Intramicrogel Complexation of Oppositely Charged Compartments As

Article pubs.acs.org/Macromolecules

Intramicrogel Complexation of Oppositely Charged Compartments As a Route to Quasi-Hollow Structures Andrey A. Rudov,†,‡ Arjan P. H. Gelissen,§ Gudrun Lotze,⊥ Andreas Schmid,§ Thomas Eckert,§ Andrij Pich,‡,∥ Walter Richtering,§ and Igor I. Potemkin*,†,‡,# †

Physics Department, Lomonosov Moscow State University, Leninskie Gory 1-2, Moscow 119991, Russian Federation DWILeibniz Institute for Interactive Materials e.V., Forckenbeckstraße 50, Aachen 52056, Germany § Institute of Physical Chemistry, RWTH Aachen University, Aachen 52056, Germany ⊥ High Brilliance Beamline ID02, ESRFThe European Synchrotron, 71, Avenue des Martyrs, CS40220, 38043 Grenoble Cedex 9, France ∥ Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Aachen 52056, Germany # National Research South Ural State University, Chelyabinsk 454080, Russian Federation ‡

S Supporting Information *

ABSTRACT: We have predicted using computer simulations and have detected with SAXS measurements that pH-sensitive core−shell polyampholyte microgels can form a dense layer (“skin”) at the core−shell interface. The microgels have cationic core and neutral shell at low pH, whereas the core becomes neutral and the shell becomes anionic at high pH. The core and shell are oppositely charged at intermediate pH values. The layer formation is a result of the electrostatic complexation between oppositely charged subchains. We have studied microgels with different core−shell ratios and fractions of ionizable groups and analyzed radial distribution of polymer volume fraction and volume fractions of cationic and anionic groups. We have demonstrated that in many cases complexation of oppositely charged subchains (intermediate pH values) or swelling of charged core with neutral shell (low pH) are responsible for the formation of quasi-hollow structures with a loose core of strongly swollen subchains and dense shell of interpenetrating core- and shell-forming subchains. The most pronounced quasi-hollow structures are predicted in computer simulations for highly charged microgels. On the contrary, practically homogeneous swelling of the microgels is observed at high pH, when electrostatics-driven swelling of the anionic shell promotes swelling of the neutral core. All structures are colloidally stable due to the spatial segregation of the opposite charges. Therefore, the microgels can be useful as carriers for pH-controlled uptake, storage, and release of neutral guest molecules, which can be trapped within the microgel at low and intermediate pH and released at high pH.

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INTRODUCTION

New intriguing types of soft matter with complex architecture consisting of at least two different polymers or polyelectrolytes have been synthesized.26 Novel methods like in situ electron and super-resolved fluorescence microscopy enable direct visualization of different compartments within adaptive microgels.27 The development of future applications for μGs crucially depends on our ability to purposefully manipulate their architecture and placement/distribution of functional groups.28 A sophisticated concept of compartmentalized μGs was developed by combining stimuli responsive polymers with e.g. different LCSTs, separated in multiple domains29 or in physically distinct, spatially separated concentric core−shell regions.30−33 In recent years the synthetic route has been extended in such a way that it has become possible to

Nano- or microgels (μGs) are soft sensitive colloidal particles in the size range from tens of nanometers to several micrometers.1 Having structural similarity to macroscopic gels, they can reveal reversible swelling and collapse triggered by temperature,2 pH,3,4 solvent5 (quality and composition), ionic strength,6 light,7 electrochemical potential,8 etc. However, mainly due to the size of the μGs, their sensitivity and response rate are much higher.9,10 At the same time, μGs reveal colloidal nature. Colloidal stability, a high surface area and controlled particle size are inherent properties of μGs.11 Therefore, the above-mentioned features of the μGs make them very attractive for a number of applications. For example, μGs can be used for targeted uptake, storage and release of guest molecules,12−17 as deformable and permeable alternative of solid particles for emulsion stabilization,18−23 actuators and microswimmers,24 modifiers of polymeric membranes,25 etc. © XXXX American Chemical Society

Received: March 15, 2017 Revised: May 5, 2017

A

DOI: 10.1021/acs.macromol.7b00553 Macromolecules XXXX, XXX, XXX−XXX

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of both. This study is divided in two parts. First, we simulate experimentally accessible polyampholyte core−shell microgels and then compare our results with experimental findings. We probe at which charge ratios oppositely charged subchains interpenetrate in the interfacial region and form dense interpolyelectrolyte complexes62,63 (a dense interfacial “skin”). This peculiarity opens a great potential to use such μGs as carriers, which can be loaded with neutral molecules. In swollen state, the cargo can penetrate both the core and the shell and switching the pH will lock them inside the μG via the formation of a dense skin of complexed subchains. These carriers are colloidally stable because positive and negative charges are segregated in space and their neutralization proceeds in the skin only. The polyampholyte core−shell μGs are more biocompatible due to the anionic shell. Hence, specific cell uptake or low cytotoxicity is difficult to achieve with cationically charged polymers.64 In the locked state, the trapped molecules can be transported and released upon a switch of pH. In the second part, we will design systems that take maximum advantage of the interfacial skin effect. We probe the formation of thermodynamically stabile quasi-hollow structures of the core−shell μGs.

synthesize unique hollow doubly temperature-responsive μGs.34,35 The interest to compartmentalized soft matter stems from the fact that these systems combine the properties and response of both compartments under external stimuli which are highly desirable for chemical engineering like (bio)sensing,36,37 or responsive coating.38 Especially in the field of biotechnology, catalysis,39 drug or gene delivery40−45 the introduction of a permeable or degradable polymeric shell allows to control the diffusive mobility of active molecules, to enhance the loading and release efficiency of the μGs and colloidal stability of complexes.46 However, targeted drug delivery systems have to fulfill many requirements and their success mainly depends on our ability to find an optimal design for the polymer where all different functionalities interplay in a constructive way. Copolymerizing ionizable monomers into thermoresponsive μGs makes them multistimuli responsive (thermo- and pH). In polyelectrolyte μGs, the acidic or basic groups become ionized with change in pH. As soon as charged moieties are present in the subchains, macroscopic electric neutrality of the system is provided by counterions. Some of them are localized within the μGs to partially neutralize their charge and others occupy outer solvent to get an entropic gain of translational motion. As a result, a difference in the osmotic pressure of inner and outer counterions together with repulsion of unscreened charged groups of the subchains are responsible for a very strong swelling of the μGs.47,48 Polyelectrolyte networks can absorb up to 100 times more solvent compared to uncharged systems.49 The ability to synthesize and analyze colloidally stable polyampholyte μGs has been of interest in recent works.4 Antipolyelectrolyte behavior is observed at intermediate pH where the size of these polyampholyte μGs increases with increasing salt concentration.50 These μGs show reversible parabolic swelling as a function of pH and an adjustable isoelectric point depending on their composition.51 Complementary experimental, theoretical, and computer simulations studies have been made to rationalize the pH-controlled swelling and collapse of these polyampholyte μGs with random distribution of cationic and anionic groups.52 Swelling of the μGs at high and low pH is due to the excess charge on the subchains: they swell because of unscreened electrostatic repulsion between charged groups and osmotic pressure of counterions, which are localized in the μG.52 Similar behavior is observed for polyampholyte core−shell μGs.53 There are numerous studies dealing with theory and computer simulations of μGs having simplest structure, i.e., cross-linked homopolymer chains. These studies pointed out and explained the thermodynamics and kinetics of the volume phase transitions of neutral μGs,9,10,54 peculiarities in the behavior of polyelectrolyte (PE) μGs,47,55−57 effects of charged groups and counterions,58,59 and many other aspects.60 It was experimentally found that cross-link density and the ratio between core and shell masses are crucial parameters, which determined swelling behavior within both compartments and the μG as a whole. It was pointed out that in core−shell μGs the swelling properties of core and shell networks are coupled. Hanson and co-workers61 developed a theory that qualitatively reproduces and explained these effects. In the present paper, we investigate equilibrium structures of polyampholyte core−shell μGs with oppositely charged core and shell. We analyze different core−shell ratios with equal and variable charge densities to study how an opposite sign of charge between core and shell influences the coupled swelling

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EXPERIMENTAL SECTION

The core−shell molar ratio is reflected in the subscripts of the sample names, e.g. in sample C1−S7 the core−shell molar ratio is 1:7. Figure 1

Figure 1. Initial (before annealing) structures of the core−shell μGs with fixed number of the beads in the core (dark gray), NC = 3500, and different numbers in the shell (light gray) (series 1). Left-to right: bare core C = (3500:0), core−shell C1−S1 = (3500:3500), C1−S3 = (3500:10500), and C1−S7 = (3500:24500). Red and blue dots depict cationic and anionic groups in the core and shell, respectively. shows those types of μGs designed for the simulations. The molar ratios were chosen to correspond to experimental systems. The molecular weight of the core is fixed, NC = 3500, and the increasing molar ratio is due to the increase of the shell volume (series 1), Figure 1. The maximum fraction of charged groups in the core and the shell of the microgels of the series 1 is considered to be equal for all molar ratios. Figure 2 shows structures of microgels, which are aimed on maximization of the skin effect (series 2). These microgels are designed in a way that the total number of the beads is fixed (N =

Figure 2. Core−shell μGs of equal total number of the beads, N = 14000, and different core−shell composition (series 2). Left-to-right: bare core C = (14000:0), core−shell C1−S1 = (7000:7000), C1−S3 = (3500:10500), and C1−S7 = (1750:12250). Red and blue dots depict cationic and anionic groups in the core and shell, respectively. B


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Macromolecules

monovalent buffer solutions, and ionic strength was set to 50 mM by addition of a low molecular weight salt (NaCl). The following buffers have been used: glycine−HCl (pH 2), acetate (pH 4), MES (pH 6), TRIS (pH 8), and glycine−NaOH (pH 10). Evaluation of Scattering Intensity Data. To extend the experimental available q-range scattering intensity data of SLS and SAXS experiments are combined. The low q values are from the SLS measurements. A model free indirect Fourier transformation (IFT) is applied to the angular dependent scattering intensity I(q) to obtain pair distance distribution functions p(r).68 The radius of gyration Rg was calculated from the pair distance distribution function according to the following equation:

14000). Consequently, all microgels have the same size in the initial state (before annealing). Variation of the molar ratio is accompanied by variation of the core size, Figure 2. For series 2, we confine ourselves by analysis of the fixed number of ionizable units in the core and the shell (maximum 1400 in each). It means that variation of the core−shell composition results in variation of the fraction of cationic and anionic groups: smaller volume of the compartment will correspond to a higher charge density. Materials. The initiator 2,2′-Azobis(2-methylpropionamidine)· 2HCl (AAPH), and the comonomers N-[3-(dimethylamino) propyl] methacrylamide (DMAPMA) and dimethyl itaconate (DMI) were purchased from Sigma-Aldrich. The monomer N-isopropylacrylamide (NIPAM) was purchased from Acros Organics. The cross-linker N,N′methylenebis(acrylamide) (BIS) was purchased from Alfa Aesar. The surfactant cetyltrimethylammonium bromide (CTAB) was purchased from Fluka Biochemica. Glycine, sodium acetate, 2-(N-morpholino)ethanesulfonic acid (MES) and Tris(hydroxymethyl)aminomethane (TRIS) were all purchased from Sigma-Aldrich. All chemicals from commercial sources were used without further purification. All experiments were performed in bidistilled water. The μG core has been synthesized and characterized as described before.65 The amounts of the chemicals applied for synthesis are listed in Table S1 of the Supporting Information. A core−shell architecture is achieved by so-called seed-and-feed polymerization, where the collapsed core μGs serve as nuclei for further polymerization.66 Control of the ionizable groups in the core−shell μG system is important to evaluate our molecular dynamics simulations. To avoid possible aggregation during synthesis, the comonomer dimethyl itaconate is used as a precursor for itaconic acid. The methyl groups are removed by saponification with sodium hydroxide. The saponification process is performed over several days and was stopped when the desired number of acid groups was reached. The resulting ratio of ionizable groups is given in the indices: C1−S1 corresponds to the same amount of ionizable cationic groups in the μG core as ionizable anionic groups in the μG shell, whereas C1−S7 indicates a 7fold amount of anionic groups in the μG shell as compared to the μG core. The amount of chemicals used and a detailed description of the synthesis procedure can be found in the Supporting Information. The polyampholyte core−shell μGs have an amine-functionalized core and an itaconic acid monomethyl ester functionalized shell. These functional groups are protonated at low pH, resulting in a cationic (swollen) core and a neutral shell. At intermediate pH, both functional groups in core and shell are partially charged and possess the opposite sign of charge. Electrophoretic Mobility. Measurements of the electrophoretic mobility μ were performed on a NanoZS zetasizer (Malvern). The pHdependence of Rh and electrophoretic mobility μ was measured by titration of aqueous solutions of the μGs using a MPT-2 autotitrator. Measurements were performed in disposable capillary cells (Malvern, DTS1061C). Electrophoretic mobility was measured at scattering angle of 17° and the hydrodynamic radius at a scattering angle of 173° using a laser beam wavelength of 633 nm. Titration process was performed from pH 11 to pH 3 in steps of 0.5 using 0.1 M NaOH and 0.1 M HCl. The average of three measurements at each pH value is shown. Measurements were performed at 20 °C, if not stated otherwise. Static Light Scattering (SLS). Static light scattering experiments were performed on a modified Fica (SLS Systemtechnik, Denzlingen) equipped with a 658 nm HeNe laser (Picotronic GmbH, 10 mW). Highly diluted samples were measured at 20 °C in 20 mm diameter cylindrical quartz cells (Hellma QS). The average scattering intensity was typically measured at scattering angles from 15° to 146° with 1° increments. Solvent scattering was subtracted from scattering of the samples. Small Angle X-ray Scattering (SAXS). SAXS measurements were carried out at the ESRF, Grenoble, France at beamline ID02. With a sample-to-detector distance of 5 m and energy of 12.5 keV, the accessed q-range was 0.0145−1.5408 nm−1. Details of the beamline, data collection, and q-calibration can be found in reference.67 All samples were measured at 20 °C, pH was adjusted with 5 mM

∞

R g2

=

∫0 p(r) r 2 dr ∞

∫0 p(r) dr

(1)

Under the assumption of spherical symmetry of the μGs, density distributions could be computed using the Fortran program DECON (developed by Glatter et al., 1981, 1998). This program uses the socalled Convolution Square Root69 to deconvolute the p(r) functions of polydisperse samples.70 Various models can also describe the form factor of a μG. Assuming a spherical shape, pronounced differences are mainly caused by an inhomogeneous polymer density of the μG. Swollen PNIPAM μGs are usually considered as fuzzy spheres.71 To account for intramicrogel complexation, we fit the scattering traces with a fuzzy core−shell model, allowing differences in density and a gradual decrease in density at the μG surface.31 A scaling factor was used to fit these scattering traces, consequently only normalized density profiles are obtained and general trends are discussed, rather than absolute values.

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MODELING SECTION Brownian Molecular Dynamics (BD). We performed Brownian molecular dynamic simulations of a single polyampholyte μG with core−shell distribution of charges on the subchains within a coarse-grained model and implicit solvent. All structural units of the μG (charged and uncharged monomer units, cross-links) and counterions are modeled as Lennard-Jones particles (beads) of the same diameter, σ, and of the mass, m. The μGs are designed as depicted in Figure 1 (series 1) and Figure 2 (series 2). Fully stretched chains of equal length, n = 10 beads, are connected through tetrafunctional cross-links and repeat a unit cell of the diamond crystal lattice. Considering that 4 halves of the chains accounts for each tetrafunctional cross-linker, the estimated fraction of the 1 cross-linkers is 4 × 5 + 1 ∼ 0.05. Then, we construct a cube consisting of 10 × 10 × 10 unit cells, inscribe a spherical frame of predetermined radius and delete all monomer units, which are outside the frame. As a result, we can obtain a series of spherical μGs of different sizes containing both subchains and dangling chains. After that using another concentric spherical frame of smaller radius we mark the core and the shell regions. NC and NS are the numbers of the beads in the core and the shell regions, respectively. In this paper, computer simulations N 1 will be performed with μGs of the ratio NC = 1 , 1 , and 1 . Such S

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7

choice of the parameters correlates with the experimental data and corresponds to slim, comparable and thick shell of the μG as compared to the size of the core. Let us denote by φ+ and φ− fractions of positively and negatively charged monovalent groups in the core and the shell of the μG, respectively, so that the total numbers of the cations and anions are φ+NC and φ−NS. The charged groups were introduced as follows. n+ = φ+NC and n− = φ−NS neutral beads C


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Macromolecules in the core and the shell were randomly selected and converted into positively and negatively charged beads, respectively. Positively and negatively charged counterions are added into the system to provide overall electric neutrality. To mimic the effect of pH, the fractions of charged units φ− and φ+ (or the numbers n− and n+) were considered to be linearly dependent on pH value (see ref 52 for details). Briefly, the number of positively charged beads linearly reduces from the maximum value, n+, at low pH to 0 at high pH, whereas the number of negatively charged beads linearly rises from 0 to the maximum value, n−. The maximum fractions of the charged groups are fixed for all microgels of the series 1, φ+max = φ‑max = 0.1. The interaction between any pair of the particles is described through the truncated-shifted Lennard-Jones potential.72,73 Similar to the model described in ref 73, we set the cutoff distance rcut= 2.5σ for the monomer−monomer interactions in the subchains, and rcut = 21/6σ for pairwise interactions between counterions, and counterions with the monomers. The solvent quality is quantified by the Lennard-Jones interaction parameter εLJ. We have fixed it to the value 0.01 kBT which corresponds to the case of good solvent. The value of the Lennard-Jones parameter for monomer-counterion and counterion-counterion interactions was set to 1 kBT. Electrostatic interactions between any pair of charged particles are described by Coulomb potential. The value of the Bjerrum length was fixed and equal to lB = 3σ, which corresponds to aqueous solutions. Connectivity of the particles into polymer chains was realized by the finite extension nonlinear elastic (FENE) potential.74 The simulations were performed using the open source software LAMMPS.75,76 The simulation cell was a cubic box of the size Lx = Ly = Lz = 200σ. The calculations were carried out in NVT ensemble with periodic boundary conditions. The electrostatic interactions between charged particles of the system were calculated by the Ewald summation method with the accuracy of 10−5. Annealing of the μG at various values of the interaction parameter εLJ was performed during 20 × 106 simulation steps. Averaging has been made in the last 5 × 106 steps.

dependent swelling curves and corresponding results of MDsimulations can be found in the Supporting Information. Table 1. Hydrodynamic Radius of the μGs at a Reference State of 60 °Ca experiment (T = 60 °C)

simulation (εLJ = 1 kBT, NC = 3500)

microgel

RH [nm]

Vcore Vshell : Vmg Vmg

NC:NS

Rg [σ]

core C1−S1 C1−S3 C1−S7

81 92 − 183

1.00:0.0 0.68:0.32 − 0.08:0.92

1:0 1:1 1:3 1:7

6.6 8.3 9.9 13.9

Vcore Vshell : Vmg Vmg

1.00:0.0 0.503:0.497

To avoid interaction between core and shell, the μGs were measured before saponification of the DMI in 0.1M KCl at pH = 6. Molar ratio in computer simulations, NC:NS, and gyration radius, Rg, of collapsed microgels at εLJ = 1 kBT. a

The molar amount of N-[3-(dimethylamino) propyl] methacrylamide (DMAPMA, ionizable group in the μG core) was determined to be 12 mol % by a 1H nuclear magnetic resonance (1H NMR). The charges in the shell were obtained by partial saponification of the dimethyl itaconate (DMI) ester groups into itaconic acid monomethyl ester groups. After partial saponification, the signal ratio of NIPAM: DMI changed. Evaluation of the 1H NMR spectrum indicates successful saponification of only 40% of the DMI groups. Every DMI monomer bears two ionizable groups which brings the total amount of ionizable groups to 9 mol % in the shell of the C1− S7 μG. In case of the C1−S1 μG, the amount of ionizable groups (Table 2) was found to be 10 mol % in the μG shell. Spectra and a detailed explanation of the procedure can be found in the Supporting Information. Influence of pH on Microgel Size: Predictions from Simulations. The total charge of different μGs of series 1 as a function of pH is presented in Figure 3 (left) by different straight lines. They start in a common point Qtotal=+350 of maximally charged core at pH = 2 (φ+max = 10%) and end up in

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Table 2. Amount of Ionizable Groups in Core and Shell of the μGsa

RESULTS AND DISCUSSION Polyampholyte core−shell microgels are synthesized using one well-defined and characterized microgel core and apply seedand-feed polymerization with two different monomer feeds. In this way, two types of polyampholyte core−shell microgels with a different core−shell ratio are obtained. These systems are directly comparable with simulated ones (series 1). In the following sections, we will first compare characteristics of the simulated with the experimental systems. Second, we will describe the influence of pH on the microgel size and electrophoretic mobility. Third, structural details are elucidated. We found a good agreement between experimental and simulation results (series 1). Finally, we will predict by simulations, which special features polyampholyte core−shell microgels have by optimizing the various parameters we identified. These systems (series 2) are synthetically not yet available and will be the scope of future work. Characteristics of Experimental and Simulated Systems. At 60 °C, all measured μGs are in a collapsed state and considered as homogeneous spheres. The increase in μG size at 60 °C and a monomodal size distribution strongly indicates a successful core−shell synthesis (Table 1). Temperature

microgel core cationic groups (DMAPMA) anionic groups (MIA) microgel C1−S1 cationic groups in core cationic groups in microgel anionic groups in shell anionic groups in microgel microgel C1−S7 cationic groups in core cationic groups in microgel anionic groups in shell anionic groups in microgel

1

H NMR (%)

simulation (%)

monomer feed (%)

10

10

0 simulation (%)

0 monomer feed (%)

10 5

10 5

12 6

10 5 simulation (%)

10 5 monomer feed (%)

10 5 1 H NMR (%)

10 1.25

10 1.5

12 1.5

10 8.75

10 8.75

12 0 H NMR (%)

1

9 7.88

a

Listed are the amount used in simulation (Series 1) and monomer feed and compared with 1H NMR. Results are within the experimental error of the experiment. D


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cationic μGs: first the electrophoretic mobility weakly decreases with pH (until pH = 8) and then the decay proceeds faster and finally μG becomes neutral at pH = 11. The core−shell architecture of the μGs strongly influences the surface charge of the polyampholyte μGs. Cationic charges present in the μG core are shielded by a neutral shell at low pH. The electrophoretic mobility of C1−S1 and C1−S7 is significantly lower at pH 3 as compared to the core μG. The electrophoretic mobility of the C1−S1 μG is higher than the one of C1−S7, which is a μG with a thick shell; thus a thin shell does not completely shield the cationic charges within the μG core. The remaining weak cationic surface charge of the C1−S7 μG at low pH might be only due to cationic initiator moieties present at the μG surface. When moving from low to high pH, the sign of charge reverses. The pH-value at which the charge reversal occurs strongly depends on the μG composition. An approximately 7-fold excess of anionic moieties in the C1−S7 μG induces a charge reversal at lower pH. The experimentally observed electrophoretic mobility of polyampholyte core−shell μGs correlates with the thickness of the shell and the composition of the μG. The influence of pH on responsive polyampholyte core− shell μGs is investigated by SAXS at five different charge ratios in core and shell by varying the pH. In order to compare our experimental results with computer simulations, the radius of gyration is preferred over the hydrodynamic radius, because in both simulation and static scattering experiments the radius of gyration (Rg) is obtained, which makes comparison more reliable. Additionally, we prefer to use the radius of gyration as a measure to describe the influence of pH on the swelling behavior of the polyampholyte μGs, because Rg is independent of the μG shape and easy to obtain from scattering profiles of the μGs. The analysis was started by calculating the p(r) function trough indirect Fourier transformation and subsequent calculation of the radius of gyration. Figure 4 depicts the Rg as a function of pH for the systems evaluated. The size of the core C gradually decreases with pH. Deprotonation of the amine-functionalized core with the increase of pH weakens electrostatic interactions and osmotic pressure of counterions and results in a decrease of the μG size. Scattering intensity data and corresponding evaluation of all investigated μG systems can be found in the Supporting Information. For the core−shell microgels, the decrease in Rg indicates electrostatic interaction between the heterogeneously distributed cationic and anionic moieties in the core and shell, respectively. This so-called intramicrogel complexation results in a nearly symmetric pH-dependent swelling curve of the μG when an equal amount of charges is distributed in both core and shell (C1−S1), Figure 4. An asymmetric pH-dependent swelling curve was observed when charges are unequally distributed (C1−S7). The isoelectric point is shifted toward the pKa of the itaconic acid monomethyl ester, which is in excess. The functional groups are deprotonated at high pH, which results in a neutral core and an anionic (swollen) shell. Comparing the experimental data (Figure 4) with computer simulations (Figure 3) demonstrates a qualitative agreement: swelling curves reveal a minimum at the isoelectric point of the C−S μGs and gradual decrease of the size of the bare core μG with pH. Also, computer simulations correctly predict a shift of the isoelectric point upon variation of the core−shell molar ratio. Therefore, the proposed simple model is quite accurate for the description of the experimental data.

Figure 3. (Left) The total charge Qtotal of the μGs as a function of pH. All microgels of the series 2 are characterized by one straight (brown). All other straights correspond to μGs of series 1 having different molar ratio. (Right) Dependence of the radius of gyration of the core−shell μGs (series 1) on pH for different core/shell composition in μGs: bare core C (black), core−shell C1−S1 (gray), C1−S3 (red), and C1−S7 (blue).

different points corresponding to maximum fraction of anionic groups in the shell, φ‑max = 10%, at pH = 10. It has to be mentioned that the proposed linear dependence Qtotal−pH is a simplest approximation rather than calculated result. However, already this assumption nicely proved itself for polyampholyte microgels with random distribution of ionizable groups.52 It correlates very well with electrophoretic mobility and gives very good agreement with experimental data on microgel swelling vs pH. The gyration radius of the core−shell μGs of the series 1 as a function of pH is shown in Figure 3 (right). The μG without shell (black line) deswells with pH because the electrostatic interactions weaken and swelling at high pH occurs only because of the excluded volume repulsion of the beads (good solvent for the neutral beads). On the contrary, the core−shell μGs reveal a nonmonotonous shape of the swelling curve. First, the μGs deswell due to reducing of the electrostatic repulsion in the core. The minimum of the swelling degree is achieved at the isoelectric point when complexation of oppositely charged subchains in the interfacial region occurs. Further swelling of the μGs proceeds because of emerging electrostatic repulsion between unscreened anionic groups in the shell and osmotic pressure of those counterions, which are localized within the shell. That is why the μG with the biggest shell, C1−S7, starts swelling at lower pH (the isoelectric point is shifted to the left, Figure 3 (right)). Size and Electrophoretic Mobility: Experimental Results. The pH-dependence of the electrophoretic mobility μ of the different μGs is depicted in Figure 4 (right). The surface charge of the μG is affected by acid−base reactions. The NIPAM-co-DMAPMA core μG C shows typical behavior of

Figure 4. Left: Dependence of the radius of gyration Rg on pH for the bare core μG (C) and for different core−shell compositions: C1−S1 and C1−S7. Right: Dependence of the electrophoretic mobility on pH for the core μG (C) and for different core−shell compositions C1−S1 and C1−S7. E


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Figure 5. Polymer volume fraction of μGs (series 1) as a function of radial coordinate r at εLj = 0.01kBT (good solvent). Columns correspond to different μGs: C, C1−S1, and C1−S7. Different rows distinguish ratio of the fraction of charged groups in the core and the shell, φ+−φ−: 0%−0% (noncharged microgels); 10%−0% (pH = 2); 7%−3% (pH = 4.4); 5%−5% (pH = 6); 0%−10% (pH = 10). Dark gray and light gray regions depict polymer volume fraction of the core and the shell, respectively. Black curve denotes the total polymer volume fraction. Volume fractions of cationic and anionic groups in the microgels are shown by red and blue curves, respectively. Left (black) and right (blue) vertical axes measure polymer volume fraction and volume fraction of charged groups, respectively.

Internal Microgel Structure: Computer Simulation Results. Figure 5 depicts polymer volume fraction at different ratio of charged groups in the core and the shell (at different pH) under good solvent conditions. The first row demonstrates that neutral microgels have nearly homogeneous distribution of polymer throughout the whole volume independently on the core−shell composition. Charging the core and keeping the shell neutral (see Figure 5, C1−S1 and C1−S7 at pH = 2), we can observe a decrease of the polymer volume fraction in the core. The shell plays a role of a corset confining the swelling of the core. The thickness of the shell slightly decreases in comparison with the neutral μGs (Figure 5, C1−S1 and C1−S7 noncharged) due to the exerting core. However, if the shell bears an opposite charge (increase pH), the maximum of the polymer concentration shifts toward interfacial core−shell region (Figure 5, pH = 4.4 and 6). Elevation of the concentration is a result of the electrostatic complexation of oppositely charged subchains, which can interpenetrate in the interfacial region and form dense interpolyelectrolyte complex62,63 (a dense interfacial “skin”). The depth of the interpenetration (the overlap regions of red and blue curves in Figure 5) is determined by core−shell composition of the microgel, length of the subchains and fraction of charged units: increase of the fraction of charged units and length of the subchains promotes the thickening of the skin layer. Indeed, the longer the subchains, the softer the microgel and the subchains of opposite charge can interpenetrate at larger length scales. On the other hand, those parts of the core and the shell, which are not complexed, remain swollen due to the electrostatic repulsion of unscreened similarly charged groups and osmotic

pressure of those counterions, which are localized within the μG. The swollen regions of the microgels provide their colloidal stability. The typical snapshots of the μGs, corresponding to the density profiles of Figure 5, are shown in Figure 6. Structure of Core−Shell μGs: Experimental Results. First, deconvolution of the p(r) function by assuming a spherical geometry resulted in the corresponding electron density profiles without the need of a model describing the polymer density within the μG. As depicted above in Figure 4, the μG appears to be smaller at intermediate pH as compared to acidic or basic pH. At pH 6 an increase in polymer density could be observed toward the corona of the μG. Both the p(r) function and corresponding DECON-fit can be found in the Supporting Information. Second, reconstruction of the scattering traces by fitting with appropriate models elucidates the radial density profile of the μG. Inspired by deconvolution results we opt for a core− corona μG model with a gradual transition between core and shell and a smooth μG surface (fuzzy core−shell model). A fit of the experimental data and corresponding density profile is depicted in Figure 7. The C1−S1 shows no differences in density between core and shell at pH 2. The density of the neutral shell decays gradual at the μG surface. At pH 10, the swelling of the charged μG shell causes a smearing of the density profile over a wide pH-range. At intermediate pH, the density profile indicates some pronounced differences compared acidic or basic pH. A denser polymer layer around the μG core was observed; this can be explained by intramicrogel complexation. The lack of dangling chains at the μG surface caused a sharp decay of the density. After F


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So far, we could demonstrate that the results obtained from simulations were reliable and are in line with our experimental results. Highly Charged Polyampholyte Core−Shell Microgels to Maximize the Skin Effect. In this section, we optimize the design of polyampholyte core−shell microgels in computer simulations: the molecular weight of all microgels remains the same, 14000 beads (Series 2), and higher charge densities are used with the aim to make these systems attractive for uptake and release of neutral guest molecules. Keeping in mind that the maximum numbers of cationic groups in the core (pH = 2) and anionic groups in the shell (pH = 10) are 1400 for all molar ratios, the fractions of the charged groups in the core and shell will be different except for the C1-S1: φ+max−φ‑max = 20%−20% (C1-S1), 40%−13% (C1-S3), 80%−11% (C1-S7). The gyration radius of the novel μGs as a function of pH is shown in Figure 8. All the curves have U-like shape with equal

Figure 8. Gyration radius Rg as a function of pH. The maximum numbers of charged groups in the core and the shell are fixed and equal to 1400 (series 2). Different compositions of the μG are shown by gray (C1−S1), red (C1−S3), and blue (C1−S7) lines.

Figure 6. Equilibrium structures of the core−shell μGs (a thin slice around the center of mass) with different core−shell composition: C, C1−S1 and C1−S7 depending on the fraction of positively (red) and negatively (blue) charged groups φ+−φ−: 10%−0% (pH = 2); 7%−3% (pH = 4.4); 5%−5% (pH = 6); 3%−7% (pH = 7.6); 0%−10% (pH = 10). Counterions are not shown. εLj = 0.01kBT.

isoelectric point. The equality is due to the equal number of cationic and anionic groups in the core and shell, respectively, and their symmetric changing with pH for all microgel molar ratios, Figure 3 (left). However, the swelling degree is different at different pH. Smaller swelling of the C1-S7 μG at lower pH is related to smaller molecular weight of highly charged core in comparison with the shell (1/8 of the total weight of the μG). The small charged core cannot provide high swelling of the whole μG. Furthermore, a high swelling degree of the core− caused by electrostatic repulsion of high fraction of unscreened charged groups (φ+max = 0.8) and by osmotic pressure of counterions localized in the core - is protected by the shell, which acts as a corset: practically fully stretched subchains penetrate into the neutral shell at pH = 2 and the μG takes a quasi-hollow structure, Figure 9. Maximum of concentration of charged groups at the periphery, Figure 10, pH = 2, C1-S7, is related to the decrease of the electrostatic energy. This effect was detected recently for structurally homogeneous polyelectrolyte microgels, where quasi-hollow structure is formed due to preferential redistribution of charged groups to the periphery.32 Therefore, in the core−shell microgel with strongly charged core (pH = 2), there are two physical reasons leading to the formation of the dense shell: (i) effect of corset and (ii) migration of the charged groups to the periphery. Increasing pH switches on negative charges in the shell, which electrostatically attract to the cations of the core forming interpolyelectrolyte complex. The distinct quasi-hollow structure of C1-S7 μG is stable within a wide range of pH values, Figures 9 and 10: pH = 2−7.6. Only charged shell and neutral

Figure 7. Left: Scattering profiles of C1−S1 at different pH-values. The curves have been shifted vertically by a constant factor for clarity: I × 100 (pH = 2) and I × 10 (pH = 6). Experimental data were fitted with a fuzzy core−shell model (solid lines). Experiments were carried out at 5 mM buffer concentration and a total ionic strength of 50 mM. Right: Resulting radial density profiles according to a fuzzy core−shell model (black) and deconvolution (different colors).

normalizing the area of the density profiles the modeled density profile agrees almost perfectly with the density profile obtained by deconvolution at acidic and basic pH. The general trend of a denser corona formed at intermediate pH could be observed for both methods; however, a rather small difference in μG size was obtained. G


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the fraction of charged groups: the overlap regions of red and blue curves in Figure 10 are wider than those in Figure 5. The question arises how to quantify capacity (available space) of the quasi-hollow microgels for the guest molecules. At first glance, the capacity should depend on the size of the cavity. However, the latter does not have a straightforward definition. If we would define the spatial coordinates of junctions between the core and shell of the microgels as the radius of the cavity, it would not be correct because the junctions can deeply penetrate into the dense shell like shown in Figure 9, C1-S7, pH = 2. More reasonable way to define the size is the analysis of the density profiles, Figure 10. Despite the boundary between the cavity and the shell is not sharp, we can define the imaginary boundary like a place, where the polymer volume fraction is in-between maximum and minimum values. However, the size of the cavity is not enough to characterize its capacity for guest molecules. The polymer volume fraction in the cavity plays also important role: the smaller the volume fraction, the higher the capacity. In this sense, the polymer density profiles carry more complete information about the capacity than the size of the cavity. Summarizing the peculiarity of the swelling behavior of the core−shell μGs with different composition and fraction of charged groups, one can conclude that there is a wide range of parameters, where the equilibrium structure of the μG exhibits a quasi-hollow motif: very loose core of strongly stretched subchains and dense periphery. The higher concentration of monomer units at the periphery can be caused by interpenetration of the subchains. The driving force for the interpenetration can be strong electrostatic repulsion of monomer units in the core leading to its strong swelling and to the effect of a corset of the neutral shell (Figure 9 and Figure 10, C1−S7 at pH = 2). In addition, electrostatic complexation of oppositely charged subchains is responsible for the increase of concentration at the periphery (Figure 9 and Figure 10, pH = 6 and 7.6). Similar to homogeneous μGs,55 electrostatic interactions play a dominant role in formation and further evolution of the quasi-hollow structure in the core−shell μGs. In contrast to the polyampholyte μGs with random distribution of ionizible groups,52 the core−shell μGs reveal better colloidal stability at the isoelectric point due to the core− shell distribution of opposite charge: if the shell is sufficiently thick, electrostatic complexation proceeds within the μG and noncomplexed charged subchains on the surface prevent aggregation of the μGs. This peculiarity opens a great potential to use such objects as carriers for molecular objects, which can be loaded and released via variation of pH. For example, consider the C1−S7 μGs at pH = 10 shown in Figure 9. They are colloidally stable due to the charged shell and can be loaded with neutral molecules, which can penetrate both into the core and the shell. Decreasing the pH will lock them via the formation of a dense skin of complexed subchains (Figure 9, pH = 7.6−2) and the stability of the loaded μG will be highest at lowest pH = 2 when the shell becomes neutral. In this state, the trapped molecules can be transported with the μG and released upon increase of pH. Furthermore, the polyampholyte core−shell μGs can efficiently be used for uptake and release of charged molecular objects, which will be discussed in forthcoming publications.

Figure 9. Equilibrium structures of the core−shell μGs (a thin slice around the center of mass) of the fixed of overall molecular weight (14000 beads) and different core−shell composition: C1−S1, C1−S3 and C1−S7 (series 1). The ratio between the number of cations and anions in the core and the shell, n+−n−, is defined as follows: 1400−0 (pH = 2), 980−420 (pH = 4.4), 700−700 (pH = 6), 420−980 (pH = 7.6), and 0−1400 (pH = 10). Red and blue dots in the core and the shell depict cations and anions, respectively. Counterions are not shown. εLj = 0.01kBT.

core (pH = 10) provide homogeneous swelling: swollen charged shell radially stretches the neutral core, Figures 9 and 10. Better swelling of the C1-S3 μG at low pH (Figure 8) is related to higher molecular weight of charged core (1/4 of the total weight of the μG). The maximum swelling degree at pH = 2 is observed for the C1−S1 μG because half of the beads form charged core. The minimum size of all μGs is obtained for the case of isoelectric point (Figure 8). Here, complexation of oppositely charged subchains around the core−shell interface leads to their interpenetration, which is accompanied by an expansion of the core (Figure 9, pH = 6). The concentration profiles in the corresponding regimes (Figure 10) reveal strong inhomogeneities with the maximum at the periphery and very small concentration in the center for all molar compositions. However, the biggest difference in concentration is observed for the C1-S7 microgel due to higher fraction of the charged groups in the core. Further increase of pH results in homogeneous swelling of all μGs independently on their molar ratio, Figure 10, pH = 10. Figure 10 also clearly demonstrates that the depth of interpenetration of the complexed subchains increases with H


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Figure 10. Polymer volume fraction of μGs as a function of radial coordinate r at εLj = 0.01kBT (good solvent). Columns correspond to different μGs: C1−S1, C1−S3, and C1−S7. Different rows distinguish ratio of the number of charged groups in the core and the shell, n+−n−: 1400−0 (pH = 2), 980−420 (pH = 4.4), 700−700 (pH = 6), 420−980 (pH = 7.6), and 0−1400 (pH = 10). Dark gray and light gray regions depict polymer volume fraction of the core and the shell, respectively. Black curve denotes the total polymer volume fraction. Volume fractions of cationic and anionic groups in the microgels are shown by red and blue curves, respectively. Left (black) and right (blue) vertical axes measure polymer volume fraction and volume fraction of charged groups, respectively.

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CONCLUSIONS Computer simulations and SAXS measurements revealed formation of dense interfacial layer (“skin”) in polyampholyte core−shell microgels. The skin is formed due to the electrostatic complexation of subchains near the core−shell interface under condition that the core and shell are oppositely charged. The thickness of the layer is determined by the depth of interpenetration of the subchains, which is controlled by their length, fraction of charged groups and core−shell composition. The density of the layer is mainly controlled by the fraction of charged groups: the higher the fraction, the denser the layer. We have studied pH-sensitive microgels. Cationic core with neutral shell and neutral core with anionic shell are the states of the microgels at low (pH = 2) and high (pH = 10) pH, respectively. The complexation proceeds at intermediate pH values. We have shown that the microgels reveal quasi-hollow structure of strongly swollen core and dense periphery especially in the case of high fraction of charged groups. There are few physical reasons for that. Microgels of cationic core with neutral shell at pH = 2 swell due to the electrostatic repulsion of similarly charged groups and osmotic pressure of counterions, which are localized within the core. As a result, the core strongly swells whereas neutral shell plays a role of corset constraining swelling: the boundary subchains of the core penetrate into the shell forming dense periphery, Figure 9 (C1-S7). Also, such penetration is driven by electrostatic repulsion of the charged groups: higher concentration of charged groups at the periphery, Figure 10 (C1-S7), reduces the electrostatic energy.47 At intermediate pH values, the quasi-hollow structure is a consequence of complexation of

oppositely charged subchains, Figure 9, pH = 6. Homogeneous swelling of the microgels (similar swelling of the core and shell) is obtained at high pH (pH = 10), Figure 10. Because of the charge segregation, the microgels are colloidally stable in the whole range of the pH values including isoelectric point. Thus, the core−shell microgels can be efficient as a carrier of neutral guest molecules whose uptake, storage and release are pHcontrolled.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b00553. Microgel synthesis, dynamic light scattering, 1H NMR, NMR analysis of different microgels and estimation of amount of comonomers, evaluation of scattering data, temperature measurements of cationic core microgel and different core-shell particles, and computer simulations (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (I.I.P.). ORCID

Andrij Pich: 0000-0003-1825-7798 Walter Richtering: 0000-0003-4592-8171 Igor I. Potemkin: 0000-0002-6687-7732 I


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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The financial support of the Deutsche Forschungsgemeinschaft (DFG) within Collabolative Research Center SFB 985 “Functional Microgels and Microgel Systems” and the Russian Science Foundation, Project No. 15-13-00124, is gratefully acknowledged. The work was supported by the Government of the Russian Federation within Act 211, Contract No. 02.A03.21.0011. A.P.H.G. thanks Larissa Laurini for her help with microgel characterization experiments and Dr. Andrea Scotti for fruitful discussion. The authors gratefully acknowledge the computing time granted by the John von Neumann Institute for Computing (NIC) and provided on the supercomputer JURECA77 at the Jülich Supercomputing Centre (JSC). The European Synchrotron Radiation Facility (ESRF), Grenoble, France, is gratefully acknowledged for allocation of the beamtime at the High Brilliance Beamline ID02.

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