Article pubs.acs.org/Langmuir
Magnetic Compression of Polyelectrolyte Microcapsules for Controlled Release Yanan Hu,† Chuanyong Liu,‡,§ Dongzhi Li,‡,§ Yue Long,*,† Kai Song,*,† and Chen-Ho Tung∥ †
Laboratory of Bio-Inspired Smart Interface Science and ∥Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, and ‡Beijing National Laboratory for Molecular Sciences, Key Laboratory of Photochemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China § University of the Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *
ABSTRACT: In this study, microcapsules with a magnetic particle as the core and polyelectrolyte multilayers as the shell were fabricated. The cavity of the microcapsules was created by etching the SiO2 layer, which was first coated on the magnetic core particle, and the size of the cavity can be adjusted by the thickness of the SiO2 layer. This magnetically responsive microcapsule deforms upon application of a constant magnetic field and results in the release of the core content, and the release velocity could be controlled by the strength of the magnetic field. This release mechanism is proactive and repeatable, combined with its localized and remote controllability; it can be a powerful tool for delivering medical agents on site.
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the alignment of magnetic particles in a constant magnetic field to cause deformation of the shell when embedding them in the microcapsule shell, and the core releases upon deformation.18−20Nevertheless, this type of microcapsule is normally prepared using emulsification methods with size ranges from tens to hundreds of micrometers. When regarded from the drug delivery perspective, this size is less suitable in certain applications. Layer-by-layer assembly is a common method for producing microcapsules due to the ease of preparation and versatility of the material choice.21−23 More importantly, some of the polyelectrolytes are also biocompatible and environmentally benign which makes them greatly favored in biomedical and pharmaceutical applications. The basic idea of layer-by-layer assembly is to alternately adsorb oppositely charged polyelectrolyte on the surface of a template, and remove the template in the consequent step. The conventional release mechanism of the polyelectrolyte microcapsules is diffusion based. This slow and passive drug release hinders an optimal medical effect in certain applications, and also lacks control in localization and rate of release. In the work reported here, a magnetically responsive microcapsule is designed via the use of constant magnetic field to deform the microcapsule and release the core content with the aim of enhancing and tuning the drug release rate. The microcapsule is composed of polyelectrolyte multilayers as the
INTRODUCTION The past few decades have been witness to unprecedented advancement in microencapsulation technique.1,2 Because of its appealing advantages such as protecting and isolating the active components during storage, and releasing them at the desired time and place, it has become strategically important in various applications. In drug delivery area especially, it has proven to be efficient in achieving better therapeutic efficacy and limiting side effects.3−9 As the advance of the technique, strategies that recognize and adhere to infected regions and allow for targeted release of the medical agents in these regions only are desirable. Stimuli-responsive microcapsules which provide tunable permeability for medical agents with a controllable release profile under a given environmental stimulus make the target more accessible.10−14 Among them, magnetically responsive microcapsules that could remotely deliver the medical agents to the targeted area and trigger the release with negligible change in the biological and chemical environment of the body are especially advantageous. The release of magnetically responsive microcapsules can mainly be divided into two categories. The first one is employing the thermal and vibrational behavior of magnetic nanoparticles in an alternating magnetic field.15−17 When subjecting the microcapsules in the alternating magnetic field, the nanoparticles which were embedded in the shell produce heat and mechanical vibration, resulting in destruction of the whole or part of the shell, and release the core content instantly. However, this strategy escalates the local temperature, which may potentially harm the healthy organs, hence placing a restriction on the clinical use. The other approach is to exploit © XXXX American Chemical Society
Received: June 17, 2015 Revised: August 17, 2015
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DOI: 10.1021/acs.langmuir.5b02229 Langmuir XXXX, XXX, XXX−XXX
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concentration of 10 M was added overnight to etch the SiO2 layer before washing with water. Preparation of Fe3O4 Particles. Fe3O4 particles used in the SiO2 coating study were prepared according to the method described elsewhere.15 FeCl3·6H2O (1.62 g), NaOAc (8 g), and PEG (1.5 g) were dissolved in a mixture of EG and DEG (VEG/VDEG = 1:9, 60 mL) under magnetic stirring at room temperature. After vigorous stirring for 2 h, the precursor was transferred to two Teflon-lined stainlesssteel autoclaves, and heated at 200 °C for 10 h. The obtained magnetic particles were washed 3 times with ethanol and deionized water (1:1) after cooling to room temperature. Controlled Release of Magnetically Responsive Microcapsules. The microcapsules were immersed in an aqueous FITC− dextran solution (10−4 M) and kept in the dark. After 12 h, the microcapsules were washed three times with water until the fluorescence intensity of the supernatant was nearly zero. In a release test without applying a magnetic field, an aqueous dispersion of microcapsules was placed in the dark; the sample was shaken to ensure that the dispersion was well mixed, and then, an aliquot of solution (0.2 mL) was taken from the supernatant at various time intervals between 1 and 80 min after the microcapsules sediment to the bottom of the container. The fluorescence intensity of the solution was examined using a fluorometer. The release of the microcapsules with an external magnetic field was performed the same way, with the only exception being that a permanent magnet was held under the sample container. The microcapsule dispersion was also shaken before each measurement, during which the magnet was removed. Three replicas were used for each sample. The release of microcapsules by centrifugation was also performed. Samples were centrifuged at 800 and 1500 rpm, respectively. The fluorescence intensity of the supernatant was measured at different time intervals between 0 and 80 min. The sample used for all the release tests was prepared from 125 mg of the dried Fe(CO)5@SiO2 particles, and further coated through the LbL method in a parallel manner. The loading efficiency of microcapsules was also calculated from the total encapsulated FITC-dextran (base on the fluorescence intensity) in the microcapsules using the ratio of the mass of drug in microcapsules to the mass of the microcapsules. The loading efficiency of the microcapsule is 7%. Characterizations. Scanning electron microscopy (SEM, JEOL S4800 field emission scanning electron microscope) was used to examine the morphology of the Fe(CO)5@SiO2 microspheres. Transmission electron microscopy (TEM, JEM-2100) was used to examine the structure of the Fe(CO)5@SiO2 microspheres and the microcapsules. Surface charge of the microcapsules was characterized using a zeta potential instrument during the adsorption steps of PDADMAC and PSS. The fluorescence of the microcapsules was visualized using confocal laser scanning microscopy (CLSM, FV1000IX81). The fluorescence intensity was examined using a fluorometer (Hitachi, F-7000).
shell, and a carbonyl iron particle as the core. As the magnetic field was applied, microcapsules were compressed against the supporting surface due to the attraction between the magnetic core particle and the field, leading to the release of core content as shown in Scheme 1. At the same time, the upper layer also Scheme 1. Schematic Representation of the Compression of Microcapsules under a Constant Magnetic Field
applied pressure to the microcapsules underneath as they piled up, which further deformed the microcapsules and enhanced the release. Therefore, the release rate was dominated by the degree of deformation caused by the magnetic field. This release method is more proactive than the conventional polyelectrolyte microcapsules, which can trigger and control the release on demand, and the insertion of a magnetic particle renders the microcapsule localizable and remotely controllable.
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EXPERIMENTAL SECTION
Materials. Pentracarbonyl iron (Fe(CO)5, D = 2.6−3.5 μm) was purchased from Mengtaiyouyan technology development center (Beijing, China). Tetraethoxysilane (TEOS, 98%), polyethylene glycol (PEG, Mw 2000), diethylene glycol (DEG, 99%), and poly(styrene sulfuric acid) sodium (PSS, Mw 70,000) were purchased from Alfa Aesar. Poly(diallyldimethylammonium chloride) (PDADMAC, Mw 100,000−200,000, 20 wt % in water) was purchased from Aldrich. Polyvinylpyrrolidone (PVP, Mw 40,000) was purchased from Tokyo Chemical Industry Co., Ltd. Acetate sodium (NaOAc) was purchased from Acros. Tetramethylammonium hydroxide (TMAH, 10 wt % in water), iron(III) chloride hexahydrate (FeCl3·6H2O), and ethylene glycol (EG) were purchased from Sinopharm Chemical Reagent Co., Ltd. Fluorescein isothiocyanate-dextran (FITC-dextran, Mw 40,000) was purchased from Sigma-Aldrich. The water used throughout all the experiments was purified using a Millipore system. Preparation of Silica Coating on Fe(CO)5 Particles. The silica coating process was accomplished using a modified Stöber method. First, Fe(CO)5 particles (1.0 g) were added into an aqueous solution (300 mL) of PVP (5.0 g), and stirred overnight.The dispersion was washed with ethanol and water (1:1) 3−5 times before being dried in air. The resulting PVP modified Fe(CO)5 particles (500 mg) were redispersed in a mixture of ethanol (500 mL), deionized water (100 mL), and TMAH (1.2 mL) under mechanical stirring. Solutions of TEOS in ethanol with concentrations of 1.667% (200 μL), 3.333% (400 μL), and 6.667% (400 μL) were consecutively added dropwise from lower to higher concentrations. The product was then washed with ethanol and water (1:1) 3−5 times. This TEOS addition step was repeated 6 times to complete the silica coating process. Fabrication of Microcapsules via Layer-by-Layer (LbL) Assembly. Fe(CO)5@SiO2(300 mg) microspheres were dispersed in an aqueous PDADMAC solution (15 mL, 2 mg/mL). After ultrasonic treatment for 5 min, microspheres were collected by a magnet. The resulting particles were ultrasonically washed with water (15 mL) for 5 min and collected by a magnet. Then, the microspheres were dispersed in an aqueous PSS solution (15 mL) with a concentration of 2 mg/mL, and ultrasonicated for 5 min, followed by washing with water (15 mL). The adsorption process was repeated 7 times, after which aqueous NaOH solution (5 mL) with a
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RESULTS AND DISCUSSION Preparation of Microcapsules. Magnetically responsive microcapsules were prepared by a modified layer-by-layer method (Scheme 2). A carbonyl iron particle was first coated with SiO2. Oppositely charged PDADMAC and PSS were then deposited on the surface of the resulting particle to form the polyelectrolyte shell. In the following step, the SiO2 layer was etched to create the cavity. Herein, polyelectrolyte microcapsules with a magnetic core were prepared. Coating of SiO2. Fe(CO)5 particles are not uniform in size; therefore, it is difficult to characterize the thickness of the SiO2 coating. As an alternative strategy, monodispersed Fe3O4 microparticles with an average size of 400 nm were chosen as the core particle to study the SiO2 coating. SEM images of the resulting Fe3O4@SiO2 microspheres with different amounts of TEOS added in the coating step are shown in Figure 1a−c. The average diameter of the resultant Fe3O4@SiO2 microspheres is B
DOI: 10.1021/acs.langmuir.5b02229 Langmuir XXXX, XXX, XXX−XXX
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by a zeta potential instrument as shown in Figure 2. It can be observed from the graph that 12 layers of polyelectrolyte were successfully adsorbed on the particle surface.
Scheme 2. Schematic Representation of the Preparation of Magnetically Responsive Microcapsulesa
a
Inset is the enlarged illustration of the polyelectrolyte shell. Figure 2. Zeta potential of microcapsules measured during the alternating absorption of PDADMAC and PSS.
To produce the microcapsules, the SiO2 layer was etched by NaOH solution overnight. TEM images of the microcapsules after etching were shown in Figure 3a. The polyelectrolyte shell of microcapsules was contracted after etching due to the loss of support in a dry environment during sampling, and was extended when dispersed in water again as shown in Figure 3b and c. The structure of the microcapsules was further characterized using CLSM as shown in Figure 3b,c, and FITC-dextran was loaded by immersing the microcapsules overnight. As shown in Figure 3b, the microcapsule is constructed with a dark core, and a bright circle can be observed surrounding the core particle. By comparison with the bright field image of the same microcapsule in Figure 3c, it can be confirmed that the bright circle is the cavity of the microcapsules which wraps the magnetic core particle. The completion of the bright circle reflects that the polyelectrolyte shell remained unharmed after the etching step. Controlled Release of Magnetically Responsive Microcapsules. In the controlled release test of microcapsules, a magnet was subjected under the sample container, and the microcapsules were attracted to the bottom. A dye, FITCdextran, was used as a model drug to monitor the release of magnetically controlled microcapsules. The release was studied via time-resolved measurement of the fluorescence intensity of the bulk solution over 80 min using a fluorometer. The percentage release of core content is calculated by eq 1.
Figure 1. SEM images of the Fe3O4@SiO2 microsphere with different amount of TEOS added in the coating step: (a) 0.7 mL, (b) 1.7 mL, and (c) 2.9 mL. (d) TEM image of the Fe3O4@SiO2 microsphere with 2.9 mL of TEOS added in the coating process.
500 (a), 600 (b), and 920 nm (c), respectively, as 0.7, 1.7, and 2.9 mL of TEOS was added. The TEM image of the Fe3O4@ SiO2 microsphere with diameter of 920 nm is shown in Figure 1d. It can be clearly seen that a uniform layer of SiO2 was formed on the surface of the Fe3O4 particle, which will be the cavity of the microcapsules after etching. The increased diameter of Fe3O4@SiO2 microspheres proved that the thickness of the SiO2 can be tuned by the input of TEOS in the synthesis step, which will further affect the size of the cavity of the microcapsule. This result is in agreement with the previous studies.24,25 The tunable cavity is of significant importance to the drug delivery application since the dosage of the drug can be specifically tailored, and the side effect and wastage of the drug can therefore be reduced. Layer-by-Layer Assembly and SiO2 Etching. LbL assembly of PDADMAC/PSS layers was performed by alternating adsorption of the polyelectrolyte on the Fe3O4@ SiO2 microsphere surface. The bare Fe3O4@SiO2 microsphere was negatively charged (−23.8 mV), so the coating started with the positive PDADMAC layer. The microspheres were washed with pure water after each layer deposition step to remove the residual nonadsorbed polyeletrolyte. The succession of the adsorption was monitored through the surface charge measured
M=
Mt × 100% Mo
(1)
where Mt is the amount of FITC-dextran released at time t, and Mo is the total encapsulated FITC-dextran in the microcapsules (Mo is calculated by breaking the microcapsules via ultrasonication and measuring the fluorescence intensity of the supernatant). A control sample (0G) was first examined with no magnetic field applied during the release, and the core release reached 22% in 80 min (Figure 4a). In comparison, the accumulated release of microcapsules under magnetic field strengths of 4000 and 5800 G was79% and 96%, respectively, suggesting a higher release rate under the effect of a magnetic field. To quantify the release of microcapsules under various magnetic field strengths, the release kinetics of the microC
DOI: 10.1021/acs.langmuir.5b02229 Langmuir XXXX, XXX, XXX−XXX
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Figure 3. (a) TEM image of the microcapsule formed from LBL process after SiO2 etching;CLSM images of the microcapsules loaded with FITCdextran: (b) dark field and (c) bright field.
seen that the initial release rate increased by 6- and 14-folds after applying the magnetic fields of 4000 and 5800 G, respectively. As the proposed release mechanism mentioned above, the microcapsules were compressed vertically on both sides because of the attraction between the magnetic core and the field, which leads to the enhancement of the release. To verify the release mechanism, a similar experiment was conducted by centrifugation of the microcapsules, wherein the microcapsules were sedimented to the bottom of the sample container during the process, and were compressed by centrifugal force along the direction of the axis of the centrifuge. Two speeds, 800 and 1500 rpm, were chosen, and the fluorescence intensity of the supernatant liquid was measured at different time intervals as shown in Supporting Information S2. It is shown that the release profile of microcapsules under centrifugation is very similar to the one measured under the stimulus of a magnetic field (increased exponentially with time). The rate of release also increased with the increase of the rotation speed, in other words, the force of compression.
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CONCLUSIONS Magnetically responsive microcapsules with a magnetic core and polyelectrolyte shell were prepared in this study. The cavity of the microcapsules were created by etching the SiO2 layer which was first coated on the carbonyl iron core, and the size of the cavity can be tuned by the thickness of the SiO2 layer. The initial release rate was increased by 6-fold when subjecting the microcapsules to a magnetic field of 4000 G, and by 14-folds for 5800 G. Therefore, a system where the core release can be tuned by the magnetic field is prepared. This release method is proactive, repeatable, and remote-controllable, which is of interest for opening up opportunities to make full use of magnetically responsive microcapsules in drug delivery applications.
Figure 4. Release profile of the microcapsules: (a) accumulated release of microcapsules under magnetic field of 0, 4000, and 5800 G; (b) release kinetics of the microcapsules calculated from (a).
capsules was calculated and shown in Figure 4b. The concentration of FITC-dextran increased exponentially with time as shown in Figure 4a; the release rate can be presented as ⎛ −t ⎞ ΔV (t ) = Vo − Vo exp⎜ ⎟ ⎝ τ ⎠
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(2)
where ΔV is the volume of the dye release, Vo is the total volume, and τ is the time constant. As the total volume is difficult to quantify, the value of Vo is assumed to be 1 in the calculation. The volume flow rate Q can be expressed by eq 3 after taking the time derivative of eq 2. Note that this is a simplified empirical model, and the results obtained are relative release rates which are only used for comparison. Q (t ) ×
Vo ⎛ −t ⎞ exp⎜ ⎟ ⎝ τ ⎠ τ
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.5b02229. Calculations and fitted plots of Figure 4a; fluorescence intensity of the supernatant liquid (PDF)
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(3)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected].
The relative initial release rate of microcapsules was obtained from the equation as follows: 3.28 × 10−3, 2.18 × 10−2, and 4.53 × 10−2 Vo/min for microcapsules at 0, 4000, and 5800 G, respectively (calculations and fitted plots of Figure 4a are provided in Supporting Information S1). Therefore, it can be
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of D
DOI: 10.1021/acs.langmuir.5b02229 Langmuir XXXX, XXX, XXX−XXX
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liposomes formed from Fe 3 O 4nanoparticles and thermosensitive block copolymers. Small 2011, 7, 1683−1689. (18) Long, Y.; Liu, C.; Zhao, B.; Song, K.; Yang, G.; Tung, C. Bioinspired controlled release through compression-relaxation cycles of microcapsules. NPG Asia Mater. 2015, 7, e148. (19) Patel, R.; Upadhyay, R. V.; Mehta, R. V. Microscopic observation of magnetodeformational effects in magnetic nanocomposite micelles. J. Phys.: Condens. Matter 2008, 20, 204116. (20) Degen, P.; Peschel, S.; Rehage, H. Stimulated aggregation, rotation, and deformationof magnetite-filled microcapsules in external magnetic fields. Colloid Polym. Sci. 2008, 286, 865−871. (21) Skirtach, A. G.; Yashchenok, A. M.; Möhwald, H. Encapsulation, release and applications of LbL polyelectrolyte multilayer capsules. Chem. Commun. 2011, 47, 12736−12746. (22) Tong, W.; Song, X.; Gao, C. Layer-by-layer assembly of microcapsules and their biomedical applications. Chem. Soc. Rev. 2012, 41, 6103−6124. (23) Boudou, T.; Crouzier, T.; Ren, K.; Blin, G.; Picart, C. Multiple functionalities of polyelectrolyte multilayer films: new biomedical applications. Adv. Mater. 2010, 22, 441−467. (24) Ding, T.; Liu, Z.; Song, K.; Tung, C. Synthesis of monodisperse ellipsoids with tunable aspect ratios. Colloids Surf., A 2009, 336, 29− 34. (25) Graf, C.; Vossen, D.; Imhof, A.; van Blaaderen, A. A general method to coat colloidal particles with silica. Langmuir 2003, 19, 6693−6700.
the manuscript. Yanan Hu and Chuanyong Liu contributed equally. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge the State Basic Research Program of China (2013 CB834505) and the program of the National Natural Science Foundation of China (21273248) for their financial support.
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