFFT) is a muchemployed technique to investigate latex polymer film formation. MFFT is usually defined as the higher value of the temperature of the transition from a turbid or cracked film to a clear and coherent film. Latex-based formulations that rapidly develop mechanical integrity before appreciable dehydration has occurred are often desirable to prevent flow after application. One way to reduce the flow upon application is to reduce the amount of water in the latex formulation; however, this also increases the viscosity of the formulation, which quickly leads to undesirable rheological properties for the application. Therefore, latex compositions that are stable in storage and rapidly “set” at the appropriate time without the addition of other materials (“single-pot” systems) are desirable to simplify the use of these products. Several methods of decreasing the set time using pH changes have been demonstrated. Rose et al.336 have introduced a controlled ionic coacervation (CIC) process that rapidly forms uniform, gel-like latex films with significant mechanical integrity without loss of water from the film. This process uses latex particles that contain both strong cationic charges and weak protonated acid groups. The coacervation is defined as any progress that causes the particles of a dispersed system to agglomerate in large numbers, which includes precipitation, gelation, flocculation, and coagulation.346 Schmidt et al.347 introduced the concept of a “controlled ionic coacervation” and they defined CIC as “a controlled aggregation of soluble polymer molecules without precipitation to yield clear, rapid-set films”. This concept was extended by Rose et al.336 to latex particles containing both acidic and cationic functionalities, so CIC is a “controlled aggregation of latex particles without coagulation or phase separation”. Ionization of the weak acid groups initiates the CIC process for these latexes. Thus, any latex whose particles have fixed cationic charges and weak acid groups is potentially a “coacervate latex”. After ionization of the acid groups, the coacervating latex rapidly develops mechanical integrity even before significant water loss. Furthermore, during this CIC process and throughout the dehydration process, the latex maintains a homogeneous, opaque, gel-like appearance that, upon drying, yields a clear, uniform film. This was demonstrated experimentally by Rose et al.,336 where the CIC process does not require a water-soluble polymer to obtain the rapid-set film properties. Also, the mechanism for the CIC process is consistent with models for rapid, irreversible, particle−particle aggregation. The self-organization of cationic latex particles on different substrates was reported by Watanabe.348 Annealing at temperature above the Tg of the latex particles enhanced the adhesive strength of particle monolayers.

particles: swelling occurs when the ionic repulsion and the osmotic forces are higher than the attractive forces, i.e., hydrogen bonds and van der Waals and hydrophobic interactions. The multifunctional properties of nanogels can be achieved by altering the cross-linking density, chemical functional groups, and surface-active and stimulus-responsive constituents.350 The ability the nanogels have to undergo large reversible changes in volume make them interesting and suitable materials to be used as carriers for the uptake and release of compounds or other materials. Nanogels exhibit a behavior that goes from a polymeric solution (swell form) to a hard particle (collapsed form). As previously commented, they can be considered stimulus-responsive materials.290 Nanogels can respond to physical stimuli (temperature, ionic strength, magnetic or electric fields, ...), chemical stimuli (pH, ions, specific molecules, ...), and biochemical stimuli (enzymatic substrates, affinity ligands, ...).351 Among them, temperature is most studied because it is an effective stimulus in a number of applications. Nanogels which are able to undergo a volumetric phase change by changing the temperature of the dispersion medium are very interesting in biotechnological applications needing the delivery of an active compound, molecule, or material in media in which the main variable to consider is the temperature (see Figure 30). Another type of sensitivity with

Figure 30. PNIPAM vs PVCL thermosensitive nanogels. Differing phase transitions. Reprinted with permission from ref 363. Copyright 2012 Royal Society of Chemistry.

interest in biomedical applications is the response to pH changes. This is the case for pH-sensitive nanogels (they swell when the pH approximates the pKa of the ionic monomer incorporated by copolymerization in the cross-linked chains constituting the particles); they are useful in the case of releasing a biologically active compound in a physiological medium in which the main characteristic is the change in pH. From the biotechnological application point of view, the interest in nanogel particles comes from their stimulusresponsive nature, i.e, from their ability to suffer reversible phase transitions in response to stimuli or changes in the medium. Moreover, nanogel particles can respond to changes in the medium more quickly than macroscopic gels due to their nanometric small size. The nanogels’ sensitivity to the medium conditions is an advantageous property if the application consists of drug delivery because a response under physiological pH and temperature can be obtained. Nanogels are being proposed as new carriers for the delivery of active ingredients or drugs due to the possibility of encapsulation of those compounds in an aqueous environment and under relatively soft conditions. An ideal nanogel drug delivery carrier should

4. CATIONIC MICRO/NANOGELS Another type of nanoparticle is the microgel or nanogel. Micro/ nanogels are cross-linked colloidal particles which can swell by absorption (uptake) of large amounts of solvent, but they do not dissolve due to the constituent structure of the polymeric network, physically or chemically cross-linked.349 Some authors call them “smart” gels, but their behavior is governed by the solution thermodynamics of the cross-linked polymeric chains. In this way, their “intelligence” is relative, and in general, their behavior (swelling/deswelling) depends on the constituent components and interactions. This behavior is governed by the balance of the attractive and repulsive forces acting in the 407


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considered as an adequate material for the design of biomedical devices and useful in drug delivery systems.363 With respect to pH-sensitive nanogels,364 the choice of polymer depends on the physiological conditions of the target in which the delivery is needed.

have a few common features, including, but not limited to, a smaller particle size (10−200 nm), biodegradability and/or biocompatibility, a prolonged blood circulation time, a higher amount of drug or enzyme loading, and/or entrapment and protection of molecules from the immune system of the body.352 Some of the active components are extremely hydrophobic, without cellular permeability, and susceptible to metabolic degradation; because of this, their use is limited. This type of agent can be transported without any problem through physiological media by using this type of nanoparticle. On the other hand, the size of the particles forming the nanogel is an important parameter because it governs the efficiency of the delivery system. For this type of application, particles having a diameter smaller than 1 μm are especially useful.353 The drugs are taken up into the polymeric nanoparticles by adsorption, absorption or “entrapment”, or covalent bonding, and they are delivered by desorption, diffusion, polymer degradation, or a combination of these mechanisms.354 Different authors indicate that the objectives to reach in the future design and development of delivery systems based on nanogels for in vivo applications require a high degree of control of their properties,355 among them an excellent stability for their circulation in blood, new functionalities for subsequent bioconjugation/biovectorization, nanometric dimensions in diameter, biocompatibility and/or biodegradability for their easy expulsion, and drug sustained delivery. Another objective should be an improvement in the design of nanogels with specific groups which permit a selective absorption into specific cells. Different polymerization methods or techniques in dispersed media are being used for the preparation of nanogels, among them emulsion polymerization, inverse microemulsion polymerization, anionic copolymerization, cross-linking between neighboring chains, and others. At this point it is necessary to comment that some authors prefer to apply the terminology of polymers accepted in IUPAC Recommendations 2011,356 and they use “precipitation polymerization” for the polymerization process used to produce nanogels instead of using “emulsion polymerization” due to the high monomer solubility in water compared to that of the produced polymer. This IUPAC recommendation proposes the use of “precipitation polymerization” for a polymerization in which monomer(s), initiator(s), and colloidal stabilizer(s) are dissolved in a solvent, and this continuous phase is a nonsolvent for the formed polymer beyond a critical molecular weight. Special interest is focused on micro/nanogels based on polymers which have a lower critical solution temperature (LCST) near the physiological temperature. In the case of sensitive polymer-based nanogels, the phase transition of the nanoparticles is observed as a volume phase transition temperature (VPTT). The most frequently used family of polymers in the synthesis of sensitive nanogels is that of temperature-sensitive poly(alkylacrylamides), more specifically PNIPAM. However, its toxicity prevents its use in biomedical applications. Nevertheless, during the past few years a number of papers and patents have appeared on this type of nanogel. Among biocompatible and temperature-sensitive monomers there is N-vinylcaprolactam (VCL), which is a water-soluble monomer.357 The corresponding polymer (poly(N-vinylcaprolactam), PVCL) combines useful and important properties because together with its biocompatibility,358 it has a phase transition in the physiological temperature region (32−38 °C).359−362 This combination of properties allows it to be

4.1. Strategies To Produce Cationic Micro/Nanogels, Characterizations, and Applications

Searching in the databases for the synthesis, characterization, and applications of cationic nanogels led us to a few references on this type of nanogel. Therefore, it can be said that, as in the case of cationic latexes, at the moment they are less studied than anionics. However, they are very useful as drug delivery systems to introduce drugs or biomolecules into cells. As was commented previously, cationic vectors facilitate cellular uptake, and cationic character for the carriers is necessary to cross the cell membrane. On the other hand, by reviewing in detail the literature on cationic micro/nanogels, it seems that, to date, the interest is more focused on the bioapplication than on the synthesis procceses to obtain them. Because of this, in this part, the syntheses, characterizations, and applications of cationic micro/ nanogels are considered together. An exception is made with the part dedicated to the characterization of PNIPAM-based micro/nanogels, which is presented separate from the rest due them being a more studied type of micro/nanogel. 4.1.1. Conventional Production of Micro/Nanogels. 4.1.1.1. PNIPAM-Based Micro/Nanogels. Special attention has been paid to temperature-sensitive aqueous microgels since Pelton and Chibante prepared cross-linked PNIPAM particles in 1986.365 As commented previously, PNIPAM particles exhibit a temperature-induced volume transition. It is generally believed that hydration of the PNIPAM chains originates local ordering in the water molecules around the amide group by means of hydrogen bonding. An increase in temperature, however, increases molecular agitation, which in turn causes a disruption of the H-bonding between water and the amide groups. This leads to a breakdown of local water structure around the PNIPAM chains that triggers hydrophobic attraction among isopropyl groups. This feature causes hydration of polymer chains below the LCST, and consequently, microgel particles are swollen, while above the LCST the particles collapse. The LCST for PNIPAM in water is around 32 °C.366,367 ̈ For many years, the group of Pichot and Elaissari at the CNRS in Lyon, France, has been active in producing and using PNIPAM-containing cationic latexes useful in different bioapplications. Although these nanoparticles are not really nanogels, their works are commented on this part of the review due to the thermosensitive nature of the PNIPAM polymer. They started in 1995 by using cationic PNIPAM-based latex particles for covalent immobilization of oligonucleotide probes,368 followed by an analysis of the particle size and morphology vs polymerization process369 together with a discussion on the surface and colloidal characteristics of cationic amino-containing PNIPAM−styrene copolymer particles.370 The application of amino-containing cationic latexes based on polystyrene and PNIPAM to diagnostic test sensitivity enhancement200 and the use of a hydrophilic and cationic latex based on PNIPAM particles for the specific extraction of nucleic acids371 were reported the following year. Keeping in mind the increasing interest in the application of magnetic particles in the biomedical field, these French authors 408


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positive comonomer together with the N-isopropylacrylamide (NIPAM) in the polymerization reaction,383 as well as a cationic initiator, commonly V-50.368,384,385 A number of techniques have been extensively used to characterize these microgels, including PCS,386 potentiometric titrations,385 differential scanning calorimetry (DSC),386,387 isothermal titration calorimetry,388−391 rheology,392 nuclear magnetic resonance spectroscopy,393 fluorescent probes,394 and scanning transmission X-ray microscopy.395 It is very usual to examine the particle size (particle swelling ratio), electrokinetic properties, and colloidal stability of the cationic PNIPAM microgels as a function of the salinity, temperature, and ionic specificity.396,397 In some cases, a good correlation between the charge of the cationic microgel network and its size is found.398 In a comparison study on anionic and cationic microgels, Lopez-Leon et al.396 found that the main difference is in the electrokinetic behavior of both types of microgels. The electrophoretic mobility of the cationic PNIPAM microgel shows a linear dependence on rh−2 (rh is the hydrodynamic particle radius), whereas two-step linearity is found for the anionic PNIPAM microgel. This is due to differences in the internal structure between both microgel samples.396 For that reason, in a subsequent work, the same authors studied the ionic specificities on the electrokinetic behavior of both negative and positive PNIPAM microgels. The term “Hofmeister effects” 399 is broadly used to refer to ionic specificities in many different physical, chemical, and biological phenomena. More precisely, Hofmeister effects, series, or sequences refer to the relative effectiveness of anions or cations in specifically modifying diverse properties of a wide range of phenomena: cloud points of nonionic surfactants, CMCs, solubilities of salts, surface tensions, pH measurements, ζpotentials, molecular forces, colloidal stabilities, protein solubilities, fluid viscosities, etc. Different authors have studied the Hofmeister effects on the electrokinetic behavior of cationic microgels,397,400,401 on other cationic polymer nanoparticles,402−405 and on an IgG-coated cationic latex.406,407 Two mechanisms underlining Hofmeister effects are the ion accumulation at the particle surface and water structure alterations, and they are present in the behavior of the cationic microgels. Although both mechanisms act together, they exert different effects on the properties of these smart systems. Due to the extraordinary property of solvency of PNIPAM, which manifests polymer as well as hard-sphere behavior, it is possible to investigate both mechanisms independently. Hydrodynamic diameter measurements prove to be sensitive to ionic specificities associated with changes in the structure of the water molecule, while electrophoretic mobility data are related to ionic accumulation exclusion processes. It is quite striking that a concentration of 0.01 mol/dm3 NaSCN is enough to reverse the electrophoretic mobility of the cationic PNIPAM particles.400 Another interesting aspect is the solubility of PNIPAM in alcoholic mixtures. At room temperature PNIPAM is soluble in both water and alcohols with low molecular weight but tends to become insoluble in mixtures of the two solvents at the same temperature.401 This is termed “cononsolvency” and gives rise to a re-entrant-phase diagram; i.e., when the solvent composition is varied systematically, the gel undergoes two transitions: a discontinuous collapse followed by a discontinuous swelling. The re-entrant transition defines a closed-loop instability phase boundary having both upper and lower critical

prepared monodisperse hydrophilic functional magnetic particles also based on PNIPAM.372,373 The adsorption of magnetic iron oxide nanoparticles onto various cationic latexes and the encapsulation of adsorbed iron oxide nanoparticles were analyzed and discussed. The particles were presented as good candidates for solid phases in immunoassays. The presence of a PNIPAM shell should avoid nonspecific immobilization of proteins, and the presence of carboxylic groups provided by the functional monomer (itaconic acid) would allow, after activation, covalent binding of proteins. In 2001, the same group reported the synthesis and properties of functional polystrene−PNIPAM core−shell particles or poly(N-isopropylmethacrylamide) (PNIPMAM) microgel particles together with some biomedical applications (enhancing the sensitivity of genetic tests, for the concentration of proteins or nucleic acids, among others) of these stimulusresponsive particles.374 Focusing their interest on core−shell latex particles, the adsorption/desorption behavior and covalent grafting of an antibody onto cationic amino-functionalized poly(styrene−N-isopropylacrylamide) core−shell latex particles was investigated as a function of the temperature, pH, and salinity.375 The synthesis of cationic poly(MMA)−PNIPAM core−shell latexes prepared by a two-stage emulsion copolymerization was also analyzed in terms of the influence of the cross-linker (N,N′-methylenebisacrylamide, MBA) and comonomer (AEMH) concentrations on the thickness and swelling capacity of the PNIPAM-based shell layer.376 Another active group working on cationic nanogels based on PNIPAM is that of Kokufuta at the Graduate School of Life and Environmental Sciences, University of Tsukuba, Japan. In 2006 they published a work on light scattering studies of polyelectrolyte complex formation between anionic and cationic nanogels in an aqueous salt-free system,377 followed by a study by dynamic and static light scattering of the geometrical characteristics of polyelectrolyte nanogel particles and their polyelectrolyte complexes378 and a paper on the electrochemically induced aggregation of intraparticle cationic nanogel complexes with a stoichiometric amount of bound polyanions.379 In these studies PNIPAM-based anionic, cationic, and neutral nanogels were used. More recently, the same group analyzed the water dispersibility of complexes formed between cationic polyelectrolyte nanogels and anionic polyions and their complexation by conductometric and light scattering studies, respectively.380,381 In addition, Hu et al.382 published the synthesis and physicochemical properties of cationic microgels based on PNIPMAM. Microgels were synthesized by surfactant-free radical precipitation polymerization of NIPMAM and the cationic comonomer N-(3-aminopropyl)methacrylate hydrochloride (APMH). The resultant amine-laden microgels show the expected swelling properties of thermoresponsive cationic microgels as a function of temperature, pH, and ionic strength, as well as reactivity in standard amine bond-forming reactions. Characterization of PNIPAM-Based Micro/Nanogels. There are numerous papers which refer to the characterization of anionic PNIPAM particles. Characterization can involve gel structure, swelling, surface activity, rheology, electrical properties, colloidal stability, and interactions with other molecules (surfactants, drugs, proteins, etc.). Characterization of cationic PNIPAM microgels, however, is not so usual in the literature, as these types of particles have appeared in the past decade. Cationic PNIPAM microgels are usually obtained by adding a 409


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points.408 One of them was realized by changing the composition of the solvent (water−methanol mixture) and the other by applying the osmotic pressure to a gel network, which was generated by adding large molecules to the outer solution.409 PNIPAM cononsolvency in water−alcohol mixtures has been extensively studied with microgels and chains adsorbed onto latex particles.408−411 Despite the number of works published on this subject, the molecular origin of this phenomenon is still controversial. Nowadays, there are three explanations for the PNIPAM cononsolvency in alcohol−water mixtures: (1) The earliest and most widespread interpretation involves complexation between the two solvents. Calculations based on the Flory−Huggins thermodynamic theory suggest that the re-entrant behavior results from the perturbation of the alcohol−water interaction parameter (χ12) in the presence of PNIPAM. Consequently, the formation of alcohol−water complexes would be dominant over the hydrogen bonds between PNIPAM and water.408,409,412 This model, however, has problems explaining why cononsolvency is also observed in highly dilute PNIPAM solutions where the effect of the polymer on the solution properties should be negligible. (2) Schild et al.413 suggested that any mechanism to explain the re-entrant transition must involve local solvent− polymer interactions. Such a collapse transition mechanism based on local concentration fluctuations was previously proposed by de Gennes414 and would require the preferential adsorption of alcohol on PNIPAM. The validity of this theory for these phenomena remains to be experimentally confirmed. (3) Recently, Tanaka et al.415 have proposed a third alternative according to which cononsolvency results from the competition between PNIPAM−water and PNIPAM−alcohol hydrogen bonding and a cooperative solvation mechanism. Their results, however, contrast with other experimental findings that argue for a reentrant transition fully controlled by the water−alcohol complexation.416,417 The exact nature of the PNIPAM cononsolvency in alcoholic solutions thus remains an open question. In summary, we can conclude that the cononsolvency phenomenon observed for PNIPAM chains in alcohol−water mixtures therefore involves an intricate balance between the attractive and the repulsive components of several different types of forces. Also in this case the cationic systems look to have a behavior different from that shown by anionic systems. A comparison study was accomplished by Mielke and Zimehl418 on the behavior of negatively and positively charged PNIPAM particles in alcohol−water mixtures at a temperature (20 °C) below their phase transition (∼32 °C). Methanol, ethanol, 1propanol, and 2-propanol were used between 0 and 100 wt %. In general, the results obtained by these authors with anionic PNIPAM showed a minimum in particle diameter between alcohol concentrations of 20 and 40 wt %. At low alcohol fractions deswelling of the anionic PNIPAM particles can always be observed. Alcohol weight fractions larger than approximately 80% cause the microgel particles to take up liquid in excess: the microgel particles swell considerably. The general trend did not appear to be altered using alcohols of greater chain length. On the other hand, for cationic PNIPAM particles, the above-mentioned behavior can only be observed

in methanol. For ethanol−water mixtures the change in diameter of these particles showed a slight maximum at 20 wt %. This maximum (swelling effect) increases for 1-propanol and is even more pronounced for 2-propanol. Clearly, in an alcohol of higher chain length the properties of cationic PNIPAM show reverse behavior of the anionic PNIPAM. At alcohol contents above 50 wt % the cationic microgel deswells. Thus, in these alcohol−water mixtures containing low weight fractions of alcohol (ethanol, 1-propanol, and 2-propanol) anionic and cationic PNIPAM particles exhibit the opposite swelling and shrinking behavior at 20 °C. This reverse behavior of crude cationic PNIPAM particles in alcohols with two or more CH3 groups can be explained by specific alcohol adsorption, which produces swelling of the PNIPAM even at very low alcohol contents. Cononsolvency cannot take place. At slightly greater alcohol fractions (above 40 wt %), free alcohol molecules appear in solution competing for water. In this case, deswelling occurs. The behaviors of cationic and anionic microgel particles are then similar in nature. At a temperature (40 °C) above their phase transition, the cationic PNIPAM particles behave similarly to those at 20 °C. Moreover, very recently, López-León et al.401 have studied the effect of salt on the cationic PNIPAM cononsolvency in water−ethanol mixtures. The results obtained with NaSCN are especially interesting. SCN− has a strong chaotropic character; i.e., this ion interacts with water weaker than water with itself (structure-breaker). The effect of ions in the cononsolvency of PNIPAM microgels depends obviously on the molar fraction of the alcohol in the binary mixtures. In the intermediate region of ethanol volume fractions, as the concentration of this ion was increased, the PNIPAM solvation was first controlled by polymer−water interactions and second by polymer−ethanol interactions. The ethanol−water mixtures have also been used to prepare novel cationic pH-responsive poly((N,N′-dimethylamino)ethyl methacrylate) microgels. In this case, the maximum ratio of volume change of the prepared microgels in response to pH variation was more than 11-fold.419 The following components have been adsorbed onto a cationic microgel: (1) Magnetic particles.372,373 (2) Proteins.420,421 (3) Heavy metals.422 (4) Surfactants.423 In general, the microgel particles can be envisaged as spongelike materials having a spherical conformation consisting of numerous interstitial spaces where these compounds can be adsorbed. 4.1.1.2. PDMAEMA and PDEAEMA-Based Micro/Nanogels. Poly(2-(N,N′-dimethylamino)ethyl methacrylate) (PDMAEMA) and poly(2-(N,N′-diethylamino)ethyl methacrylate) (PDEAEMA) are pH-, temperature-, and ionic strengthresponsive polymers with interesting and potential uses in biomedical applications due to these sensitive properties. The group of Nagasaki at the Department of Material Science & Technology at the Tokyo University of Science, Japan, has been very active in synthesizing different DMAEMAbased nanogels. In 2004, using DMAEMA with ethylene glycol dimethacrylate as the cross-linking agent and α-(vinylbenzyl)ω-carboxy-PEG as the stabilizer, they reported the synthesis via emulsion polymerization of pH-sensitive DMAEMA-based nanogels with controllable diameters in the range of 50−680 410


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Figure 31. Schematic illustration of the pH-responsive PEGylated nanogel and endosomal escape mechanism. Reprinted with permission from ref 429. Copyright 2007 Springer-Verlag.

nm.424 These nanogels have a PEG shell layer with a carboxyl acid group at the distal end of each PEG strand confirmed by ζpotential measurements at varying pH values. This location could be an available conjugation site of various ligands. These features indicate the potential utility of these nanogels in applications such as diagnostics and controlled drug-releasing devices. Taking into account that PEGylated nanogels show unique properties and functions in synchronizing with the reversible volume phase transition of PDEAEMA in response to various stimuli, such as pH, ionic strength, and temperature, the same group proposed the synthesis and characterization of stimulusresponsive PEGylated nanogels composed of a cross-linked PDEAEMA core and PEG-tethered chain that bear a carboxylic acid group as a platform moiety for the installation of biotags.425 Some of the potential biotechnological applications of the nanogels are listed, among them, as endosomolytic agents for nonviral gene delivery, drug delivery carriers, nanoreactors, and skin-specific nanocatalysts for reactive oxygen species (ROS), thermosensitive drug and gene carriers, and ion sensors. The loading of the anticancer drug doxorubicin (DOX) was carried out in the pH-sensitive PEGylated nanogels based also on DMAEMA and prepared by emulsion polymerization having biheterofunctional PEG as in the first work presented in 2004.426 The loading by solvent evaporation method yielded 26% DOX in the PDMAEMA core. The DOX-loaded, pHsensitive PEGylated nanogel showed almost no initial burst release of DOX under physiological pH, whereas significant release of DOX was observed at endosomal pH. The antitumor activity of the loaded nanogels against a human breast cancer

cell line and a human hepatoma cell line, which is a natural drug-resistant tumor line, was analyzed, showing that the new nanogels have higher antitumor activity than both free DOX and the DOX-loaded, pH-insensitive, PEGylated nanogels. These findings suggest that these nanogels are promising nanosized carriers for anticancer drug delivery systems in vivo. The same group reported the synthesis of pH-responsive PEGylated nanogel platinum particles, which can be utilized in skin-specific ROS scavengers for skin aging,427 by using similar PDMAEMA-based nanogels. Platinum nanoparticles with a size of less than 2 nm were synthesized through the reduction of K2PtCl6 within the PEGylated nanogels. The resulting nanogels showed significant catalytic activity for ROS in response to the skin environmental pH (acidic), whereas almost no catalytic activity for ROS was observed at physiological pH due to the VPTT of the PDMAEMA core. Similar PEGylated nanogels based on PDMAEMA-containing gold nanoparticles were synthesized through the autoreduction of HAuCl4, which gives an average number of 10 Au nanoparticles per nanogel particle having a 6 nm diameter.428 The surface plasmon band of the Au nanoparticles containing nanogels was shifted in response to the pH, indicating that the cross-linked PDMAEMA core of the nanogels acts not only as a nanoreactor but also as a pH-sensitive matrix. Another bioapplication was reported with these pHresponsive PEGylated PDMAEMA-based nanogels consisting of their use as targetable and low invasive endosomolytic agents to induce the enhanced transfection efficiency of nonviral gene vectors.429 Polyplexes composed of PEG-block-poly(L-lysine) copolymer and plasmid DNA exhibited a far more efficient 411


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transfection ability in the presence of the nanogels without any cytotoxicity (see Figure 31). In 2009, the group of Nagasaki published the enhanced cytoplasmic delivery of small interfering RNA (siRNA) using a stabilized polyion complex based on PEGylated nanogels with cross-linked PDMAEMA-based structure.430 The nanogel− siRNA complex was observed to undergo a remarkable enhancement of the gene-silencing activity against a firefly luciferase gene expressed in HUH-7 cells. By using confocal fluorescence microscopy, they demonstrated an efficient endosomal escape capability for the transportation of siRNAs into the cytoplasm, probably due to the buffering effect of the PDMAEMA core, showing the potential of these nanogels to be effective siRNA carriers for the development of in vivo therapeutic applications of siRNA (see Figure 32).

Figure 33. SEM micrographs of different PDEAEMA-g-PEG nanogels. Reprinted with permission from ref 432. Copyright 2010 Elsevier Ltd. Figure 32. Schematic illustration of the nanogel−siRNA polyion complex. Reprinted from ref 430. Copyright 2009 American Chemical Society.

Cationic nanogels based on PEGylated PDMAEMA (PEG− PDMAEMA) with potential application in gene delivery were synthesized via the in situ formation of micelles by an amphiphilic trithiocarbonate macro-RAFT agent by Yan and Tao436 by a one-step surfactant-free RAFT process. Nanogel particles of about 20 nm and +30 eV ζ-potential, which are a potential gene delivery system for further biomedical applications, were synthesized. In the second work, new thermoresponsive and aciddegradable poly(methoxydiethylene glycol methacrylate (MeODEGM)−2-aminoethyl methacrylamide hydrochloride (AEMA))-based nanogels via RAFT polymerization using poly([2-(methacryloyloxy)ethyl]phosphorylcholine (MPC)) macro-RAFT agent were synthesized.437 The sizes of these nanogels can be tuned by varying the amount of cross-linker and MeODEGM chain length. AEMA provides the cationic character to the nanogel core, which facilitates the encapsulation of oppositely charged proteins (insulin, BSA, and βgalactosidase). The loading efficiency of these proteins depends on the pore size of the nanogels, the cationic component, and the size of the protein. Degradation and controlled release profiles were analyzed, concluding the existence of promising applications of these nanogels for targeted drug delivery systems and controlled release (see Figure 34). 4.1.1.4. Micro/Nanogels Based on Miscellaneous Monomers. Polyampholyte cationic gel particles were synthesized by aqueous redox polymerization in the presence of sodium dodecylbenzenesulfonate as the surfactant using 1-vinylimidazole as the cationic monomer, incorporated into the network of NIPAM cross-linked with MBA. A detailed comparison of experimental mobilities with theoretical calculations was made in terms of three different models.438 The same group439 studied the formation of intra-interparticle polyelectrolyte complexes between cationic nanogels and a strong polyanion, potassium poly(vinyl alcohol) sulfate (KPVS), demonstrating that the cationic nanogels form

Thermoresponsive cationic nanogels based on NIPAM, DMAEMA, and quaternary alkylammonium halide salts of DMAEMA were synthesized by dispersion polymerization.431 The thermoresponsive characteristics of the nanogels and polyplexes obtained by complexation of these nanogels with salmon sperm DNA were analyzed, and the results demonstrated that these nanogels, with controllable responsive properties determined by the nature of the cationic charge incorporated, may have potential as vehicles for DNA delivery. Recently, Marek et al.432 reported the synthesis of cationic nanogels based on DMAEMA by a new inversion emulsion (water-in-oil) polymerization method. Nanogels of PDEAEMA and polyethylene glycol-n monomethyl ether monomethacrylate (P(DEAEMA-g-EGn)) were synthesized. The effects of this novel nanoparticle synthesis route of PDEAEMA on several polymer properties, including surface charge and swelling response, together with the effects of the cross-linking ratio and PEG tether length on the physical properties were also examined. The network morphology was also studied, and the potential for these systems to be used as drug delivery agents was evaluated (see Figure 33). 4.1.1.3. Use of Living Radical Polymerizations To Synthesize Cationic Micro/Nanogels. As can be seen in the different works reviewed, generally, the synthesis of nanogels is carried out in diluted monomer solutions or in heterogeneous media, such as a microemulsion or emulsion, under the assistance of a surfactant. Living radical polymerizations such as atom transfer radical polymerization (ATRP),433 nitroxide-mediated polymerization (NMP),434 and reversible addition−fragmentation transfer (RAFT)435 have also been used for the synthesis of a small amount of nanogels. As examples, the following two works are briefly discussed. 412


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Figure 34. Core cross-linked micelles with thermoresponsive and degradable cores. Reprinted from ref 437. Copyright 2011 American Chemical Society.

Figure 35. Schematic diagrams for (a) the release of PrHy-loaded nanogel under different pH values and (b) the release of IMI-loaded nanogel under different pH values. Reprinted with permission from ref 443. Copyright 2007 Elsevier Ltd.

junctions. As the name implies, the BBB serves as a barrier that prevents the passage of cells and proteins, including therapeutic agents, present in the bloodstream from gaining access to the central nervous system (CNS). They developed nanoparticles, including dendritic nanoparticles, cationic f″cyclodextrin, and polysaccharide-based nanogels, for controlled drug delivery across the BBB. The permeability of the nanoparticles with/without model protein drugs, BSA and nerve growth factor (NGF), through a bovine retina endothelial cell (BREC) monolayer, an in vitro BBB model, was investigated. The authors’ hope is that their work will have a significant impact on the treatment of neurological disorders in the brain. Sahiner et al. reported the synthesis and characterization of microgel, nanogel, and hydrogel−hydrogel semi-interpenetrating polymer network (semi-IPN) composites for biomedical applications.441 In this work, quaternary ammonium salt hydrogels from a cationic monomer, (3-acryamidopropyl)trimethylammonium chloride ((APTMA)Cl), in a variety of sizes such as bulk, micro, and nano, are synthesized by water-inoil microemulsions using lecitin and dioctyl sulfosuccinate sodium salt (AOT). Hydrogel−hydrogel composite semi-IPNs were synthesized by dispersing previously prepared micro/

polyelectrolyte complexes with the strong polyanion in the aqueous KCl-free and KCl-containing systems and dividing the resulting complexes into two types: intra- and intercomplex colloid systems in which the complex formation takes place with bound KPVS and through electrostatic forces, respectively. In the same year, 2005, during the AIChE Annual Meeting Conference, Nichenametla et al.440 presented the work “Novel nanoparticles for controlled drug delivery across the bloodbrain barrier”, analyzing some interesting aspects, including the following: the cost of developing an average new therapeutic agent, which is approximately $150 million. However, the use of these therapeutic agents is frequently still hampered by the lack of an effective route and mode of delivery. The reasons for this reduced efficacy are that many of these therapeutic agents, especially therapeutic proteins and peptides, have very short half-lives, do not cross biological barriers, and are metabolized at other tissue sites. Therefore, improving the effectiveness of therapeutic agents by optimizing their delivery and dosage and minimizing side effects may be a better investment and more beneficial to patients than creating entirely new pharmaceuticals. The blood−brain barrier (BBB) is a dynamic and complex structure composed principally of specialized capillary endothelial cells held together by highly restrictive tight 413


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polyelectrolyte components. The results indicated that the whole and a part (segment) of the complexed polyanions undergo dissociation−association reactions on the surface of a SPENC particle, depending on the ionization state of the cationic gel component. These reactions seem to be a key factor for the water dispersibility of the SPENC. The second work was focused on understanding the water dispersibility of their stoichiometric nanogel complex having a core−shell or corona structure in terms of its uptake of counterions by conductometric and light scattering studies. For finishing with this part devoted to synthetic micro/ nanogels, it is interesting to comment that a very recent work on self-assembly of biodegradable polyurethanes445 declares that the use of these materials in controlled drug delivery applications constitutes an important area of research for the development of polymeric materials in biomedicine. In particular, colloidal polyurethane assemblies can increase the solubility and stability of hydrophobic compounds and improve the specificity and efficiency of drug action. Their nanoscale size and modular functionality make them promising for the injectable, targeted, and controlled delivery of various therapeutic agents and imaging probes into required cells. Additionally, cationic polyurethanes are able to self-assemble with nucleic acids into nanoparticles to enter cells for efficient gene transfection. These emerging nanocarriers open the door for addressing the failure of traditional localized delivery systems and present a compelling future opportunity to achieve personalized therapy as versatile candidates. This review paper highlights the research progress in the self-assembly of biodegradable polyurethanes for controlled delivery applications, with particular attention being paid to some representative vehicles such as self-assembled polyurethane micelles, nanogels, and polyurethane−DNA complexes, which have emerged as the focus of interest in recent years. 4.1.2. Nonconventional Production of Micro/Nanogels. 4.1.2.1. PEI-Based Micro/Nanogels. PEI is a well-known cationic polymer that has previously been shown to have significant potential to deliver genes in vitro and in vivo. PEI is widely used to prepare different nanogels useful for nonviral gene delivery strategies. PEI is employed as a DNA-compacting molecule because of high cationic charge and high transfection efficiency. Upon contact with DNA, PEI condenses bulky DNA into a nanosized complex ranging from 50 to 200 nm by ionic interactions between amine groups in PEI and phosphate groups in the DNA backbone. The group of Vinogradov at the Center for Drug Delivery and Nanomedicine in Nebraska, published in 2005 two papers446,447 on polyplex PEI-based nanogel formulations for drug delivery of cytotoxic nucleoside analogues and the role of the cellular membrane in drug release. The data demonstrate that the carrier-based approach presented for delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects usually observed in cancer chemotherapy. On the other hand, cationic nanogels synthesized can encapsulate large amounts of nucleoside analogues. The complexes were evaluated as potential cytotoxic drug formulations for breast carcinoma cells. A substantial release of encapsulated drug was observed following interactions of drug-loaded nanogels with cellular membranes (see Figure 36). In 2006, Xu et al.,448 keeping in mind the idea that cationic polymer nanogels, positively charged submicrometer polymeric particles that swell in water, have attracted increasing research attention in recent years because of their potential applications

nanogels into neutral monomers such as AAm or 2hydroxyethyl methacrylate (HEMA) before network formation. Hydrogel swelling and pH response behaviors were investigated for bulk gels. Using TEM, SEM, and AFM the morphology, structure, and size of nanomaterials, micromaterials, and bulk materials were analyzed. It was confirmed by gel electrophoresis that a completely charged nanogel forms a strong complex with DNA. At the previously cited 55th Society of Polymer Science Japan Annual Meeting in Nagoya (2006), the design of a core− shell-type nanogel for high-performance bionanospheres was presented.442 The lactose-installed core−shell-type nanogels were prepared via emulsion copolymerization of DEAEMA with CH2CHPhCH2-PEG−lactose in the presence of crosslinking agent in an aqueous medium. The core of the obtained nanogels showed a drastic volume phase transition in the pH region at around 7. The cytotoxicity of the obtained nanogels decreased with increasing chain length of the PEG on the nanogel surface. The longer PEG chain improved the compartmentalization of the PDEAEMA gel core to prevent exposure of the cationic charge to the outside. Notably, the cytotoxicity of the nanogel did not change regardless of the lactose installation on the surface. Cellular uptake of Texas Red labeled dextran in HuH7 cells was increased in the presence of the lactose-installed nanogel, but not in the presence of that without a lactose moiety at the PEG chain end. Taking into account that delivery systems based on pHresponsive nanoparticles can control the release of rapidly metabolized drugs and/or have the ability to protect sensitive drugs, Tan et al.443 presented comparative drug release studies of two cationic drugs from pH-responsive nanogels. These nanogels consisted of methacrylic acid−ethyl acrylate (MAA− EA) cross-linked with diallyl phtalate (DAP) and were synthesized by emulsion polymerization. The release of two different drugs (procaine hydrochloride (PrHy) and imipramine hydrochloride) loaded via two distinctly different interaction forces (hydrophobically bound and electrostatically bound enhanced by hydrogen bonding, respectively) was analyzed under different pH values, MAA−EA molar ratios, and DAP contents by using a drug-selective electrode (DSE) to measure the concentrations released from the MAA−AE nanogels (see Figure 35). The same group proposed the following year (2008) how to avoid and control the undesirable burst release phenomenon commonly encountered in nanostructured delivery systems.444 For that, the layer-by-layer assembly technique was proposed. Drug (PrHy)-loaded MAA−EA-based nanogels of sizes smaller than 200 nm were coated with alternating layers of poly(allylamine hydrochloride) (PAH; catonic) and poly(sodium 4styrenesulfonate) (PSS; anionic) polyelectrolytes. With every layer of polyelectrolyte, the radius increased by 2 nm, and the ζpotential alternated between positive and negative values. PSScoated nanogels were stable at all pH values, while PAH-coated nanogels were stable up to pH 8. By using a DSE, the concentration of PrHy released was measured. The high burst release was reduced or minimized when the number of layers of polyelectrolyte was increased. Recently, Kokufuta and Doi380,381 reported a study on the water dispersibility of a 1/1 stoichiometric complex between a cationic nanogel and linear polyanion (SPENC) composed of a cross-linked (using MBA as the cross-linker) copolymer of 1vinylimidazole and NIPAM and discussed in terms of the association−dissociation reactions between both of the 414


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In 2007, the same group reported a work on formulations of biodegradable nanogel carriers with NTPs of nucleoside analogues that display a reduced cytotoxicity and enhanced drug activity. Nanogels were synthesized by using two methods proposed by the same group: the emulsification−evaporation method447 and the micellar approach.449 PEI-based biodegradable nanogels were synthesized by the same methods but using biodegradable PEI. The results show that the toxicity of nanogels was clearly dependent on the total positive charge of carriers and was 5−6-fold lower for carriers loaded with NTP. The toxicity of drug-loaded nanogels focusing on respiratory chain components of cells was evaluated and compared with cell viability assays for drug or drug formulations. Vinogradov et al.450 also presented in 2010 the use of nanogel−nucleoside 5′triphosphate formulations for the treatment of drug-resistant tumors (see Figure 38). Lee and Yoo451 prepared the so-called DNA nanogels by chemically conjugating Pluronic (to be defined later) to the surface of a PEI−DNA complex to prepare thermoresponsive nanogels with endosomal disrupting abilities. The sizes and ζpotentials of these nanogels changed significantly when the temperature was increased from 20 to 37 °C. The cytotoxicity and transfection efficiency of the nanogel were also affected by temperature changes. The results indicate that surface modification of nanogels can be potentially applied to thermoresponsive gene carriers, where temperature-responsive cytotoxicities or transfection efficiencies are required (see Figure 39). Delivery of synthetic siRNA remains the major obstacle to the therapeutic application of RNA interference. To overcome this problem, PEI is also useful as reported by Laisheng et al.452 In this work, the synthesis and characterization of PEI− polyethylene glycol diacrylate nanogel useful as an siRNA carrier is reported. A new nanogel composed of hydrophilic polyethylene glycol and cationic polyethylenimine for siRNA delivery was synthesized via inverse microemulsion polymerization and characterized. Such a noncytotoxic nanogel is suitable for siRNA loading by electrostatic interaction. The siRNA delivery efficiency of the nanogel was evaluated, and the results indicated that the nanogel induced a high gene-silencing effect. With the proper particle size, a strong siRNA binding ability, and an efficient gene-silencing function, this nanogel− siRNA formulation has potential for efficient siRNA delivery in therapeutical application. Wei and co-workers synthesized PEI-based nanogels for the delivery of specific genes to inhibit cell proliferation in colon carcinoma453 and antitumoral efficacy in lung metastasis.454 Heparin−PEI (HPEI) nanogels were prepared through amide bond heparin-conjugated PEI molecules and used as a nonviral gene vector. HPEI−selected gene complexes were formed in each different case. Efficient growth inhibition of ovarian cancer

Figure 36. Cellular trafficking of drug-loaded nanogels analyzed by confocal microscopy in MCF-7 cells after 30 min of incubation (A, D), 60 min of incubation (B, E), and 120 min of incubation (C,F) with NG(PEG) (A−C) or NG(P85) (D−F) at concentrations of 0.01 mg/ mL NG(PEG) or 0.005 mg/mL NG(P85). Rhodamine-labeled nanogels (red) contained encapsulated BODIPY FL ATP (green). Pictures are superimposed bright field and fluorescence images at 100× magnification. Reprinted from ref 446. Copyright 2005 American Chemical Society.

as gene carriers, presented the synthesis via photochemistry in surfactant-free aqueous solution of novel PEI nanogels to be used as potential gene carriers. In this work, a novel method to synthesize PEI nanogels with sizes ranging from 80 to 200 nm via UV irradiation at room temperature in aqueous solution without addition of any kind of surfactant is presented. The morphology of the nanoparticles is determined to be spherical. The nanogels are of high stability, high transfection efficiency, low toxicity, and low immunogenicity, as has been confirmed by in vivo tests with mice as an animal model and by in vitro tests with human lung and liver cancer cells as well. In 2006, Vinogradov et al.449 presented the synthesis and characterization of new cationic nanogels composed of amphiphilic polymers and cationic PEI for encapsulation and delivery of cytotoxic nucleoside analogues 5′-triphosphates (NTPs) into cancer cells. Nanogels were synthesized by a novel micellar approach and compared with carriers prepared by the emulsification/evaporation method. Complexes of nanogels with NTP were prepared; the particle size and in vitro drug release were characterized. Resistance of the nanogelencapsulated NTP to enzymatic hydrolysis was analyzed by ion pair high-performance liquid chromatography (HPLC). Binding to isolated cellular membranes, cellular accumulation, and cytotoxicity were compared using some breast carcinoma cell lines (see Figure 37). In vivo biodistribution of labeled NTP encapsulated in different nanogels was evaluated in comparison to that of the injected NTP alone. The results show that formulations of nucleoside analogues in active NTP form with these nanogels will improve the delivery of these cytotoxic drugs to cancer cells and the therapeutic potential of this anticancer chemotherapy.

Figure 37. Nanogel synthesis using the micellar approach. Activated Pluronic block copolymers (A) formed micelles (B) in aqueous solutions, which could be covered with a layer of PEI (C) cross-linked by activated PEG molecules (D). Reprinted with permission from ref 449. Copyright 2006 Springer Science + Business Media, Inc. 415


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Figure 38. A cationic network of the nanogel decorated with multiple small-tumor-specific peptide ligands is capable of attracting oppositely charged triphosphate drug molecules from aqueous solution and binding them with the formation of compact drug nanoformulations for systemic administration. Reprinted with permission from ref 450. Copyright 2010 Elsevier Ltd.

Figure 39. Intracellular delivery of a polycation−DNA complex modified with Pluronic: (A) non-cold-shock treatment (only proton sponge effects); (B) cold-shock treatment (proton sponge effect plus disruption by extended Pluronic). Reprinted with permission from ref 451. Copyright 2008 Elsevier Ltd.

is also reported455,456 in which the tumor weight decreased by almost 72% and 87% in the treatment group compared with that in the empty-vector control group. Meanwhile, decreased cell proliferation, increased tumor cell apoptosis, and reduction in angiogenesis were observed compared with those in the control groups. All these results indicated that HPEI nanogels delivering specific genes inhibiting tumor growth might be of value in the treatment against human colon, lung, and ovarian cancers (see Figure 40). Wei et al.457 also published the use of HPEI nanogels for in vivo pulmonary metastasis therapy. Taking into account first that the clinical application for systemic administration of adenoviral (Ad) vectors is limited, as these vectors do not efficiently penetrate solid tumor masses, and second that PEI is nondegradable and exhibits a high cytotoxicity as its molecular weight increases, low molecular weight PEI (Mn = 1800) was conjugated to heparin (Mn = 4000−6000) to produce a new type of cationic degradable nanogel (HPEI), which was then used to modify Ad vectors. The resulting HPEI−Ad complexes

Figure 40. Preparation scheme of the heparin−PEI nanogel. Reprinted with permission from ref 454. Copyright 2011 Wiley Periodicals, Inc.

were used to infect CT26 and HeLa cells in vitro. Additionally, the HPEI−Ad complexes were administrated in vivo via 416


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Figure 41. Formation of FA-CS-PF127 (folate-mediated chondroitin sulfate-decorated Pluronic) nanogels. Reprinted with permission from ref 462. Copyright 2009 Elsevier Ltd.

to inhibiting drug efflux transporters, such as P-glycoprotein (Pgp). Pluronic has been widely applied also to drug delivery for its unique thermosensitive gelation property. Above the LCST, it forms physical gels by a hydrophobic interaction between hydrophobized PPO blocks. Many studies have employed this thermogelation property to control the release of many bioactive molecules in response to temperature modulations. Among those, Pluronic was conjugated to PEI to prepare thermosensitive gene carriers in an aim to modulate transfection efficiencies according to temperature changes.461 Wang and co-workers used Puronic F127, one of the polymers that can inhibit drug efflux transporters in cancer therapy, to produce amphiphilic nanocarriers for DOX.462 Folate-mediated chondroitin sulfate-decorated Pluronic nanogels via a simple free radical reaction were synthesized, and a further grafting of a tumor-targeting moiety onto the exterior shell was prepared. The loading efficiency and release behavior of DOX and the cellular uptake of the nanogels in cells were analyzed (see Figure 41). 4.1.2.3. Cationic Micro/Nanogels for DNA and siRNA Delivery. In the context of gene therapy, several colloidal drug carriers have been proposed to improve nucleic acid tumor localization and bioavailability, while reducing toxicity. McAllister et al.463 produced via inverse microemulsion polymerization nanogels for cellular gene and antisense delivery. Monodisperse anionic and cationic nanogels were produced with controllable sizes ranging from 40 to 200 nm in diameter by using (2-acryloxyethyl)trimethylammonium chloride (AETMAC), 2-hydroxyethyl acrylate (HEA), and polyethylene glycol diacrylate (PEGdiA). The polymeric and colloidal characterizations, cell viability, uptake, and physical

intravenous injection, and tissue distribution was assessed using luciferase assays; the therapeutic potential of HPEI−Ad complexes for pulmonary metastasis mediated by CT26 cells was also investigated. In vitro, HPEI−Ad complexes enhanced the transfection efficiency in CT26 cells, reaching 36.3% compared with 0.1% for the native adenovirus. In vivo, HPEI− Ad complexes exhibited greater affinity for lung tissue than the native adenovirus and effectively inhibited the growth of pulmonary metastases mediated by CT26 cells. The results indicate that Ad vectors modified by HPEI nanogels to form HPEI−Ad complexes enhanced transfection efficiency in CT26 cells, targeted to the lung, and demostrated a potential therapy for pulmonary metastasis. 4.1.2.2. Pluronic-Based Micro/Nanogels. Besides the work of Lee and Yoo previously cited,451 there are some others focusing on the use of Pluronics to synthesize nanogels. Pluronic is a triblock copolymer composed of poly(ethylene oxide) (PEO)−poly(propylene oxide) (PPO)−PEO. Pluronic copolymers have been extensively explored for controlled drug delivery applications, especially in a form of micelles. The hydrophobic PPO segments comprise a hydrophobic core, which is a microenvironment for the incorporation of lipophilic drugs. The hydrophilic PEO corona prevents aggregation, protein adsorption, and recognition by the reticuloendothelial system (RES).458 Low cytotoxicity and weak immunogenicity give Pluronic copolymers the possibility of topical and systemic administrations.459 Pluronic copolymers have been studied to promote active membrane transport of numerous anticancer drugs because they can overcome the multidrug resistance (MDR) effect. The complex mechanisms of Pluronic effects in MDR cells were throroughly reviewed460 and mainly attributed 417


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This research group presented in the same symposium two more studies. One study was on the characteristics of nanogel−DNA complexes for gene carriers,466 reporting that nanogels were formed by the self-assembly of CHPs. They synthesized various cationic groups bearing CHPs. (Diethylamino)ethyl (DEAE), (ethylamino)ethyl (EEAE), and spermine groups were selected. In this study, they investigated the interaction between cationic CHP nanogel−plasmid DNA complexes and cells. They selected the plasmid DNA to express the green fluorescent protein (GFP) in mammalian cells for use as a transfection marker. The cells that were incubated with cationic CHP nanogel−plasmid DNA complexes expressed GFP. The results indicate that CHP−spermine nanogel acts as efficient DNA carriers compared with CHP−DEAE and CHP−EEAE. They also presented another study dealing with the characteristics of nanogel−DNA complexes.467 In this work, nanogels were also produced by the self-assembly of CHPs. In this case, CHP-NH2 was synthesized and CHP-NH2 formed monodisperse cationic nanogels (∼20 nm) in water. CHP-NH2 nanogels formed complexes with DNAs. The interaction between CHP-NH2 nanogel−plasmid DNA complexes and cells was studied. They selected the plasmid DNA to express the GFP in mammalian cells for use as a transfection marker. The cells that were incubated with CHP-NH2 nanogel−plasmid DNA complexes expressed GFP. This result indicates that the CHP-NH2 nanogel could be used as an efficient DNA carrier. In the 55th Society of Polymer Science Japan Annual Meeting in Nagoya (2006), the group of Akiyoshi presented a study on the design of a new nanogel carrier as a protein carrier.468 In this work, nanogels of CHP with a cationic charge were used as intracellular protein carriers. Proteins such as fluorescein isothiocyanate (FITC)−BSA and FITC−antibody were effectively internalized to HeLa cells in the presence of the nanogels even in the serum medium, showing that the efficiency is higher than that of conventional carriers such as cationic liposome or peptide-based carriers. They also presented the work “Functional nanogel as nucleic acid carrier”,469 reporting that hydrogel nanoparticles (nanogels) were formed by self-assembly of CHPs. They performed the synthesis of various cationic groups bearing CHPs. The cationic CHPs formed monodisperse cationic nanogels (30−40 nm) in water. The characteristic of cationic nanogel−nucleic acid complexes together with the interaction between cationic nanogel−nucleic acid complexes and cells were analyzed. The results indicate that various cationic nanogels and nucleic acids were complexed and formed nanosize particles. The CHP nanogel, which modified spermine, acts as an efficient nucleic acid carrier in cells. It is well-known that charge is a key parameter of the polymer for DNA binding, interaction with the cell surface, endosomal escape, and subcellular localization. The nature of the polymer charge can enhance the transfection efficiency but may also result in undesirable cytotoxicity. Both cationic polymer charge and polymer degradability play a crucial role in packaging and delivering plasmid DNA. High-density cationic charge enhances the transfection efficiency but may give rise to undesirable cytotoxicity by destabilizing the plasma membrane, interacting with cellular components, and inhibiting normal cellular processes.470 Taking all these facts into account, Khondee et al.471 synthesized PVAm nanogels bearing discrete amounts of surface charge and used them to examine the balance between transfection efficiency and cytotoxicity.

stability of nanogel−DNA complexes were evaluated under physiological conditions. The nanogels demonstrated extended stability in aqueous media and exhibited low toxicity in cell culture. Cationic nanogels formed monodisperse complexes with nucleotides and showed enhanced oligonucleotide uptake in cell culture. The nanogels synthesized demonstrate potential utility as carriers of oligonucleotides and DNA for antisense and gene delivery (see Figure 42).

Figure 42. Toxicity study indicating the percentage of HeLa cells living after incubation with nanogels: solid bar, MTS assay (16 h incubation at 0.125 mg/mL); cross-hatched bar, dye exclusion assay (40 h incubation at 0.25 mg/mL). Nanogel samples contain 12 wt % PEGdiA with 0 wt % AETMAC (a), 12 wt % AETMAC (b), and 25% AETMAC (c). Positive control: polylysine (d). Negative control: blank (e). Reprinted from ref 463. Copyright 2002 American Chemical Society.

Hasegawa et al.464 reported a novel carrier for quatum dots (QDs) for intracellular labeling. Nanogels of cholesterolbearing pullulan (CHP) modified with amino groups (CHPNH2) were mixed with QDs and internalized into the various cells examined. The efficiency of cellular uptake was much higher than that of a conventional carrier (cationic liposome), and the hybrid nanoparticles could be a promising fluorescent probe for bioimaging (see Figure 43).

Figure 43. CLSFM images of cells labeled with CHP-NH2(15)−QD nanoparticles: (A) TIG-3, (B) MRC-5, (C) MCF-7, and (D) YKG-1. All pictures were taken at a magnification of 400×. Reprinted with permission from ref 464. Copyright 2005 Elsevier Ltd.

From 2005 to now, the group of Akiyoshi at the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, in Japan, has been one of the most active in the synthesis and characterizations of cationic nanogels and their bioapplications.465 They presented in 2005 the design and functional evaluation of a new nanogel carrier. In this study, CHP modified with amino groups was synthesized by carbonyldiimidazole (CDI) activated synthesis. Using 1H NMR and elemental analysis, the numbers of cationic groups per 100 glucose units were calculated. CHP derivatives formed nanogels by self-associations. 418


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Raemdonck et al.478,479 synthesized cationic dextran nanogels (dex-HEMA-co-TMAEMA) using a UV-induced emulsion polymerization. They used photochemical internalization (PCI), a method that employs amphiphilic photosensitizers to destabilize endosomal vesicles to liberate a fraction of the siRNA−nanogels trapped in endocytic vesicles, resulting in an additional siRNA dose that is released in the cell cytoplasm, prolonging the therapeutic effect (see Figures 45 and 46).

Poly(N-vinylformamide) (PNVF) nanogels were prepared by an inverse emulsion polymerization process using an acid-labile cross-linker. Nanogels were hydrolyzed to yield varying degrees of primary amines. The degree of conversion from PNVF to PVAm was controlled using different concentrations of NaOH and hydrolysis times. Low charge degradable nanogels reduce cytotoxicity without compromising the overall transfection efficiency. The group of Akiyhoshi472 recently reported the development of a new gene delivery system capable of endosome disruption using a polysaccharide-based cationic nanogel. The system is composed of a hexadecyl group-bearing cationic cycloamylose nanogel and a lipolytic enzyme (phospholipase) to hydrolyze membrane phospholipids. The nanogel is able to encapsulate phospholipase to provide an endosome escape function. The nanoparticles complexed with pDNA (plasmid DNA) and enhanced its expression. Codelivery of phospholipase and pDNA using a nanogel is a novel concept for gene delivery with enhancement of endosomal escape. siRNAs show potential for the teatment of a wide variety of pathologies with a known genetic origin through squencespecific gene silencing. However, siRNAs do not have favorable druglike properties and need to be loaded into nanocarriers designed to cross the intracellular barriers and deliver siRNA to the cytoplasm of the target cell (see Figure 44).

Figure 45. Chemical structure of dextran hydroxyethyl methacrylate (dex-HEMA), [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAEMA), and dextran methacrylate (dex-MA). Dex-HEMA, supplemented with 0.1% photoinitiator (irgacure 2959) and TMAEMA, is emulsified in mineral oil/ABIL EM 90 by ultrasonication to obtain a water-in-oil emulsion. UV irradiation initiates the polymerization of dex-HEMA and TMAEMA in the nanodroplets. The image on the right represents an AFM image of dex-HEMA-coTMAEMA nanogels (DS 21). The scale bar equals 1 mm. Reprinted with permission from ref 478. Copyright 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Polymer siRNA complexes (siRNA polyplexes) are being actively developed to improve the therapeutic application of siRNA, but the major limitation for many siRNA polyplexes is the insufficient mRNA suppression. Given that modifying the sense strand of siRNA with 3′-cholesterol (chol-siRNA) increases the activity of free-nuclease-resistant siRNA in vitro and in vivo, Ambardekar et al.480 proposed the complexation of chol-siRNA to increase mRNA suppression by siRNA polyplexes. The characteristics and siRNA activity of selfassembled polyplexes formed with chol-siRNA or unmodified siRNA were compared using three types of cationic polymers: a PEI-based biodegradable nanogel synthesized using PEG as a cross-linker through carbamate bonds, a PEI−PEG-based graft copolymer, and two PEG-based linear block copolymers. The results indicate that chol-siRNA increases nuclease protection and mRNA suppression at the target tissue by select siRNA polyplexes.

Figure 44. Functional cycloamylose nanogel−PLA2−DNA delivery system. Reprinted with permission from ref 472. Copyright 2011 Elsevier Ltd.

From 2008 to 2011, the active group of Akiyoshi referenced before reported several works on cationic nanogels useful for intracellular protein delivery,473 nanogels self-assembled with oligo-DNA and their function as artificial nucleic acid chaperones,474 nanogels of cholesterol-bearing cationic cycloamilose for siRNA delivery,475 and a nanogel antigenic protein delivery system for intranasal vaccines;476 here cycloamilose (CA) was used as a new polysaccharide-based biomaterial to attach catonic spermine groups to take advantage of the superior activity for the transfection of siRNA shown by spermine derivatives. They also reported works on using nanogels to deliver proteins to myeloma cells and primary T lymphocytes477 and on a polysaccharide nanogel gene delivery system with an endosome escape function.472 In the majority of these works, except for the cases using CA, CHP is used to form nanoparticles by self-assembly in water.

5. CONCLUSIONS AND FUTURE PERSPECTIVES As was commented previously in the Introduction, cationic polymer particles and nanogels are being used in emerging biomedical technologies due to the strong interaction between nucleic acids and cationic polymer colloids, the acid-swellable 419


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Figure 46. Gene-silencing kinetics by siRNA-loaded dex-HEMA-co-TMAEMA nanogels as a function of the degree of substitution of the nanogels. Reprinted with permission from ref 479. Copyright 2010 Elsevier Ltd.

behavior of the nanoparticle/nanogel, and the ability to form oriented bonds with proteins, among other aspects. Regarding the cationic latexes, in the future the use of new techniques will be able to achieve a more detailed characterization of their interfacial morphology, which is scarcely known. In this sense, the role played by the water molecules around ions of the electrical double layer and the interaction of hydrated ions with positively charged interfaces will have to be found at the 1 nm scale. It will be possible to prepare hairy, grafted, or hard latex particles with a known and controlled behavior at solid−liquid, liquid−liquid, and liquid−gas interfaces. The preparation of Janus particles with positively and negatively charged faces will be a new challenge. In the next decades, there will be a growing interest in the use of cationic latexes in practical biomedical applications such as immunoassays, vaccines, and so on. Although throughout this review several new features of the cationic nanogels are envisaged for future bioapplications of these nanoparticles, numerous challenges are still open in optimizing their synthesis strategies, characterization, and uses. One of the most challenging applications is the use of cationic nanogels as carriers or vectors for in vivo siRNA delivery. As commented before, the use of RNA interference to

treat or prevent a variety of diseases, including cancer, is nowadays a challenge in the biomedical field of therapeutics. The demands to be fulfilled by siRNA nanocarriers comprise the following: (1) Adequate siRNA protection by nanogels during circulation, preventing clearance, aggregation, degradation, and premature release. New nanogel arquitectures or nanostructures should be envisaged for the adequate and controlled cell-specific siRNA release. (2) Improved stealth properties for the nanogels, avoiding recognition by the immune system (phagocytes), and enhancement of tumor accumulation, taking advantage of the EPR (enhanced permeability and retention) effect in tumors. To overcome these challenges, adequate nanogel sizes and shells are required. (3) Nanogel penetration into dense tissues. To reach cells, it becomes necessary to pass through the extracellular matrix of the targeted tissues. The stimulus-sensitive character of the nanogels enables their mobility in these specific locations. In this way, the design of new nanogels sensitive to or able to respond to other in vivo stimuli different from the pH, temperature, or ionic strengh is needed. 420


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(4) Optimization of cell targeting and endosomal escape mechanisms for in vivo transfection, proposing different and new moiety-targeted cationic nanogels. (5) Avoiding toxicity. Biocompatibility is the first characteristic to be fulfilled and biodegradability is the next for the in vivo use of nanogels. Biocompatible and biodegradable polymer-based cationic nanogels are needed, the degradation pathway being enzymatic or hydrolytic depending on the target. As a general conclusion and taking into account the variety of

Jacqueline Forcada is an Associate Professor of Chemical Engineering at the University of the Basque Country. She received her Ph.D. in Chemistry from the University of the Basque Country in 1987 under the supervision of Prof. Jose Mariá Asua. Her research focuses on the synthesis, characterization, modeling, and biotechnological applications of functionalized polymeric and hybrid nanoparticles and biocompatible and biodegradable nanogels. She has published more than 70 scientific papers in international high-ranking journals, and she is the author of 7 patent applications (ES, EP, PCT, and US). She has supervised 10 Ph.D. theses.

features required to use cationic nanogels for in vivo siRNA delivery, the synthesis of new stimulus-responsive nanoparticles with new abilities to overcome the challenges listed above is a broad and open path for the near future.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Roque Hidalgo-Alvarez is a Professor of Applied Physics at Granada University in Spain. He was born in La Carolina (Jaén), Spain, in 1952 and received his M.S. in Chemistry (1975) and Ph.D. (1979) in Physics from Granada University under the supervision of Professor Fernando González-Caballero. During 1984 and 1985, he spent a year at Wageningen Agricultural University as a visiting scientist, working with Professor Bert Bijsterbosch. He was promoted to a full professorship in 1992 at Granada University. His research and teaching interests lie in the general area of colloid and interface sciences with a special emphasis on electrokinetic phenomena and colloidal stability. He has published 235 scientific papers in international journals and has supervised 21 Ph.D. theses. He has been recently appointed as a member of the Academy of Sciences.

Jose Ramos obtained his B.Sc. in 2000 and his Ph.D. in 2005, both from the University of the Basque Country. His Ph.D. thesis focused on the synthesis and characterization of cationic latex particles and microgels for biomedical applications under the supervision of Prof. Jacqueline Forcada. He spent six months of his Ph.D. study at the

ACKNOWLEDGMENTS In the past several years a great number of colleagues have been helpful in discussing the preparation and characterization of cationic polymer particles and nanogels. R.H.-A. particularly thanks Professor Bert Bijsterbosch and Mr. Ab van der Linde, who were with the Laboratory for Physical and Colloid Chemistry at the Wageningen Agricultural University (The Netherlands). J.R. and J.F. thank Dr. Ainara Imaz for her frienship and for sharing her work during the past 10 years. We

University of Bristol with Prof. Brian Vincent. In 2008 he obtained a postdoctoral position in the group of Prof. Roque Hidalgo-Alvarez. Currently, he is at the University of the Basque Country, and his research interests include the design of polymer and hybrid nanoparticles and temperature- and pH-responsive biocompatible and biodegradable nanogels. 421


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thank the Spanish Plan Nacional de Materiales (Grants MAT2009-13155-C04-01, MAT2012-36270-C04-01, and MAT2010-15101). J.R. and R.H.-A. acknowledge Project ́ P10-FQM-5977 from “Junta de Andalucia”. R.H.-A. also acknowledges funding received from CEIBioTic Granada 20F12/16.

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