Article pubs.acs.org/Langmuir
Nanoparticle-Filled Complex Colloidosomes for Tunable Cargo Release Jonathan S. Sander and André R. Studart* Complex Materials, Department of Materials, ETH Zurich, 8093 Zurich, Switzerland S Supporting Information *
ABSTRACT: Capsules with a shell made out of nanoparticles, so-called colloidosomes, are very interesting for controlled encapsulation and release because of their selectively permeable shell, their mechanical stability, and the possibility to make them from many materials. Here, we report the creation of complex colloidosomes that can release encapsulated cargo on-demand in single or multiple release events. Unprecedented on-demand, multiple release is achieved by incorporating functional nanoparticles within the colloidosome hollow core. The entrapped nanoparticles enable pH-triggered release by either swelling to rupture the capsule shell in one single event or desorbing on-demand cargo molecules initially adsorbed on their surface. Implementation of such mechanisms in capsules with magnetically responsive shells enabled the creation of colloidosomes exhibiting unique spatiotemporal control of cargo release.
nanoparticle-filled colloidosomes. The entrapped nanoparticles are used either (I−III) to enable multiple on-demand release of molecules adsorbed on their surface or (IV) to irreversibly rupture the capsule under an external stimulus. The realization of the colloidosome architectures proposed in Figure 1a requires the facile incorporation of colloidal nanoparticles in the interior of the capsules and the formation of capsule shells that are sufficiently tight to effectively trap such incorporated particles. Nanoparticle-filled colloidosomes can be produced by simply dispersing the active colloidal particles in the innermost phase of the double emulsion templates during microfluidic emulsification (Figure 1b). Because the active nanoparticles are kept dispersed inside the capsules, our ability to deliberately add other functional nanoparticles to the middle phase that will later constitute the shell is retained, allowing us to take full advantage of the protective function and other magnetic, catalytic, and biological properties that can be associated with the colloidosome shell.3,5,7,18,19 The multilayered nature of shells obtained through this double emulsification route (images c−e of Figure 1) ensures uniform permeability and facilitates the efficient entrapment of the active colloidal particles inside the capsule.20,21 Entrapment is eventually achieved by ensuring that the shell pore size is significantly smaller than the diameter of the nanoparticles loaded into the colloidosome. Such a pore size can be independently controlled by changing the size of the colloidal particles that form the shell without interfering with the active nanoparticles involved in the triggered release mechanism.3
Colloidosomes are hollow capsules exhibiting a shell made from colloidal particles.1,2 The intrinsic porosity arising from the interstitials between the particles leads to capsules with unique semi-permeable shells. In addition to their semi-permeable nature, colloidosomes can also display other interesting properties, such as magnetism, photocatalytic activity, or tunable dissolution behavior, if specific functional particles are used in the shell.3−7 Among the various synthetic routes that have been used to create colloidosomes,1,2,4,7−9 the use of double emulsions as soft templates is particularly interesting because it allows for the formation of thick, multilayered particle shells with independently controlled thickness and interstitial pores.3 This opens the possibility to obtain capsules whose semi-permeable shell can be designed to not only be size-selective but to also control the release kinetics of the encapsulated cargo. Although this high flexibility makes colloidosomes promising candidates for controlled encapsulation in many applications,10−14 most studies thus far have only explored the passive diffusion of encapsulants through the interstices of the particle shell as a possible release mechanism. A few recent studies have shown that it is also possible to control the release of chemicals from colloidosomes using pHdegradable material or swellable particles in the core9 or shell.6,15−17 However, cargo release in these systems cannot be triggered multiple times on demand or often relies on shells with specific chemistries. Thus, the multifunctionality and sizeselective nature of the shell have not yet been fully exploited for the creation of colloidosomes with multiple, on-demand release of encapsulated cargo. Here, we show that colloidosomes with tunable release patterns can be made if functional nanoparticles are entrapped in the interior of the capsule to provide an externally triggered mechanism for on-demand release. Figure 1a shows a schematic overview of the possible triggering mechanisms in such © 2013 American Chemical Society
Received: July 30, 2013 Revised: November 19, 2013 Published: November 22, 2013 15168
dx.doi.org/10.1021/la402901c | Langmuir 2013, 29, 15168−15173
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(calcein) that strongly adsorbs on oppositely charged Al2O3 nanoparticles (Figure 2). At pH 5, the oppositely charged
Figure 2. (a) Fluorescence signal of encapsulated dye measured throughout a 0.5 mm wide glass compartment containing several capsules filled with calcein adsorbed on trapped Al2O3 nanoparticles (see also Figure S2 of the Supporting Information). At low pH, the dye remains adsorbed on the nanoparticles, keeping the capsule in a dormant state, as indicated by the constant intensity inside the glass compartments in periods I and III. At high pH, the dye desorbs from the nanoparticles, switching the capsules to an active state, as shown by the decreasing fluorescence in periods II and IV. (b) Fluorescence (top) and bright-field (bottom) microscopy images of a capsule in different dormant and active stages. Scale bar: 75 μm
Figure 1. (a) Schematics illustrating the concept used to achieve ondemand release with nanoparticle-filled colloidosomes: (I) on−off release upon triggered desorption of cargo molecules from entrapped nanoparticles, (II) combination of active on−off and passive mechanisms to enable multiple cargo release with independently controlled temporal patterns, (III) incorporation of magnetic nanoparticles in the shell to allow for manipulation of on−off capsules, and (IV) one-time release induced by swelling of trapped nanoparticles. (b) Snapshot of the double emulsification process in a microcapillary device indicating the innermost aqueous fluid in which the active nanoparticles are dispersed. (c−e) Details of the semi-permeable shell of a colloidosome made from 250 nm SiO2 particles. Image c depicts a cross-section of the shell of a broken colloidosome, whereas images d and e exhibit the outer surface of the shell. The inset in image d shows the capsule at a lower magnification (scale bar = 50 μm).
molecules and nanoparticles remain coupled (constant fluorescence inside the capsule) and the system is in a dormant state. Increasing the pH to 10, above the isoelectric point of the nanoparticles (Figure S1), leads to desorption of the dye from the nanoparticle surface, which triggers a transition of the system to an active state, where dye is released (decreasing fluorescence inside the capsule). Release during the active state continues until the solution pH is changed back again to 5, which is indicated in Figure 2b as dormant state III. In the dormant state, molecules that have not yet diffused out of the capsule re-adsorb on the nanoparticle surface and stay trapped again. This can be repeated multiple times as long as there is still cargo inside the capsule (Figure 2a and movie S1 of the Supporting Information). To better quantify the release kinetics in the active states, we measured the decrease in fluorescence intensity of an individual capsule subjected to cyclic pH changes between 5 and 10 in a microfluidic compartment (see Figure S3 of the Supporting Information). Taking into account that the shell thickness h is considerably smaller than the capsule radius r, the diffusion coefficient of the dye molecules through the colloidosome shell during the active states was estimated by fitting the change in
The high flexibility in colloidosome fabrication offered by the microfluidic emulsification route was eventually employed to create the on-demand release systems depicted in Figure 1a. To illustrate the potential of such nanoparticle-filled colloidosomes, we first demonstrate the on-demand repeated release of cargo from the same capsule. Repeated on−off switching of the release is possible with nanoparticle-filled colloidosomes by adsorbing the encapsulant on the surface of the entrapped particles (I in Figure 1a). Because the adsorption and desorption of molecules on their surfaces is usually pHdependent,22 oxide nanoparticles provide a convenient platform for the controlled on−off release triggered by pH. This is demonstrated here using a negatively charged fluorescent dye 15169
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fluorescence intensity I as a function of time t using the following relation:3,23 ⎛ I − I∞ ⎞ ⎜ ⎟ ≈ e−(3D / hr)t ⎝ I0 ⎠
(1)
where D is the diffusion coefficient of the dye molecules through the shell and I0 and I∞ are the initial and final fluorescence intensities, respectively. Assuming an average shell thickness h of 4 μm, we obtained diffusion coefficients (D) in the range of 0.36−0.58 μm2/s. These values are 1 order of magnitude higher than the diffusion coefficients of fluorescent probes of similar size permeating through colloidosome shells with 10-fold smaller interstitial pore sizes.3 It is important to note that the flexibility offered by the proposed colloidosomes in changing the material of the trapped nanoparticles as well as the particles forming the shell is crucial to design a system that favors the selective adsorption of the encapsulant on the trapped nanoparticles rather than on the shell. In the example shown in Figure 2, this was achieved using negatively charged SiO2 particles in the shell, which prevented adsorption of encapsulants of the same charge by simple electrostatic repulsion. With the numerous particle types available to form the shell5 and the availability of oxide nanoparticles with different isoelectric points, these coloidosome systems can be potentially tuned to obtain similar on−off patterns at many specifically targeted pH ranges. The ability to deliberately switch the release state from dormant to active using nanoparticle-filled colloidosomes opens several new possibilities for the design of encapsulation systems with tailored release. The basic concept of release mediated by entrapped nanoparticles shown in Figure 2 can be extended to more complex systems containing more than one cargo to achieve different release patterns of several distinct molecules from the same capsule. To illustrate this potential, we assembled complex colloidosomes that combine the on−off features of the Al2O3−calcein system (Figure 2) with the passive release of an additional neutral non-adsorbing molecular dye (II in Figure 1a). This design allows for continuous release of the neutral dye through the interstitial pores of the colloidosome shell, while the charged dye is released independently upon deliberate changes in the pH (Figure 3). In this example, the independent release patterns could be detected using a negatively charged dye emitting in the blue spectrum for the intermittent on−off release and a neutral green fluorescent dye for the continuous passive release. Keeping the system at pH 5 results in the passive release of the green dye, while the negatively charged dye remains adsorbed on the surface of the Al2O3 nanoparticles inside the colloidosomes. This is indicated by the decreasing and constant fluorescence intensity of the green and blue dyes inside the colloidosome, respectively (panels a, c, and e of Figure 3). Shifting the pH of the surrounding solution to 10 causes the initially trapped blue dye to desorb from the encapsulated alumina nanoparticles and to also diffuse into the outer medium. This changes the delivery pattern of the system from selective to combined release (panels b, d, and f of Figure 3). Estimates of the diffusion coefficient D using eq 1 lead to comparable values in the range of 0.19−0.26 μm2/s for both actively and passively released cargos (panels e and f of Figure 3). The lower D values obtained for the two-cargo colloidosomes as compared to the capsules with only one type of cargo (Figure 2) might be attributed to the different
Figure 3. pH-controlled switching from selective to combined release of two encapsulants from the same complex colloidosome. (a−d) Fluorescence microscopy images of colloidosomes taken 0 and 2 h after the solution pH was changed to 5 (a and c) and 10 (b and d). The brightness in the images reveals the fluorescent intensity detected in the blue (a and b) and green (c and d) light spectra. Measuring the fluorescence intensity inside the capsules shows the (e) selective release of only one of the encapsulants at low pH and (f) simultaneous release of both cargo molecules at higher pH. The full red lines are the theoretical fittings (eq 1) used to obtain the following diffusion coefficients, D: 0.23 μm2/s for the actively released cargo (blue) and 0.19 and 0.26 μm2/s for the passively released cargo (green channel in panels e and f, respectively). Scale bar: 75 μm
measuring conditions and, thus, distinct equilibration times in these systems. The fluorescence in the two-cargo colloidosomes (Figure 3) was measured in individual capsules in the absence of flow, whereas the signal in the one-cargo system (Figure 2) was measured in a flowing continuous aqueous medium. In addition to the independent control of the release of different types of cargo molecules from the same capsule, our ability to functionalize the shell with magnetically responsive particles5 also allows for remote manipulation of the complex colloidosomes into programmed spatial patterns. This makes the design of delivery systems with unprecedented spatiotemporal control over the release pattern possible, as illustrated by the example shown in Figure 4. In this case, colloidosomes loaded with calcein-coated Al2O3 nanoparticles (Figure 2) have their silica shells functionalized with superparamagnetic iron oxide nanoparticles. The resulting colloidosomes can be remotely manipulated from their initial position to any preprogrammed location with the help of magnets that impose an external magnetic field gradient. This is demonstrated by deliberately positioning the colloidosome into one of many possible compartments, as shown in panels a and b of Figure 4. After bringing the colloidosome to the intended spot, release of the trapped calcein is initiated by changing the solution pH from 5 to 10 (Figure 4c and movie S2 of the Supporting Information), following the mechanism previously depicted in Figure 2. Panels d and e of Figures 4 show that the fluorescence is first constant inside the capsules, confirming that the colloidosomes remain in the dormant state in their initial 15170
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Figure 4. Cargo release with spatiotemporal control using magnetically responsive complex colloidosomes. (a) Overlay of fluorescence and brightfield images of a dormant magnetic colloidosome with internally trapped calcein molecules at low pH. (b) Combination of several reflected light images showing the controlled manipulation of the colloidosome from its initial position to a selected compartment using the magnetic field gradient imposed by a rare earth magnet. (c) Overlay of fluorescence and bright-field images of the colloidosome inside the compartment after some calcein had been released at high pH. (d−g) Fluorescence microscopy images of the capsules (d and e) kept in the dormant state in their initial position at low pH and (f and g) about 0 and 16 min after exposure to a high pH to promote local release inside the compartment.
at high pH. Encapsulant release upon pH increase is evidenced by the decrease of fluorescence intensity inside the capsule over time. Microgel nanoparticle weight fractions lower than about 3 wt % result in small cracks on the capsule shell, which are not always visible with the optical microscope (Figure 5c). In contrast, higher concentrations lead to pressures that are high enough to make a large, visible crack or to crush out a piece of the capsule wall (Figure 5b). Thus, variation of the microgel nanoparticle content in the colloidosomes enables deliberate tuning of the release speed after the external trigger (panels d and e of Figure 5). This is shown in Figure 5d by measuring the intensity of a fluorescent dye as a function of time in the supernatant of a suspension containing many capsules. To quantify the effect of the microgel nanoparticle content on the release speed, we fitted the time-lapse fluorescence data shown in Figure 5d with the following equation:
position at low pH. The inhomogeneous structure observed suggests that the trapped alumina nanoparticles aggregate at this pH if calcein is adsorbed on their surface. Panels f and g of Figure 4 depict a capsule that was first moved to the selected compartment by magnetic guiding at low pH (f) and that was later exposed to a high pH for 10 min to enable local release (g). Nanoparticle-filled colloidosomes can also be designed to provide on-demand delivery systems featuring one-time release of encapsulated cargo. In this case, one-time release can be achieved using trapped nanoparticles that undergo triggered swelling to partially or fully rupture the colloidosome shell. Figure 5 depicts the one-time release of encapsulants using trapped microgel nanoparticles that swell upon pH changes. Commercially available stearin-modified poly(acrylic acid) microgel nanoparticles used in this example can expand by a factor of 4−5 in water upon a small pH change from 6 to 7 (Figure 5a). Swelling of the initially collapsed nanoparticles is caused by electrostatic repulsion between the carboxylate side chains of the cross-linked gel particles upon deprotonation at higher pH values. As long as the hydrogel nanoparticles are in the collapsed state, no transport occurs through the shell because the cargo and the active particles are too large to diffuse through the pores. Above a threshold concentration of microgel nanoparticles (0.15 wt %), their expansion at high pH leads to rupture or cracking of the colloidosome wall and, thus, release of the encapsulant, as exemplified in panels b and c of Figure 5 and movies S3 and S4 of the Supporting Information. In these examples, FITC-labeled dextran molecules (Mw = 500 000 g/mol) were used as a representative cargo physically trapped inside the capsule. The expansion of the microgel nanoparticles was triggered by adding a drop of 1 M KOH to the solution, which led to an instantaneous increase of the fluorescence intensity because of the higher emission of FITC
I ≈ 1 − e−(3Deff / hr)t I∞
(2)
Considering the heterogeneous nature of the cracked capsule shell, the Deff values obtained by fitting eq 2 to the measured data should be interpreted only as effective diffusion coefficients. Figure 5e shows that Deff values varying within 1 order of magnitude from 0.05 to 0.45 μm2/s can be obtained by simply adjusting the concentration of microgel nanoparticles initially trapped in the colloidosome. This clearly shows our ability to control both the onset and speed of cargo release in such a one-time triggered system. In comparison to responsive colloidosomes consisting of a single hydrogel core,9 the use of hydrogel microparticles for on-demand rupture of the capsule shell offers greater flexibility with regards to the size and chemistry of the encapsulated cargo. For example, living cells that would not fit into a hydrogel core can be easily 15171
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functional properties as entrapped colloids or as shell material, the proposed concept can potentially be extended to program cargo release in many other nanoparticle-based systems beyond those illustrated here.24,25 In addition to the rich diversity of release patterns that can be envisioned, the robustness and semi-permeable nature of the colloidosome shell offers mechanical protection and also restricts the interactions of the encapsulated cargo only to molecules that are small enough to diffuse through the shell. Altogether, these features open several new possibilities for the design of encapsulation systems with programmed release control for several applications in medicine, cosmetics, agriculture, food, and materials sciences.
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ASSOCIATED CONTENT
S Supporting Information *
Detailed experimental methods, ζ potential results for the Al2O3 particles used for on−off switchable release (Figure S1), images of the setup used to measure switchable release (Figure S2), results of fluorescence measurements from a single capsule subjected to consecutive on−off release cycles (Figure S3), and movies showing the (i) switchable on−off release of a fluorescent dye from a nanoparticle-filled colloidosome (movie S1), (ii) spatial and temporal control of cargo release from a magnetically responsive particle-filled colloidosome (movie S2), and (iii) pH-triggered release from colloidosomes with entrapped swellable particles (movies S3 and S4). 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 This work was funded by the Swiss National Science Foundation (Grant 200021_126646). We thank the Multifunctional Materials group and the Laboratory for Surface Science and Technology at ETH Zurich for providing the equipment for fluorescence emission spectroscopy and dynamic light scattering, respectively.
Figure 5. (a) Average size of microgel nanoparticles in water at different pH values. The insets schematically show the dormant state of the capsule when the trapped microgel nanoparticles are collapsed at low pH and the rupture of the capsule shell upon expansion of the nanoparticles at high pH. (b and c) Overlay of fluorescent and brightfield images showing the effect of KOH addition on capsules with (b) 4.5 and (c) 0.75 wt % microgel trapped nanoparticles and a fluorescent dye. Scale bar corresponds to 100 μm. (d) Normalized fluorescence intensity of a supernatant solution taken from a suspension of coloidosomes filled with fluorescent dye and ruptured using different concentrations of microgel nanoparticles. Solid lines are fitting curves obtained using eq 2. (e) Effect of the microgel content (wt %) on the diffusion coefficient D obtained from the fittings shown in panel d.
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REFERENCES
(1) Velev, O. D.; Furusawa, K.; Nagayama, K. Assembly of latex particles by using emulsion droplets as templates. 1. Microstructured hollow spheres. Langmuir 1996, 12 (10), 2374−2384. (2) Dinsmore, A. D.; Hsu, M. F.; Nikolaides, M. G.; Marquez, M.; Bausch, A. R.; Weitz, D. A. Colloidosomes: Selectively permeable capsules composed of colloidal particles. Science 2002, 298 (5595), 1006−1009. (3) Lee, D.; Weitz, D. A. Double emulsion-templated nanoparticle colloidosomes with selective permeability. Adv. Mater. 2008, 20 (18), 3498−3503. (4) Akartuna, I.; Tervoort, E.; Studart, A. R.; Gauckler, L. J. General route for the assembly of functional inorganic capsules. Langmuir 2009, 25 (21), 12419−12424. (5) Sander, J. S.; Studart, A. R. Monodisperse functional colloidosomes with tailored nanoparticle shells. Langmuir 2011, 27 (7), 3301−3307. (6) Miguel, A. S.; Scrimgeour, J.; Curtis, J. E.; Behrens, S. H. Smart colloidosomes with a dissolution trigger. Soft Matter 2010, 6 (14), 3163−3166.
encapsulated in a system containing hydrogel microparticles. Extending this general concept to other types of microgel nanoparticles should enable the use of different stimuli, such as temperature or ionic strength, to achieve well-controlled cargo release. In summary, we show that complex colloidosomes containing colloidal nanoparticles entrapped in their liquid core provide a powerful platform for the creation of capsules with programmed release patterns that can range from onetime cargo release to multiple on−off release with temporal or spatiotemporal control. Because of the flexibility in selecting nanoparticles of different sizes, shapes, chemistries, and 15172
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(7) Duan, H. W.; Wang, D. Y.; Sobal, N. S.; Giersig, M.; Kurth, D. G.; Mohwald, H. Magnetic colloidosomes derived from nanoparticle interfacial self-assembly. Nano Lett. 2005, 5 (5), 949−952. (8) Cayre, O. J.; Noble, P. F.; Paunov, V. N. Fabrication of novel colloidosome microcapsules with gelled aqueous cores. J. Mater. Chem. 2004, 14 (22), 3351−3355. (9) Kim, J. W.; Fernandez-Nieves, A.; Dan, N.; Utada, A. S.; Marquez, M.; Weitz, D. A. Colloidal assembly route for responsive colloidosomes with tunable permeability. Nano Lett. 2007, 7 (9), 2876−2880. (10) Rabanel, J.-M.; Banquy, X.; Zouaoui, H.; Mokhtar, M.; Hildgen, P. Progress technology in microencapsulation methods for cell therapy. Biotechnol. Prog. 2009, 25 (4), 946−963. (11) Kessler, M. R.; Sottos, N. R.; White, S. R. Self-healing structural composite materials. Composites, Part A 2003, 34 (8), 743−753. (12) Lee, S. H.; Yoon, S. J.; Kim, Y. G.; Choi, Y. C.; Kim, J. H.; Lee, J. G. Development of building materials by using micro-encapsulated phase change material. Korean J. Chem. Eng. 2007, 24 (2), 332−335. (13) Augustin, M. A.; Hemar, Y. Nano- and micro-structured assemblies for encapsulation of food ingredients. Chem. Soc. Rev. 2009, 38 (4), 902−912. (14) Tomaszewska, M.; Jarosiewicz, A. Use of polysulfone in controlled-release NPK fertilizer formulations. J. Agric. Food Chem. 2002, 50 (16), 4634−4639. (15) Miguel, A. S.; Behrens, S. H. Permeability control in stimulus− responsive colloidosomes. Soft Matter 2011, 7 (5), 1948−1956. (16) Cayre, O. J.; Hitchcock, J.; Manga, M. S.; Fincham, S.; Simoes, A.; Williams, R. A.; Biggs, S. pH-responsive colloidosomes and their use for controlling release. Soft Matter 2012, 8 (17), 4717−4724. (17) Shah, R. K.; Kim, J.-W.; Weitz, D. A. Monodisperse stimuli− responsive colloidosomes by self-assembly of microgels in droplets. Langmuir 2010, 26 (3), 1561−1565. (18) Hsu, M. F.; Nikolaides, M. G.; Dinsmore, A. D.; Bausch, A. R.; Gordon, V. D.; Chen, X.; Hutchinson, J. W.; Weitz, D. A. Selfassembled shells composed of colloidal particles: Fabrication and characterization. Langmuir 2005, 21 (7), 2963−2970. (19) Keen, P. H. R.; Slater, N. K. H.; Routh, A. F. Encapsulation of yeast cells in colloidosomes. Langmuir 2011, 28 (2), 1169−1174. (20) Yow, H. N.; Routh, A. F. Formation of liquid core−polymer shell microcapsules. Soft Matter 2006, 2 (11), 940−949. (21) Rosenberg, R. T.; Dan, N. R. Diffusion through colloidosome shells. J. Colloid Interface Sci. 2011, 354 (2), 478−482. (22) Hidber, P. C.; Graule, T. J.; Gauckler, L. J. Influence of the dispersant structure on properties of electrostatically stabilized aqueous alumina suspensions. J. Eur. Ceram. Soc. 1997, 17 (2−3), 239−249. (23) Dan, N. Transport through self-assembled colloidal shells (colloidosomes). Curr. Opin. Colloid Interface Sci. 2012, 17 (3), 141− 146. (24) Ghosh, P.; Han, G.; De, M.; Kim, C. K.; Rotello, V. M. Gold nanoparticles in delivery applications. Adv. Drug Delivery Rev. 2008, 60 (11), 1307−1315. (25) Coti, K. K.; Belowich, M. E.; Liong, M.; Ambrogio, M. W.; Lau, Y. A.; Khatib, H. A.; Zink, J. I.; Khashab, N. M.; Stoddart, J. F. Mechanised nanoparticles for drug delivery. Nanoscale 2009, 1 (1), 16−39.
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Nanoparticle-Filled Complex Colloidosomes for Tunable Cargo Release Jonathan S. Sander and André R. Studart* Complex Materials, Department of Materials, ETH Zurich, 8093 Zurich, Switzerland S Supporting Information *
ABSTRACT: Capsules with a shell made out of nanoparticles, so-called colloidosomes, are very interesting for controlled encapsulation and release because of their selectively permeable shell, their mechanical stability, and the possibility to make them from many materials. Here, we report the creation of complex colloidosomes that can release encapsulated cargo on-demand in single or multiple release events. Unprecedented on-demand, multiple release is achieved by incorporating functional nanoparticles within the colloidosome hollow core. The entrapped nanoparticles enable pH-triggered release by either swelling to rupture the capsule shell in one single event or desorbing on-demand cargo molecules initially adsorbed on their surface. Implementation of such mechanisms in capsules with magnetically responsive shells enabled the creation of colloidosomes exhibiting unique spatiotemporal control of cargo release.
nanoparticle-filled colloidosomes. The entrapped nanoparticles are used either (I−III) to enable multiple on-demand release of molecules adsorbed on their surface or (IV) to irreversibly rupture the capsule under an external stimulus. The realization of the colloidosome architectures proposed in Figure 1a requires the facile incorporation of colloidal nanoparticles in the interior of the capsules and the formation of capsule shells that are sufficiently tight to effectively trap such incorporated particles. Nanoparticle-filled colloidosomes can be produced by simply dispersing the active colloidal particles in the innermost phase of the double emulsion templates during microfluidic emulsification (Figure 1b). Because the active nanoparticles are kept dispersed inside the capsules, our ability to deliberately add other functional nanoparticles to the middle phase that will later constitute the shell is retained, allowing us to take full advantage of the protective function and other magnetic, catalytic, and biological properties that can be associated with the colloidosome shell.3,5,7,18,19 The multilayered nature of shells obtained through this double emulsification route (images c−e of Figure 1) ensures uniform permeability and facilitates the efficient entrapment of the active colloidal particles inside the capsule.20,21 Entrapment is eventually achieved by ensuring that the shell pore size is significantly smaller than the diameter of the nanoparticles loaded into the colloidosome. Such a pore size can be independently controlled by changing the size of the colloidal particles that form the shell without interfering with the active nanoparticles involved in the triggered release mechanism.3
Colloidosomes are hollow capsules exhibiting a shell made from colloidal particles.1,2 The intrinsic porosity arising from the interstitials between the particles leads to capsules with unique semi-permeable shells. In addition to their semi-permeable nature, colloidosomes can also display other interesting properties, such as magnetism, photocatalytic activity, or tunable dissolution behavior, if specific functional particles are used in the shell.3−7 Among the various synthetic routes that have been used to create colloidosomes,1,2,4,7−9 the use of double emulsions as soft templates is particularly interesting because it allows for the formation of thick, multilayered particle shells with independently controlled thickness and interstitial pores.3 This opens the possibility to obtain capsules whose semi-permeable shell can be designed to not only be size-selective but to also control the release kinetics of the encapsulated cargo. Although this high flexibility makes colloidosomes promising candidates for controlled encapsulation in many applications,10−14 most studies thus far have only explored the passive diffusion of encapsulants through the interstices of the particle shell as a possible release mechanism. A few recent studies have shown that it is also possible to control the release of chemicals from colloidosomes using pHdegradable material or swellable particles in the core9 or shell.6,15−17 However, cargo release in these systems cannot be triggered multiple times on demand or often relies on shells with specific chemistries. Thus, the multifunctionality and sizeselective nature of the shell have not yet been fully exploited for the creation of colloidosomes with multiple, on-demand release of encapsulated cargo. Here, we show that colloidosomes with tunable release patterns can be made if functional nanoparticles are entrapped in the interior of the capsule to provide an externally triggered mechanism for on-demand release. Figure 1a shows a schematic overview of the possible triggering mechanisms in such © 2013 American Chemical Society
Received: July 30, 2013 Revised: November 19, 2013 Published: November 22, 2013 15168
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(calcein) that strongly adsorbs on oppositely charged Al2O3 nanoparticles (Figure 2). At pH 5, the oppositely charged
Figure 2. (a) Fluorescence signal of encapsulated dye measured throughout a 0.5 mm wide glass compartment containing several capsules filled with calcein adsorbed on trapped Al2O3 nanoparticles (see also Figure S2 of the Supporting Information). At low pH, the dye remains adsorbed on the nanoparticles, keeping the capsule in a dormant state, as indicated by the constant intensity inside the glass compartments in periods I and III. At high pH, the dye desorbs from the nanoparticles, switching the capsules to an active state, as shown by the decreasing fluorescence in periods II and IV. (b) Fluorescence (top) and bright-field (bottom) microscopy images of a capsule in different dormant and active stages. Scale bar: 75 μm
Figure 1. (a) Schematics illustrating the concept used to achieve ondemand release with nanoparticle-filled colloidosomes: (I) on−off release upon triggered desorption of cargo molecules from entrapped nanoparticles, (II) combination of active on−off and passive mechanisms to enable multiple cargo release with independently controlled temporal patterns, (III) incorporation of magnetic nanoparticles in the shell to allow for manipulation of on−off capsules, and (IV) one-time release induced by swelling of trapped nanoparticles. (b) Snapshot of the double emulsification process in a microcapillary device indicating the innermost aqueous fluid in which the active nanoparticles are dispersed. (c−e) Details of the semi-permeable shell of a colloidosome made from 250 nm SiO2 particles. Image c depicts a cross-section of the shell of a broken colloidosome, whereas images d and e exhibit the outer surface of the shell. The inset in image d shows the capsule at a lower magnification (scale bar = 50 μm).
molecules and nanoparticles remain coupled (constant fluorescence inside the capsule) and the system is in a dormant state. Increasing the pH to 10, above the isoelectric point of the nanoparticles (Figure S1), leads to desorption of the dye from the nanoparticle surface, which triggers a transition of the system to an active state, where dye is released (decreasing fluorescence inside the capsule). Release during the active state continues until the solution pH is changed back again to 5, which is indicated in Figure 2b as dormant state III. In the dormant state, molecules that have not yet diffused out of the capsule re-adsorb on the nanoparticle surface and stay trapped again. This can be repeated multiple times as long as there is still cargo inside the capsule (Figure 2a and movie S1 of the Supporting Information). To better quantify the release kinetics in the active states, we measured the decrease in fluorescence intensity of an individual capsule subjected to cyclic pH changes between 5 and 10 in a microfluidic compartment (see Figure S3 of the Supporting Information). Taking into account that the shell thickness h is considerably smaller than the capsule radius r, the diffusion coefficient of the dye molecules through the colloidosome shell during the active states was estimated by fitting the change in
The high flexibility in colloidosome fabrication offered by the microfluidic emulsification route was eventually employed to create the on-demand release systems depicted in Figure 1a. To illustrate the potential of such nanoparticle-filled colloidosomes, we first demonstrate the on-demand repeated release of cargo from the same capsule. Repeated on−off switching of the release is possible with nanoparticle-filled colloidosomes by adsorbing the encapsulant on the surface of the entrapped particles (I in Figure 1a). Because the adsorption and desorption of molecules on their surfaces is usually pHdependent,22 oxide nanoparticles provide a convenient platform for the controlled on−off release triggered by pH. This is demonstrated here using a negatively charged fluorescent dye 15169
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fluorescence intensity I as a function of time t using the following relation:3,23 ⎛ I − I∞ ⎞ ⎜ ⎟ ≈ e−(3D / hr)t ⎝ I0 ⎠
(1)
where D is the diffusion coefficient of the dye molecules through the shell and I0 and I∞ are the initial and final fluorescence intensities, respectively. Assuming an average shell thickness h of 4 μm, we obtained diffusion coefficients (D) in the range of 0.36−0.58 μm2/s. These values are 1 order of magnitude higher than the diffusion coefficients of fluorescent probes of similar size permeating through colloidosome shells with 10-fold smaller interstitial pore sizes.3 It is important to note that the flexibility offered by the proposed colloidosomes in changing the material of the trapped nanoparticles as well as the particles forming the shell is crucial to design a system that favors the selective adsorption of the encapsulant on the trapped nanoparticles rather than on the shell. In the example shown in Figure 2, this was achieved using negatively charged SiO2 particles in the shell, which prevented adsorption of encapsulants of the same charge by simple electrostatic repulsion. With the numerous particle types available to form the shell5 and the availability of oxide nanoparticles with different isoelectric points, these coloidosome systems can be potentially tuned to obtain similar on−off patterns at many specifically targeted pH ranges. The ability to deliberately switch the release state from dormant to active using nanoparticle-filled colloidosomes opens several new possibilities for the design of encapsulation systems with tailored release. The basic concept of release mediated by entrapped nanoparticles shown in Figure 2 can be extended to more complex systems containing more than one cargo to achieve different release patterns of several distinct molecules from the same capsule. To illustrate this potential, we assembled complex colloidosomes that combine the on−off features of the Al2O3−calcein system (Figure 2) with the passive release of an additional neutral non-adsorbing molecular dye (II in Figure 1a). This design allows for continuous release of the neutral dye through the interstitial pores of the colloidosome shell, while the charged dye is released independently upon deliberate changes in the pH (Figure 3). In this example, the independent release patterns could be detected using a negatively charged dye emitting in the blue spectrum for the intermittent on−off release and a neutral green fluorescent dye for the continuous passive release. Keeping the system at pH 5 results in the passive release of the green dye, while the negatively charged dye remains adsorbed on the surface of the Al2O3 nanoparticles inside the colloidosomes. This is indicated by the decreasing and constant fluorescence intensity of the green and blue dyes inside the colloidosome, respectively (panels a, c, and e of Figure 3). Shifting the pH of the surrounding solution to 10 causes the initially trapped blue dye to desorb from the encapsulated alumina nanoparticles and to also diffuse into the outer medium. This changes the delivery pattern of the system from selective to combined release (panels b, d, and f of Figure 3). Estimates of the diffusion coefficient D using eq 1 lead to comparable values in the range of 0.19−0.26 μm2/s for both actively and passively released cargos (panels e and f of Figure 3). The lower D values obtained for the two-cargo colloidosomes as compared to the capsules with only one type of cargo (Figure 2) might be attributed to the different
Figure 3. pH-controlled switching from selective to combined release of two encapsulants from the same complex colloidosome. (a−d) Fluorescence microscopy images of colloidosomes taken 0 and 2 h after the solution pH was changed to 5 (a and c) and 10 (b and d). The brightness in the images reveals the fluorescent intensity detected in the blue (a and b) and green (c and d) light spectra. Measuring the fluorescence intensity inside the capsules shows the (e) selective release of only one of the encapsulants at low pH and (f) simultaneous release of both cargo molecules at higher pH. The full red lines are the theoretical fittings (eq 1) used to obtain the following diffusion coefficients, D: 0.23 μm2/s for the actively released cargo (blue) and 0.19 and 0.26 μm2/s for the passively released cargo (green channel in panels e and f, respectively). Scale bar: 75 μm
measuring conditions and, thus, distinct equilibration times in these systems. The fluorescence in the two-cargo colloidosomes (Figure 3) was measured in individual capsules in the absence of flow, whereas the signal in the one-cargo system (Figure 2) was measured in a flowing continuous aqueous medium. In addition to the independent control of the release of different types of cargo molecules from the same capsule, our ability to functionalize the shell with magnetically responsive particles5 also allows for remote manipulation of the complex colloidosomes into programmed spatial patterns. This makes the design of delivery systems with unprecedented spatiotemporal control over the release pattern possible, as illustrated by the example shown in Figure 4. In this case, colloidosomes loaded with calcein-coated Al2O3 nanoparticles (Figure 2) have their silica shells functionalized with superparamagnetic iron oxide nanoparticles. The resulting colloidosomes can be remotely manipulated from their initial position to any preprogrammed location with the help of magnets that impose an external magnetic field gradient. This is demonstrated by deliberately positioning the colloidosome into one of many possible compartments, as shown in panels a and b of Figure 4. After bringing the colloidosome to the intended spot, release of the trapped calcein is initiated by changing the solution pH from 5 to 10 (Figure 4c and movie S2 of the Supporting Information), following the mechanism previously depicted in Figure 2. Panels d and e of Figures 4 show that the fluorescence is first constant inside the capsules, confirming that the colloidosomes remain in the dormant state in their initial 15170
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Figure 4. Cargo release with spatiotemporal control using magnetically responsive complex colloidosomes. (a) Overlay of fluorescence and brightfield images of a dormant magnetic colloidosome with internally trapped calcein molecules at low pH. (b) Combination of several reflected light images showing the controlled manipulation of the colloidosome from its initial position to a selected compartment using the magnetic field gradient imposed by a rare earth magnet. (c) Overlay of fluorescence and bright-field images of the colloidosome inside the compartment after some calcein had been released at high pH. (d−g) Fluorescence microscopy images of the capsules (d and e) kept in the dormant state in their initial position at low pH and (f and g) about 0 and 16 min after exposure to a high pH to promote local release inside the compartment.
at high pH. Encapsulant release upon pH increase is evidenced by the decrease of fluorescence intensity inside the capsule over time. Microgel nanoparticle weight fractions lower than about 3 wt % result in small cracks on the capsule shell, which are not always visible with the optical microscope (Figure 5c). In contrast, higher concentrations lead to pressures that are high enough to make a large, visible crack or to crush out a piece of the capsule wall (Figure 5b). Thus, variation of the microgel nanoparticle content in the colloidosomes enables deliberate tuning of the release speed after the external trigger (panels d and e of Figure 5). This is shown in Figure 5d by measuring the intensity of a fluorescent dye as a function of time in the supernatant of a suspension containing many capsules. To quantify the effect of the microgel nanoparticle content on the release speed, we fitted the time-lapse fluorescence data shown in Figure 5d with the following equation:
position at low pH. The inhomogeneous structure observed suggests that the trapped alumina nanoparticles aggregate at this pH if calcein is adsorbed on their surface. Panels f and g of Figure 4 depict a capsule that was first moved to the selected compartment by magnetic guiding at low pH (f) and that was later exposed to a high pH for 10 min to enable local release (g). Nanoparticle-filled colloidosomes can also be designed to provide on-demand delivery systems featuring one-time release of encapsulated cargo. In this case, one-time release can be achieved using trapped nanoparticles that undergo triggered swelling to partially or fully rupture the colloidosome shell. Figure 5 depicts the one-time release of encapsulants using trapped microgel nanoparticles that swell upon pH changes. Commercially available stearin-modified poly(acrylic acid) microgel nanoparticles used in this example can expand by a factor of 4−5 in water upon a small pH change from 6 to 7 (Figure 5a). Swelling of the initially collapsed nanoparticles is caused by electrostatic repulsion between the carboxylate side chains of the cross-linked gel particles upon deprotonation at higher pH values. As long as the hydrogel nanoparticles are in the collapsed state, no transport occurs through the shell because the cargo and the active particles are too large to diffuse through the pores. Above a threshold concentration of microgel nanoparticles (0.15 wt %), their expansion at high pH leads to rupture or cracking of the colloidosome wall and, thus, release of the encapsulant, as exemplified in panels b and c of Figure 5 and movies S3 and S4 of the Supporting Information. In these examples, FITC-labeled dextran molecules (Mw = 500 000 g/mol) were used as a representative cargo physically trapped inside the capsule. The expansion of the microgel nanoparticles was triggered by adding a drop of 1 M KOH to the solution, which led to an instantaneous increase of the fluorescence intensity because of the higher emission of FITC
I ≈ 1 − e−(3Deff / hr)t I∞
(2)
Considering the heterogeneous nature of the cracked capsule shell, the Deff values obtained by fitting eq 2 to the measured data should be interpreted only as effective diffusion coefficients. Figure 5e shows that Deff values varying within 1 order of magnitude from 0.05 to 0.45 μm2/s can be obtained by simply adjusting the concentration of microgel nanoparticles initially trapped in the colloidosome. This clearly shows our ability to control both the onset and speed of cargo release in such a one-time triggered system. In comparison to responsive colloidosomes consisting of a single hydrogel core,9 the use of hydrogel microparticles for on-demand rupture of the capsule shell offers greater flexibility with regards to the size and chemistry of the encapsulated cargo. For example, living cells that would not fit into a hydrogel core can be easily 15171
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functional properties as entrapped colloids or as shell material, the proposed concept can potentially be extended to program cargo release in many other nanoparticle-based systems beyond those illustrated here.24,25 In addition to the rich diversity of release patterns that can be envisioned, the robustness and semi-permeable nature of the colloidosome shell offers mechanical protection and also restricts the interactions of the encapsulated cargo only to molecules that are small enough to diffuse through the shell. Altogether, these features open several new possibilities for the design of encapsulation systems with programmed release control for several applications in medicine, cosmetics, agriculture, food, and materials sciences.
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ASSOCIATED CONTENT
S Supporting Information *
Detailed experimental methods, ζ potential results for the Al2O3 particles used for on−off switchable release (Figure S1), images of the setup used to measure switchable release (Figure S2), results of fluorescence measurements from a single capsule subjected to consecutive on−off release cycles (Figure S3), and movies showing the (i) switchable on−off release of a fluorescent dye from a nanoparticle-filled colloidosome (movie S1), (ii) spatial and temporal control of cargo release from a magnetically responsive particle-filled colloidosome (movie S2), and (iii) pH-triggered release from colloidosomes with entrapped swellable particles (movies S3 and S4). 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 This work was funded by the Swiss National Science Foundation (Grant 200021_126646). We thank the Multifunctional Materials group and the Laboratory for Surface Science and Technology at ETH Zurich for providing the equipment for fluorescence emission spectroscopy and dynamic light scattering, respectively.
Figure 5. (a) Average size of microgel nanoparticles in water at different pH values. The insets schematically show the dormant state of the capsule when the trapped microgel nanoparticles are collapsed at low pH and the rupture of the capsule shell upon expansion of the nanoparticles at high pH. (b and c) Overlay of fluorescent and brightfield images showing the effect of KOH addition on capsules with (b) 4.5 and (c) 0.75 wt % microgel trapped nanoparticles and a fluorescent dye. Scale bar corresponds to 100 μm. (d) Normalized fluorescence intensity of a supernatant solution taken from a suspension of coloidosomes filled with fluorescent dye and ruptured using different concentrations of microgel nanoparticles. Solid lines are fitting curves obtained using eq 2. (e) Effect of the microgel content (wt %) on the diffusion coefficient D obtained from the fittings shown in panel d.
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