Article
Template-Free Uniform-Sized Hollow Hydrogel Capsules with Controlled Shell Permeation and Optical Responsiveness Junoh Kim,†,‡ Hyung-June Lim,‡ Yoon Kyun Hwang,‡ Heeje Woo,† Jin Woong Kim,*,§ and Kookheon Char*,† †
The National Creative Research Initiative Center for Intelligent Hybrids, The WCU Program of Chemical Convergence for Energy & Environment, School of Chemical & Biological Engineering, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-744, Korea ‡ R&D Center, AMOREPACIFIC Co., 314-1 Bora-dong, Giheung-gu, Yongin, Gyeonggi-do, 446-729, Korea § Department of Applied Chemistry, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do, 426-791, Korea S Supporting Information *
ABSTRACT: This study has established a robust and straightforward method for the fabrication of uniform poly(vinylamine) hydrogel capsules without using templates that combines the dispersion polymerization and the sequential hydrolysis/cross-linking. The particle sizes are determined by the degree of cross-linking as well as by the crosslinking reaction time, while the shell thickness is independent of these variables. Diffusion-limited reactions occur at the periphery of the particles, leading to the formation of hydrogel shells with a constant thickness. The treatment of the surfaces of hollow hydrogel capsules with oppositely charged biopolymers limits the permeability through the shell of species even with low molecular weights less than 400 g/mol. Furthermore, we demonstrated that the hydrogel shell phase decorated with Au nanoparticles can be optically ruptured by exposure to laser pulse, a feature that has potential uses in optically responsive drug delivery.
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INTRODUCTION In recent years, wide spectra of micro- and nanosized encapsulation techniques have been developed for fundamental studies as well as for industrial applications. In particular, a wide variety of delivery systems for targeted and controlled release of encapsulated active materials, employing carriers in colloidal forms, have been reported, including liposomes,1−3 polymersomes,4−7 colloidosomes,8−10 hydrogel capsules,11−14 polyelectrolyte-assembled capsules,15−19 polymeric nanoparticles,20−22 lipid nanoparticles,23,24 and nanoparticle-assembled capsules.25−27 Among these systems, hydrogel particles have gained considerable attention because of their excellent loading capacity, tunable permeability, controllable phase behaviors in response to external stimuli, and safety in biological applications, which make them quite useful for the drug delivery. These advantages of hydrogel particles stem from their crosslinked chain networks consisting of hydrophilic polymers. These polymer networks, which can be either physically or chemically cross-linked, not only maintain their structure even in fully hydrated conditions, but also physically entrap active ingredients between the mesh or chemically conjugate them to the polymer chains. A common feature of hydrogel particles is that the cross-link points are evenly distributed throughout the gel phase. Therefore, the whole network responds to external stimuli; thus, fine control over release kinetics is often hampered.28,29 Furthermore, hydrogel particles cannot physi© 2012 American Chemical Society
cally encapsulate water-soluble ingredients, except in some cases where specific molecular interactions, such as electrostatic interaction and lock-and-key interaction, are provided. Thus, it is still required to develop more advanced techniques that allow diversification of the internal structure and morphologies of hydrogel particles. The goal of this study is to develop a robust and straightforward approach that enables the fabrication of uniform micrometer-sized hydrogel particles with spherical shell structure. These hydrogel particles are different from conventional hydrogel particles because of their capsule structure, which consists of water-filled cores surrounded by hydrogel shells. To obtain this kind of capsule structure, template techniques have typically been available in which the core template material is removed by dissolution after the formation of capsule shells. In a different approach, our previous study demonstrated that poly(vinylamine) (PVAm) hydrogel capsules could be prepared by means of in situ hydrolysis followed by cross-linking reactions.30 Present study aims to determine the key factors in the generation of such hydrogel shell structure in order to deepen our understanding of the underlying mechanism. The controllability of shell permeation was investigated by testing permeating species with Received: May 2, 2012 Revised: July 7, 2012 Published: July 11, 2012 11899
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Scheme 1. Schematic on the Synthesis of Hollow PVAm Hydrogel Capsules
mL), then diluted with water (1.1 mL). The mixture shaken for 4 h under light-shielded conditions was washed by repeated centrifugation with water. The average capsule sizes and shell thicknesses were determined by analyzing the confocal laser scanning microscopy (CLSM) images. Scanning electron microscopy (SEM) observation was also performed after lyophilization of the hollow hydrogel capsules. Control of Permeability of Hollow Hydrogel Capsules. To modify the surface properties of the hollow hydrogel capsules, they were treated with an HA solution (1 mg/mL in 0.15 N NaCl) for 1 h and then washed by repeated centrifugation with water. The HA solution contains 0.15 N NaCl. NaCl was added in order to tune the ionic strength of the HA solution, which is essential for avoiding the formation of aggregates of the capsules with counter-charged polymers. The solutions (2 mg/mL in water) of FITC-dextran with various molecular weights were mixed with the HA-treated hollow hydrogels. After 30 min, each mixture was examined with CLSM. In order to test the permeability of the capsules with respect to a small molecule, fluorescein sodium salt solution (2 mg/mL) was used. Synthesis of Au NPs within the Hydrogel Shell Phases. The Au NPs were synthesized within the hydrogel shell phases by following the procedure reported by V. Kozlovskaya et al.31 First, 100 μL capsule suspensions (∼10% w/v in water) were treated with various amounts of GA. After GA treatment, the solutions were washed three times with a borate buffer at pH 10 and mixed with 2 mL of 2 mM HAuCl4 solution in 0.1 M borate buffer (pH 10) for 5 days in the dark. After the reaction, all suspensions were cleaned by repeated centrifugation with water. The effects of the hybridization of Au NPs with the shells of the hollow hydrogel capsules were evaluated by performing UV− visible spectroscopy measurements in a quartz cell with a 10 mm optical path by using a Cary 100 spectrophotometer (Varian). The Au NPs were examined with transmission electron microscopy (JEM2100F HR, Jeol Ltd., Japan). Optically Induced Rupture of the Au NP/PVAm Composite Capsules. A Q-switched Nd:YAG laser beam (Continuum Inc., USA, 532 nm) with varying radiant exposure was employed as the laser source. In order to observe the response to multiple laser pulses, the dispersion of hydrogel capsules loaded with Au NPs was irradiated in a standard quartz cuvette for 1 min with a 10 Hz series of 8 ns laser pulses. The laser was operated at a high pump power (400 mJ per pulse IR output) to achieve a homogeneous top hat, and the multimode laser profile was attenuated to the lower energies required by using an adjustable polarizing beam splitter to keep the beam profile constant in all experiments. After irradiation, the rupture of capsule structure was investigated with a scanning electron microscope (Hitachi S-4300, Japan).
different molecular weights. We also modified the surface of capsule shells with oppositely charged biopolymers and evaluated their permeability. Our hollow hydrogel capsules are unique in that the shell phase, consisting of PVAm networks with many primary amine groups, could undergo strong interactions with other functional species. To demonstrate the applicability of this functional hydrogel shell system, the shells were hybridized with Au nanoparticles (NPs), and their response to laser irradiation was investigated.
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EXPERIMENTAL SECTION
Materials. N-Vinylformamide (NVF), N,N′-methylenebis(acrylamide) (MBA), poly(2-ethyl-2-oxazoline) (Mw ∼50 kDa), glutaraldehyde (GA) solution (50% in H2O), fluorescein isothiocyanate (FITC), FITC-dextran (Mw ≈ 4 kDa, 40 kDa, 250 kDa, 500 kDa), and fluorescein sodium salt were purchased from Sigma-AldrichFluka. α,α′-Azobis(isobutyronitrile) (AIBN) was purchased from Junsei Chemical Co., Ltd., and sodium hydroxide and methanol were purchased from Samchun Pure Chemical Co., Ltd. Hyaluronic acid (HA) sodium salts of various molecular weights were kindly supplied by Bioland Co. Ltd. Hydrogen tetrachloroaurate(III) hydrate (HAuCl4·nH2O, n = 3.7) was purchased from Kojima Chemicals Co., Ltd. 0.1 M borate buffer (pH 10) was received from J. T. Baker. All of the chemicals were used as received. Synthesis of Hollow Hydrogel Capsules. The hollow hydrogel capsules were prepared by using the in situ hydrolysis/cross-linking reaction.30 First, poly(N-vinylformamide) (PNVF) particles were produced by using dispersion polymerization. A mixture of 19.8 g of NVF and 0.2 g of MBA was polymerized at 70 °C for 24 h in 200 mL of methanol containing an initiator (AIBN, 0.1 g) and a stabilizer (poly(2-ethyl-2-oxazoline), 2 g) under a N2 atmosphere. The stirring speed was fixed at 70 rpm. After polymerization, all unreacted monomers and additives were removed by repeated centrifugation with methanol. The diameter of the PNVF particles was 1.81 ± 0.17 μm. The PNVF particles (∼1 g) were then redispersed in 140 mL methanol containing 50% GA solution (20 g for 0.1 mol of GA, 10 g for 0.05 mol, 4 g for 0.02 mol, 3 g for 0.015 mol, 2 g for 0.01 mol). While stirring each PNVF particle dispersion, 50 g of 2 N NaOH aqueous solution was slowly added, and the reaction proceeded at 70 °C for 12 h under a N2 atmosphere. After washing the particles thoroughly through repeated centrifugation with water, uniform hollow-structured PVAm hydrogel capsules were obtained. Characterization of Hollow Hydrogel Capsules. The structure of the PVAm capsules was confirmed by direct observation with a confocal laser scanning microscope (Zeiss LSM 510, Germany). To confirm their microstructure, the hydrogel capsules were labeled with a fluorescent dye. A 0.2 mL aliquot of FITC solution (2 mg/mL in dimethyl sulfoxide (DMSO)) was added to the capsule dispersion (0.2 11900
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RESULTS AND DISCUSSION Synthesis and Characterization of Hollow Hydrogel Capsules. A typical synthetic process for the fabrication of hollow hydrogel capsules is given in a schematic in Scheme 1. The first step of this reaction is to carry out the dispersion polymerization of NVF as a main monomer and MBA as a cross-linking agent. PNVF particles were precipitated during the polymerization due to the decrease in solubility of the growing chains in methanol. After synthesis of PNVF particles, their sequential hydrolysis and cross-linking reaction led to the generation of monodisperse micrometer-sized hollow PVAm hydrogel capsules. Both the hydrolysis of vinylformamide to vinylamine and the some breakage of amide bonds between NVF and MBA, which then allows the cleaved PVAm chains to diffuse out of the particles, seem to be essential for the generation of hollow capsule structure without using templates. With the aim of obtaining a more systematic understanding of this synthetic process, the hydrolysis of vinylformamide was performed under strong basic conditions, and then the crosslinking reaction with GA was followed stepwise. We found that the stepwise or separate hydrolysis and cross-linking yielded a structure similar to that resulting from the one-shot reaction (Figure 1). This result implies that the cross-linked PVAm
In general, the variation of cross-linking density of hydrogels is known to change their physical properties, such as stiffness, swelling ratio, mesh size, and permeability. In order to determine how the shell cross-linking has an effect on particle morphology, hollow hydrogel capsules were prepared by varying the concentration of GA, which acts as a cross-linker. Figure 2 shows the change of particle diameter and shell
Figure 2. (a) Particle size and shell thickness as a function of GA concentration (with 2 N NaOH for 12 h). (b) Changes in both particle size and shell thickness plotted against cross-linking reaction time (with 2 N NaOH and 0.1 mol GA). The particle diameter and shell thickness were determined from the analysis of CLSM images.
Figure 1. (a) CLSM image of hollow PVAm hydrogel capsules after in situ hydrolysis and cross-linking (with 2 N NaOH and 0.05 mol GA for 12 h at 70 °C). (b) CLSM image of hollow hydrogel capsules prepared after the stepwise hydrolysis (with 2 N NaOH for 12 h at 70 °C) followed by cross-linking (with 0.1 mol GA for 8 h at 70 °C). In order to image the shell phase, amine groups attached to the polymer chains were labeled with FITC. (c) SEM image of hollow hydrogel capsules, shown in panel a, after lyophilization. (d) Cryo-SEM image of a freeze-fractured hollow hydrogel capsule prepared from 0.1 mol GA treatment. The scale bars in Figures 1a to 1c are 5 μm and the scale bar in Figure 1d is 2 μm.
thickness of hollow hydrogel capsules as a function of GA concentration as well as reaction time. The particle size tends to decrease with the increases in GA concentration up to 0.02 mol and then remains almost unchanged beyond that GA concentration (Figure 2a). On the other hand, the shell thickness of hollow capsules is barely affected by the variation in GA concentration. Figure 2b shows that the average diameter and shell thickness of hollow hydrogel capsules gradually decrease as the cross-linking reaction time is increased. These results indicate that the capsule size is determined by the degree of hydrolysis of formamide groups, which regulates the degree of shell cross-linking. The shell thickness of the capsules was obtained by analyzing the CLSM images of hollow hydrogel capsules prepared (see Figures S1 and S2, Supporting Information). This method may not be able to resolve the particle images in hundreds of nanometer length scales due to the diffraction limit. In order to confirm the reliability of our CLSM measurements, in this study, the shell thickness was measured again by employing
chains that are not entirely cleaved by hydrolysis are sequentially cross-linked by GA between amine groups at the periphery of PVAm particles. Since the inward diffusion of GA from the continuous phase is more favorable than the release of cleaved PVAm species, typically with much higher molecular weights, hydrogel shells are automatically generated at the periphery of colloidal particles. After the shell cross-linking, the diffusion of cleaved PVAm species out of the particles is significantly hindered but eventually replaced with water, resulting in the formation of water-filled single cores. 11901
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another analysis method, the freeze-fracture SEM. To effectively immobilize the capsules in the aqueous continuous phase, the capsule dispersion was fixed in an agar gel (2 wt %). The agar gel was then freeze-fractured. We have observed from the freeze-fracture SEM that the shell thickness of the sliced hollow capsules ranges from 250 to 350 nm (Figure 1d). This observation supports that our determination of shell thickness with CLSM analysis is fairly reliable. Control of the Permeability of Hollow Hydrogel Capsules. If these hollow hydrogel capsules are to be used as drug carriers, the permeability of the hydrogel shell phase against permeating molecules with different size and shape should be evaluated in detail. The diffusions through the hydrogel shells of FITC-labeled dextran polymers with different hydrodynamic diameters ranging from approximately 4 to 32 nm based on different molecular weights32,33 were examined with the CLSM analysis. It was observed that most FITCdextran molecules rapidly deposit within and on the shell of hydrogel capsules, leading to intensive labeling of the shell layer. FITC-dextran molecules were even detected in the waterfilled cores of shell particles. However, their concentration was relatively quite low compared with that in the shell layer. While imaging the particles with CLSM, the fluorescence intensity was tuned. After the adjustment of fluorescence intensity of the shell part, it appeared that the core part did not encapsulate any FITC dextran but it actually did. Our observation on the hollow hydrogel capsules after the addition of FITC-dextran solutions reveals that the hydrogel shells are permeable to FITC-tagged dextran up to a molecular weight of 250 kDa while FITClabeled dextrans with a molecular weight of 500 kDa cannot penetrate the hydrogel shell phase and are trapped in the shell phase (Figure S3). This result implies that although the crosslinking density of the PVAm shell phase of hollow capsules can be controlled to some extent by varying GA cross-linker concentration, the molecular weight between cross-linking points (i.e., the mesh size) seems to be sufficiently large. Thus, the hydrogel meshes allow the easy permeation of FITClabeled dextran polymers even with high molecular weight. This permeation of long polymeric chains through the hydrogel shell phase can be prevented by treating the PVAm shells with negatively charged biodegradable polymers, such as HA. This post-treatment renders the hydrogel shell phase completely impermeable even to FITC-tagged dextran with a molecular weight of 4 kDa (Figure 3). After the treatment with HA, all the FITC-dextran chains tested were accumulated on the shell surface, and there is absolutely no permeation even with small dye molecules (Figure 4). This impermeability arises because the treatment with HA of different molecular weights drastically blocks the interstitial space between cross-links mainly due to
Figure 4. Permeability of a low molecular weight anionic dye (fluorescein sodium) through a hydrogel shell phase treated with HA: (a) 0.05 mol GA without HA treatment 5 min after incubation, (b) 0.015 mol GA followed by the treatment with 250 kDa HA, and (c) 0.015 mol GA followed by the treatment with 1.45 MDa HA 60 min after incubation. All the scale bars are 5 μm.
favorable electrostatic interactions between positively charged amine groups within the capsules and negatively charged HAs. Formation of Au NPs within Hydrogel Shells. Metal NPs have recently gained significant attention because of their unique optical, electrical, catalytic, and antimicrobial properties.34−36 On the other hand, polymeric microgels have served as a nice template for the synthesis of various inorganic NPs.37 In particular, the hybridization of Au NPs embedded within polymer matrices is attractive, since unique optical properties originating from Au NPs can be utilized in a variety of biological applications.38−40 An additional nice feature of PVAm capsules in terms of molecular moieties is that these shell phases have abundant primary amine groups, which can be effectively used as the reduction sites for Au precursors to form Au NPs.41−45 Hence, it is quite likely that Au NPs can be readily formed within PVAm meshes. To demonstrate this concept, HAuCl4 precursors dissolved in a borate buffer (pH 10) were reduced within the PVAm shell phase to form Au NPs. The current study also found that the degree of crosslinking in the shell phase critically affects the number density of Au NPs formed. In a highly cross-linked hydrogel shell, relatively large Au NPs (20.3 ± 4.3 nm in diameter) were produced with low population, whereas, in a slightly crosslinked hydrogel shell, much smaller Au NPs (4 ± 1.2 nm) were prepared with a high number density (Figure S4). Thus, both the size of Au NPs and their number density within PVAm matrices can be tuned by varying the degree of cross-linking of the shell phase. The degree of cross-linking in the shell phase is directly proportional to the GA cross-linker concentration because PVAm chains were cross-linked by the removal of amine groups. Consequently, hydrogel networks with higher degree of cross-linking have less amine groups, implying that there is much less reduction site for the formation of Au NPs as well as much more spatial hindrance. Hence, hydrogel networks with lower degrees of cross-linking in the hydrogel shell phases facilitate the formation of Au NPs within PVAm meshes. Other experimental factors, such as reaction time and Au precursor concentration, also affect the formation of Au NPs, in accordance with general synthetic rules (see Figure S5). By varying the size of Au NPs in the hydrogel shells, strong vibrant colors, caused by the surface plasmon resonance (SPR) absorption, were obtained.46,47 As shown in Figure 5, Au NP/ PVAm composite shell phases prepared with different GA cross-linker concentrations exhibit absorbance peaks around 540 nm due to the SPR effect of Au NPs prepared. The increase in the intensity of absorbance is believed to arise from the increase in the number density of Au NPs in accordance
Figure 3. Permeation of FITC-labeled dextran through the hydrogel shell phases cross-linked with 0.015 mol GA followed by the posttreatment with 250 KDa HA. The numbers in the images denote the average molecular weight of FITC-labeled dextran. In all the cases shown, the permeation time was fixed at 0.5 h. All the scale bars are 5 μm. 11902
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spinodal point of water. The composite shell phases are composed of a number of materials with very different thermal expansion coefficients, thus the local heating creates significant thermal stresses within the shell phases and ultimately results in the rupture of complete shells.53
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CONCLUSIONS In summary, we have prepared uniform-sized hollow hydrogel capsules through in situ hydrolysis and cross-linking of micrometer-sized PNVF particles without resorting to template approach. The key advantage of this system is its versatility as a potent drug delivery system. We have shown that subtle changes in the permeability of hydrogel capsules can be achieved through the modification of their charged surfaces with negatively charged biopolymers such as HA. Furthermore, Au NPs, exhibiting the SPR, can be incorporated within the hydrogel shell phases, which provides a means to rupture those shells by simply irradiating them with laser at the maximum absorption wavelength for Au NPs embedded in the hydrogel matrices. The next stage of our study will focus on the development of optically tuned drug delivery, with the aim of identifying more practical applications in drug delivery systems.
Figure 5. UV−visible spectra of Au NP/PVAm composite capsules prepared with different GA concentrations, the numbers of which are shown in the figure.
with the decrease in GA concentration or the decrease in crosslinking density. Moreover, the change in the mixing ratio of Au precursor and hydrogel shell capsules shifts the maximum absorption peak from 538 to 573 nm. This red-shift of the SPR peak originates from the aggregation of Au NPs within confined hydrogel shell phases (see Figure S6).48,49 Laser-Induced Rupture of Au/PVAm Composite Shell Phases. In order to investigate the response of Au NP/PVAm composite shell phases to light triggers, those hydrogel capsules were subject to irradiation at 532 nm with a Q-switched Nd:YAG laser beam. After irradiation with multiple laser pulses, those hydrogel capsules were examined with SEM. The results are shown in Figure 6. In the absence of laser irradiation, the hollow composite capsules retain their original shape, which typically take the shape of deflated balloons in dried state. After exposure to weak irradiation (50 mJ/cm2), the outlines of individual capsules can be still identified, but most of their surfaces seem to be slightly degraded (See Figure S7). However, further exposure to higher irradiation (higher than 100 mJ/cm2) completely ruptures the shell phases, and individual capsules are no longer distinguishable. We also found that the laser-induced rupture of Au NP/PVAm composite shell phases is dependent on the number density of Au NPs (Figure S8). These results clearly show that Au NPs embedded in the hydrogel shell phases undergo photofragmentation and photofusion upon exposure to laser irradiation,50−52 which heats the composite shells above the
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ASSOCIATED CONTENT
S Supporting Information *
CLSM images of hollow hydrogel capsules prepared from different reaction conditions, additional TEM images of Au NP/PVAm composite capsules and SEM images of Au NP/ PVAm composite capsules after irradiation of laser pulses are given. 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] (J.W.K.);
[email protected]. ac.kr (K.C.). Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This study was financially supported by the National Creative Research Initiative Center for Intelligent Hybrids (No. 20100018290) through the National Research Foundation of Korea (NRF) Grant, the WCU Program (R31-10013), and the BK21
Figure 6. Rupture of Au NP/PVAm composite capsules after irradiation with 8 ns Nd:YAG laser pulses at 532 nm for 1 min at a frequency of 10 Hz. The Au NP/PVAm composite capsules were prepared with 0.02 mol GA-treated hydrogel capsules and 50 mM HAuCl4 solution. SEM images of composite capsules (a) before irradiation and (b) after strong radiant exposure of 200 mJ/cm2. Scale bar is 5 μm. 11903
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Program funded by the Ministry of Education, Science and Technology (MEST) of Korea.
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