Controlled Release Using a Polymer Stereocomplex Capsule through

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Controlled Release Using a Polymer Stereocomplex Capsule through the Selective Extraction and Incorporation of One Capsule Shell Component Toshiyuki Kida, Masataka Mouri, Kenta Kondo, and Mitsuru Akashi* Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita 565-0871, Japan S Supporting Information *

ABSTRACT: Isotactic poly(methyl methacrylate) (it-PMMA)/syndiotactic poly(methacrylic acid) (st-PMAA) stereocomplex hollow capsules were fabricated by the deposition of stereocomplex films of it-PMMA and st-PMAA on silica particles by alternate layer-by-layer assembly and the subsequent removal of the silica particles with aqueous HF. The selective extraction of st-PMAA from the itPMMA/st-PMAA stereocomplex capsule shells was successfully carried out by immersion in a pH 6−9 aqueous solution. The incorporation of st-PMAA into the resulting porous capsule shells was performed by immersion in an acetonitrile/water (1/1) solution of stPMAA. The controlled release of an encapsulated dye from the itPMMA/st-PMAA hollow capsules was achieved by combining the selective extraction of st-PMAA from the capsule shells and the incorporation of st-PMAA into the resulting porous shells.

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INTRODUCTION Hollow capsules of nanometer to micrometer size have attracted considerable attention because of their great potential applications as biomedical and pharmaceutical materials such as drug carriers and molecular containers.1−3 In particular, much effort has been devoted to the development of stimuliresponsive hollow capsules, which allow the controlled release of encapsulated substances by external stimuli.4−6 Until now, the release control of encapsulated substances has been carried out by the change in the capsule shell permeability,7−11 the shell degradation,12−15 or the opening and closing of gates embedded into the capsule shell,16,17 which respond to stimuli such as pH, ionic strength, heat, light, and enzymes. For instance, Caruso et al. reported that the encapsulated protein was released from poly(L-lysine)/poly(L-glutamic acid) capsules via the swelling of the capsule shell by pH and ionic strength changes.18 Skirtach et al. reported the controlled release of encapsulated dextran from polymeric microcapsules including aggregates of gold nanoparticles by utilizing the local heating of the capsule shell upon near-IR laser light illumination.19 We also reported the controlled release of encapsulated proteins from nanocapsules composed of chitosan-dextran sulfate multilayer films through the enzymatic degradation of the chitosan components in the capsule shell.20 However, successful on−off release control with these hollow capsules is still a challenging task, possibly because of the difficulty in allowing full release under specific stimulation conditions but retaining the complete suppression of release under normal conditions. To construct an ideal release control system, in which the on−off control of release of the encapsulated © 2012 American Chemical Society

substances is perfectly realized, a novel design concept for the fabrication of a stimuli-responsive hollow capsule is required. Poly(methyl methacrylate) (PMMA) has been widely utilized in biomedical fields because of its excellent biocompatibility.21,22 It is well known that isotactic (it) PMMA and syndiotactic (st) PMMA form a double-stranded helical assembly with van der Waals interactions in the appropriate solvents.23,24 Recently, we succeeded in the preparation of stable hollow capsules composed of PMMA stereocomplex multilayer shells by a combination of the alternate layer-by-layer (LbL) assembly25−28 of it- and stPMMAs and a silica template method.29 Our research group also reported that it-PMMA/st-poly(methacrylic acid) (stPMAA) stereocomplex films were deposited onto a Au substrate by the LbL assembly method.30 st-PMAA was selectively extracted from the stereocomplex films in an alkaline solution, and, in turn, the extracted st-PMAA could be incorporated into the remaining porous it-PMMA film to reconstruct the stereocomplex film.31 If the st-PMMA component in the stereocomplex shell of the it-PMMA/stPMMA hollow capsule is replaced by st-PMAA, then one can construct a pH-responsive hollow capsule in which the stPMAA can be selectively extracted from the it-PMMA/stPMAA stereocomplex shell in certain pH regions. However, itPMMA/st-PMAA hollow capsules can be regenerated through the incorporation of st-PMAA into the porous it-PMMA shell of the resulting hollow capsule. Herein, we report the Received: August 1, 2012 Revised: September 24, 2012 Published: September 30, 2012 15378

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(model 53131A). The quartz crystal was coated on both sides with mirrorlike polished gold electrodes. The QCM leads were coated with silicon rubber gel to prevent degradation during the polymer deposition processes. The amount of adsorbed polymer (Δm) was calculated from a decrease in the frequency of the QCM (ΔF) according to Sauerbrey’s equation: [−ΔF (Hz) = 1.15Δm (ng)].36 Before polymer deposition, the QCM surface was cleaned twice with piranha solution (H2SO4/H2O2 = 3/1 v/v) for 1 min each time, followed by rinsing with water and drying with N2 gas. The obtained hollow capsules were characterized by FT-IR/ATR spectra, X-ray diffraction (XRD) measurements, and scanning electron microscope (SEM) and transmission electron microscope (TEM) observations. FT-IR spectra were recorded using a Perkin-Elmer Spectrum One instrument. The XRD measurements were carried out using a Rigaku RINT In Plane/ultraX18SAXS-IP instrument. The SEM observations were performed with a JEOL JSM-6701F electron microscope. The TEM observations were performed with a JEM100CX-S1 electron microscope. The fluorescence intensity was measured with a Pharmacia Biotech Ultraspec 2000 spectrofluorometer. Fluorescence and confocal microscope images were obtained with an Olympus IX81 system equipped with fluorescence filters (ex. 470−495 nm/em. 510−550 nm for fluorolabeled-st-PMAA; ex. 540− 550 nm/em. 575−625 nm for rhodamine 6G).

fabrication of a novel type of stimuli-responsive hollow capsule composed of it-PMMA/st-PMAA stereocomplex shells and the on−off control of release of an encapsulated substance from this hollow capsule. Because of the large difference in water solubility between it-PMMA and st-PMAA (st-PMAA is very soluble in neutral and alkaline aqueous solutions unlike itPMMA, which is only slightly soluble in aqueous solutions), the selective extraction of st-PMAA from the stereocomplex shell should be possible in neutral and alkaline aqueous solutions. In addition, it is also expected that the reconstruction of the itPMMA/st-PMAA capsule shell could be achieved through the incorporation of st-PMAA into the porous shell of the resulting it-PMMA capsule. By utilizing this property of st-PMAA, which would function as if it were a plug for the pores of the it-PMMA capsule shell, the on−off control of release of encapsulated substances would become possible. To the best of our knowledge, this is the first example of the controlled release of an encapsulated substance from hollow capsules by utilizing the stimuli-responsive extraction of polymer plugs from the capsule shell and the incorporation of the polymer plugs into the resulting porous shell.

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RESULTS AND DISCUSSION Preparation of Hollow Capsule. The preparation of hollow capsules composed of it-PMMA/st-PMAA stereocomplex shells was carried out according to the process shown in Figure 1. We chose silica particles as a template core

EXPERIMENTAL SECTION

Materials. it-PMMA (Mn = 20 400, Mw/Mn = 1.21, isotactic (mm)/heterotactic (mr)/syndiotactic (rr) triads = 99/1/0) was synthesized by conventional anionic polymerization using MMA monomers and t-C4H9MgBr as an initiator.32 st-PMAA (Mn = 36 000, Mw/Mn = 1.30, mm/mr/rr = 1/3/96) was synthesized by anionic polymerization using trimethylsilyl methacrylate and t-C4H9Li/MeAl(2,6-di-t-butylphenoxide)2 as a monomer and an initiator, respectively, followed by the hydrolysis of the resulting polymer with 1 M HCl in methanol.33 Fluorolabeled st-PMAA was prepared by stirring 5(bromomethyl)fluorescein (10 mg) and st-PMAA (50 mg) in a 25 mL acetonitrile/water (1/1) solution for 50 h at 25 °C according to a previously reported method.34 Mesoporous silica particles with an average diameter of 2 μm were kindly supplied by Suzuki Yushi Industrial Co., Ltd., Japan. The pore size distribution of the mesoporous silica particles was calculated to be 2−8 nm from the nitrogen adsorption isotherm at 77.4 K using the BJH method.35 Preparation of Hollow Capsules. Silica nanoparticles with an average diameter of 330 nm (180 mg) were alternately immersed into a 25 mL acetonitrile/water (9/1) solution of it-PMMA (42.5 mg) and a 25 mL acetonitrile/water (1/1) solution of st-PMAA (37.5 mg) for 15 min at 25 °C with gentle shaking. After each immersion, the silica nanoparticles were separated from the solution by centrifugation and then rinsed three times with the acetonitrile/water (9/1) solution and the acetonitrile/water (1/1) solution. The immersion process was continued for 10 cycles to afford 10 double layers of it-PMMA/stPMAA. The resulting particles were then treated with 2.3% aqueous HF for 12 h at 25 °C to remove the silica cores and finally rinsed five times with water. Rhodamine 6G-encapsulated it-PMMA/st-PMAA stereocomplex hollow capsules were prepared by the deposition of it-PMMA/stPMAA stereocomplex films onto rhodamine 6G-encapsulated mesoporous silica particles with an average diameter of 2 μm (pore size = 2−8 nm) by the LbL method (10 cycles) and the subsequent removal of the silica cores with an aqueous HF solution. The encapsulation of rhodamine 6G into the mesoporous silica particles was performed by stirring the mesoporous silica particles (180 mg) in an aqueous solution of 0.1 wt % rhodamine 6G (50 mL) for 24 h and then rinsing the particles with water. The release of encapsulated rhodamine 6G from the it-PMMA/st-PMAA hollow capsule was monitored by measuring the fluorescence intensity of rhodamine 6G released into the bulk solution. Characterization. An AT-cut quartz crystal microbalance (QCM) with a parent frequency of 9 MHz was purchased from USI (Japan). The frequency was monitored with an Iwatsu frequency counter

Figure 1. Schematic illustration of the fabrication process of itPMMA/st-PMAA stereocomplex hollow capsules and it-PMMA hollow capsules.

because silica can be easily removed from the conjugate with the polymers by treatment with aqueous HF. Silica nanoparticles with an average diameter of 330 nm were alternately immersed into an acetonitrile/water (9/1) solution of itPMMA (Mn = 20 400, Mw/Mn = 1.21, mm/mr/rr = 99/1/0) and an acetonitrile/water (1/1) solution of st-PMAA (Mn = 36 000, Mw/Mn = 1.30, mm/mr/rr = 1/3/96) for 15 min at 25 °C. After each immersion, the silica nanoparticles were rinsed with the corresponding acetonitrile/water solution. This immersion process was continued for 10 cycles to generate 10 double layers of it-PMMA and st-PMAA. The resulting particles were then treated with 2.3 wt % aqueous HF to remove the silica cores. Figure 2b,c shows the transmission electron microscope (TEM) images of the silica particles coated with it-PMMA/stPMAA films and the it-PMMA/st-PMAA hollow capsules thus obtained, respectively. These images clearly indicate that itPMMA/st-PMAA hollow capsules were successfully fabricated without any damage to the shell film. The hollow capsules have a spherical shape with an average diameter of 490 nm. Their 15379

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(1690 cm−1) alone, in accordance with a previous result for the it-PMMA/st-PMAA stereocomplex films constructed on a Au substrate.30 This result confirms the formation of it-PMMA/stPMAA stereocomplex hollow capsules. XRD analysis of the it-PMMA/st-PMAA hollow capsules showed two peaks characteristic of the it-PMMA/st-PMAA stereocomplex (2θ = 12 and 15°),37 whose peaks were different from those of it-PMMA and st-PMAA alone (Figure 4a,c,d). In

Figure 2. TEM images of (a) silica particles, (b) silica particles coated with it-PMMA/st-PMAA stereocomplex films, (c) it-PMMA/st-PMAA stereocomplex hollow capsules, and (d) it-PMMA hollow capsules obtained after the extraction of st-PMAA from it-PMMA/st-PMAA stereocomplex hollow capsules.

shell thickness is about 80 nm. On the other hand, selfassembled multilayer films of it-PMMA or st-PMAA alone were not formed on the silica particles. This result shows that the formation of a stereocomplex between it-PMMA and st-PMAA is essential to the fabrication of an it-PMMA/st-PMAA multilayered film on a silica particle. Infrared (IR) spectroscopy and X-ray diffraction (XRD) analysis are effective methods for evaluating the stereocomplex formation between it-PMMA and st-PMAA. In the FT-IR/ATR spectrum of the obtained it-PMMA/st-PMAA hollow capsule (Figure 3b), two carbonyl stretching vibration peaks were observed at higher wavenumbers (1738 and 1725 cm−1) as compared to those of it-PMMA (1715 cm−1) and st-PMAA

Figure 4. XRD patterns of (a) it-PMMA/st-PMAA stereocomplex hollow capsules, (b) silica particles coated with it-PMMA/st-PMAA stereocomplex films, (c) it-PMMA, (d) st-PMAA, and (e) silica particles.

the XRD patterns of it-PMMA/st-PMAA hollow capsules, a peak of silica particles at around 22° was not observed, indicating that almost all of the silica was removed from the itPMMA/st-PMAA film-coated silica particles by HF etching (Figure 4a,b). In addition, inductively coupled plasma (ICP) emission analysis of the obtained capsules showed that more than 99.9% of the Si atoms were removed from the it-PMMA/ st-PMAA film-coated silica particles. These results strongly support the formation of hollow capsules composed of itPMMA/st-PMAA stereocomplex shells. Extraction of st-PMAA from it-PMMA/st-PMAA Stereocomplex Films. Prior to studies on the extraction of stPMAA from the it-PMMA/st-PMAA capsule shells, the extraction behavior of st-PMAA from it-PMMA/st-PMAA stereocomplex films under various pH conditions was examined by using a quartz crystal microbalance (QCM), which allows the monitoring of the extraction of st-PMMA on the nanogram scale from stereocomplex films constructed on a Au substrate, on the basis of the frequency shift of the QCM. The LbL film between it-PMMA and st-PMAA was fabricated on the QCM substrate by the alternate immersion of the QCM substrate in it-PMMA and st-PMAA solutions for 10 cycles, according to a procedure reported previously.30 The extraction behavior of stPMAA from the stereocomplex films constructed on the QCM substrate was examined in various pH solutions (Figure 5). In a pH 5 aqueous solution, st-PMAA was barely extracted from the stereocomplex film, whereas a remarkable extraction of stPMAA was observed in pH 6−9 solutions. This result can be explained by considering that in the pH 5 solution the

Figure 3. FT-IR/ATR spectra of (a) it-PMMA hollow capsules obtained after the extraction of st-PMAA from it-PMMA/st-PMAA stereocomplex hollow capsules, (b) it-PMMA/st-PMAA stereocomplex hollow capsules, (c) it-PMMA, and (d) st-PMAA. 15380

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cycles) and the subsequent removal of the silica cores with an aqueous HF solution yielded rhodamine 6G-encapsulated stereocomplex hollow capsules (Figure 6). Figure 7 shows

Figure 6. (a) Optical microscope image and (b) fluorescence microscope image of rhodamine 6G-encapsulated it-PMMA/stPMAA stereocomplex hollow capsules. The latter image was taken with a fluorescence filter for rhodamine 6G.

Figure 5. Extraction behavior of st-PMAA from it-PMMA/st-PMAA stereocomplex films constructed on a QCM substrate in various pH solutions.

dissociation of the carboxylic groups of st-PMAA (pKa = 5.7) into carboxylate ions is not sufficient to be extracted into the bulk solution from the stereocomplex film. The extraction rate of st-PMAA into the bulk solution increased with an increase in the pH of the solution. In the pH 9 solution, the st-PMAA components were almost completely extracted within 4 h. These results suggest that the extraction of st-PMAA from the it-PMMA/st-PMAA stereocomplex film can be controlled by the pH of the bulk solution. On the basis of these results, we examined the selective extraction of st-PMAA from the it-PMMA/st-PMAA stereocomplex shells of hollow capsules. Figure 3a shows the IR spectrum of hollow capsules obtained by immersing it-PMMA/ st-PMAA stereocomplex hollow capsules in a pH 6 solution for 48 h. The carbonyl peak of st-PMAA at 1725 cm−1, which was observed in the IR spectrum of the original it-PMMA/st-PMAA hollow capsule, disappeared, whereas the carbonyl peak of itPMMA at 1738 cm−1 remained. This observation indicates that the st-PMAA component was selectively and almost completely extracted from the stereocomplex capsule shell under these conditions, in accordance with the results on the st-PMAA extraction from the it-PMMA/st-PMAA stereocomplex films on a QCM substrate (Figure 5). Interestingly, the carbonyl peak of the it-PMMA remaining in the capsule shell was shifted very little after the extraction of st-PMAA, suggesting that the conformation of it-PMMA in the capsule shell, which possibly corresponded to a stable trans−trans conformation,24,38 was maintained even after the st-PMAA extraction. Figure 2d is the TEM image of the it-PMMA capsule obtained after the extraction of st-PMAA. The diameter and film thickness were barely changed by the st-PMAA extraction. However, the SEM images showed that the surface structure of the capsule was remarkably changed by the st-PMAA extraction, from a smooth surface to a rough surface with hollows of 1 to 2 nm in size (Supporting Information, Figure S1b,d). Dye Release from Hollow Capsules. The release of an encapsulated fluorescent dye from the it-PMMA/st-PMAA hollow capsules was examined in various pH solutions at 25 °C. Rhodamine 6G was employed as a fluorescent dye. The encapsulation of rhodamine 6G in the hollow capsules was easily carried out by using rhodamine 6G-entrapped mesoporous silica particles with an average diameter of 2 μm (pore size = 2−8 nm) as template cores. The deposition of itPMMA/st-PMAA stereocomplex films onto the rhodamine 6Gentrapped mesoporous silica particles by the LbL method (10

Figure 7. Release behavior of encapsulated rhodamine 6G from itPMMA/st-PMAA stereocomplex hollow capsules in various pH solutions at 25 °C.

the release behavior of rhodamine 6G from the it-PMMA/stPMAA hollow capsules in various pH solutions as a function of time. In pH 6−9 solutions, a remarkable release of rhodamine 6G was observed, whereas in the pH 5 solution, the release was not observed within 20 h. Interestingly, in pH 6−8 solutions, some induction periods were observed before the release began. The release rate of rhodamine 6G increased with an increase in the pH of the solution. In the pH 9 solution, more than 90% of the rhodamine 6G molecules were released within 5 h. This release behavior was consistent with the extraction behavior of st-PMAA from the it-PMMA/st-PMAA stereocomplex films on a QCM substrate (Figure 5), indicating that the release of rhodamine 6G from it-PMMA/st-PMAA hollow capsules can be controlled by the extraction of st-PMAA from the capsule shell into the bulk solution. To clarify the relationship between the release behavior of encapsulated rhodamine 6G and the extraction of st-PMAA from the capsule shell, we prepared hollow capsules composed of it-PMMA/fluorolabeled st-PMAA stereocomplex shells (10 double layers). Fluorolabeled st-PMAA was prepared by the reaction of 5-(bromomethyl)fluorescein with st-PMAA according to a previously reported method.34 Using these hollow capsules, the release of rhodamine 6G and the extraction of fluorolabeled st-PMAA from the hollow capsule can be simultaneously monitored with a confocal microscope. Figure 8 shows confocal microscope images of the rhodamine 6Gencapsulated hollow capsules after immersion into a pH 6 solution for 0, 6, 15, and 21 h. On the basis of the change in the fluorescence intensity of fluorolabeled st-PMAA in the capsule shell, we estimated the content of st-PMAA remaining in the 15381

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it-PMMA and st-PMAA, then the release of the encapsulated dye should be suppressed. Thus, we examined the incorporation of st-PMAA into the porous capsule shell by mixing fluorolabeled st-PMAA and porous it-PMMA capsules in acetonitrile/water (1/1) including rhodamine 6G and then rinsing the resulting capsules with acetonitrile/water (1/1) to remove rhodamine 6G completely from the nonsealed porous capsules. Confocal microscope images of the obtained capsules clearly showed that fluorolabeled st-PMAA and rhodamine 6G were incorporated into the capsule shell and core, respectively (Figure 8e). In the IR spectrum of the resulting capsules (Supporting Information, Figure S2a), two carbonyl stretching vibrational peaks were observed at higher wavenumbers (1736 and 1723 cm−1) as compared to those for it-PMMA (1715 cm−1) and fluorolabeled st-PMAA (1700 cm−1, here the carbonyl stretching vibrational peak that originated from the 5(bromomethyl)fluorescein group was also observed at around 1645 cm−1) alone, analogous to the case of it-PMMA/st-PMAA hollow capsules. This observaion confirmed the reconstruction of hollow capsules composed of it-PMMA/fluorolabeled stPMAA stereocomplex shells. The resulting it-PMMA/fluorolabeled st-PMAA hollow capsules were able to retain rhodamine 6G stably inside for more than 1 week. By combining the selective extraction of st-PMAA from the it-PMMA/st-PMAA capsule shell and the incorporation of stPMAA into the resulting porous shell, the controlled release of the encapsulated substance from the it-PMMA/st-PMAA stereocomplex capsule could be realized (Figure 10). The

Figure 8. Confocal microscope images of rhodamine 6G-encapsulated it-PMMA/fluorolabeled st-PMAA stereocomplex capsules after immersion in a pH 6 aqueous solution for (a) 0, (b) 6, (c) 15, and (d) 21 h, and (e) rhodamine 6G-encapsulated it-PMMA/fluorolabeled st-PMAA stereocomplex capsules reconstructed by the incorporation of fluorolabeled st-PMAA and rhodamine 6G into the porous itPMMA capsules.

capsule shell. In a pH 6 aqueous solution, about 50% of the stPMAA was extracted from the capsule shell after 6 h, whereas the release of encapsulated rhodamine 6G was not observed during this time (Figures 8b and 9). When the extraction of st-

Figure 10. Schematic illustration of the controlled release of encapsulated rhodamine 6G from it-PMMA/st-PMAA hollow capsules by using the selective extraction and incorporation of st-PMAA. Figure 9. (a) Extraction of fluorolabeled st-PMAA and (b) release of encapsulated rhodamine 6G from it-PMMA/fluorolabeled st-PMAA stereocomplex hollow capsules in a pH 6 aqueous solution at 25 °C.

immersion of rhodamine 6G-encapsulated hollow capsules into a pH 6 solution resulted in the release of rhodamine 6G after an induction period of 7 h (Figure 11). When the percentage of release of rhodamine 6G reached around 50%, the capsule was then immersed in an acetonitrile/water (1/1) solution of stPMAA (0.15 wt %) to incorporate st-PMAA into the porous capsule shell through stereocomplex formation with the remaining it-PMMA. Following this immersion, the release of rhodamine 6G stopped immediately. The subsequent immersion of the capsule in a pH 6 solution caused the release of rhodamine 6G after another induction period of about 5 h. These results revealed that the on−off control of release of the encapsulated substances was achieved by utilizing a combination of the extraction and incorporation of st-PMAA from and into the capsule shell, respectively.

PMAA reached 70% after immersion for about 7 h, the release of rhodamine 6G began. After 18 h, the dye release reached more than 90% and almost saturated. These results strongly support the hypothesis that the release of encapsulated rhodamine 6G is triggered by the extraction of st-PMAA from the capsule shell. From these results, it can be assumed that after the extraction of more than 70% of the st-PMAA from the capsule shell the encapsulated dye can be freely released through the resulting pores in the capsule shell. If one can seal these pores through the reconstruction of the stereocomplex between the remaining 15382

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(3) van Dongen, S. F. M.; de Hoog, H.-P. M.; Peters, R. J. R. W.; Nallani, M.; Nolte, R. J. M.; van Hest, J. C. M. Biohybrid Polymer Capsules. Chem. Rev. 2009, 109, 6212−6274. (4) Esser-Kahn, A. P.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Triggered Release from Polymer Capsules. Macromolecules 2011, 44, 5539−5553. (5) Delcea, M.; Mohwald, H.; Skirtach, A. G. Stimuli-Responsive LbL Capsules and Nanoshells for Drug Delivery. Adv. Drug Delivery Rev. 2011, 63, 730−747. (6) Wang, Y.; Hosta-Rigau, L.; Lomas, H.; Caruso, F. Nanostructured Polymer Assemblies Formed at Interfaces: Applications from Immobilization and Encapsulation to Stimuli-Responsive Release. Phys. Chem. Chem. Phys. 2011, 13, 4782−4801. (7) De Geest, B. G.; Sanders, N. N.; Sukhorukov, G. B.; Demeester, J.; De Smedt, S. C. Release Mechanism for Polyelectrolyte Capsules. Chem. Soc. Rev. 2007, 36, 636−649. (8) Ma, Y.; Dong, W.-F.; Hempenius, M. A.; Möhwald, H.; Vancso, J. Redox-Controlled Molecular Permeability of Composite-Wall Microcapsules. Nat. Mater. 2006, 5, 724−729. (9) Shchukin, D. G.; Sukhorukov, G. B.; Möhwald, H. Smart Inorganic/Organic Nanocomposite Hollow Microcapsules. Angew. Chem., Int. Ed. 2003, 42, 4472−4475. (10) Balabushevich, N. G.; Tiourina, O. P.; Volodkin, D. V.; Larionova, N. I.; Sukhorukov, G. B. Loading the Multilayer Dextran Sulfate/Protamine Microsized Capsules with Peroxidase. Biomacromolecules 2003, 4, 1191−1197. (11) Antipov, A. A.; Sukhorukov, G. B.; Möhwald, H. Influence of the Ionic Strength on the Polyelectrolyte Multilayers’ Permeability. Langmuir 2003, 19, 2444−2448. (12) Boaders, K. E.; Pastine, S. J.; Grandhe, S.; Frechet, M. J. AcidDegradable Solid-Walled Microcapsules for pH-Responsive BurstRelease Drug Delivery. Chem. Commun. 2011, 47, 665−667. (13) Esser-Kahn, A. P.; Sottos, N. R.; White, S. R.; Moore, J. S. Programmable Microcapsules from Self-Immolative Polymers. J. Am. Chem. Soc. 2010, 132, 10266−10268. (14) Fomina, N.; McFearin, C.; Sermsakdi, M.; Edigin, O.; Almutairi, A. UV and Near-IR Triggered Release from Polymeric Nanoparticles. J. Am. Chem. Soc. 2010, 132, 9540−9542. (15) Zelikin, A. N.; Li, Q.; Caruso, F. Disulfide-Stabilized Poly(methacrylic acid) Capsules: Formation, Cross-Linking, and Degradation Behavior. Chem. Mater. 2008, 20, 2655−2661. (16) Kim, J.-K.; Lee, E.; Lim, Y.-b.; Lee, M. Supramolecular Capsules with Gated Pores from an Amphiphilic Rod Assembly. Angew. Chem., Int. Ed. 2008, 47, 4662−4666. (17) Chu, L.-Y.; Park, S.-H.; Yamaguchi, T.; Nakao, S. Preparation of Micron-Sized Monodispersed Thermoresponsive Core-Shell Microcapsules. Langmuir 2002, 18, 1856−1864. (18) Yu, A.; Wang, Y.; Barlow, E.; Caruso, F. Mesoporous Silica Particles as Templates for Preparing Enzyme-Loaded Biocompatible Microcapsules. Adv. Mater. 2005, 17, 1737−1741. (19) Skirtach, A. G.; Karageorgiev, P.; Bédard, M. F.; Sukhorukov, G. B.; Möhwald, H. Reversibly Permeable Nanomembranes of Polymeric Microcapsules. J. Am. Chem. Soc. 2008, 130, 11572−11573. (20) Itoh, Y.; Matsusaki, M.; Kida, T.; Akashi, M. EnzymeResponsive Release of Encapsulated Proteins from Biodegradable Hollow Capsules. Biomacromolecules 2006, 7, 2715−2718. (21) Takeyama, T.; Sakai, Y. Poly(methyl methacrylate): One Biomaterial for a Series of Membranes. Contrib. Nephrol. 1999, 125, 9−24. (22) Bettencourt, A.; Almeida, A. J. Poly(methyl methacrylate) Particulate Carriers in Drug Delivery. J. Microencapsulation 2012, 29, 353−367. (23) Spĕvácě k, J.; Schneider, B. Aggregation of Stereoregular Poly(methyl methacrylates). Adv. Colloid Interface Sci. 1987, 27, 81− 150. (24) Schomaker, E.; Challa, G. Complexation of Stereoregular Poly(methy1 methacrylates). 14. The Basic Structure of the Stereocomplex of Isotactic and Syndiotactic Poly(methy1 methacrylate). Macromolecules 1989, 22, 3337−3341.

Figure 11. Controlled release of encapsulated rhodamine 6G from itPMMA/st-PMAA hollow capsules by using the extraction and incorporation of st-PMAA.

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CONCLUSIONS We fabricated it-PMMA/st-PMAA stereocomplex hollow capsules by the deposition of it-PMMA/st-PMAA stereocomplex films onto silica particles by alternate layer-by-layer assembly and then the subsequent removal of the silica particles. The selective extraction of st-PMAA from the itPMMA/st-PMAA stereocomplex hollow capsules was successfully carried out by immersion in a pH 6−9 aqueous solution. On the other hand, the incorporation of st-PMAA into the resulting porous capsule shells was performed by immersion in an acetonitrile/water (1/1) solution of st-PMAA. The on−off control of the release of encapsulated dye from the it-PMMA/ st-PMAA hollow capsules was achieved by using the selective extraction and incorporation of st-PMAA from and into the hollow capsule shell, respectively. We believe that these itPMMA/st-PMAA stereocomplex hollow capsules are potentially applicable in a variety of fields as drug carriers, nanocontainers, and microreactors.

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ASSOCIATED CONTENT

* Supporting Information S

SEM images and FT-IR spectra of the hollow capsules. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We appreciate the technical support for TEM observations by Mr. Toshiaki Hasegawa (Research Center for Ultra-High Voltage Electron Microscopy, Osaka University).

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