LETTER pubs.acs.org/JPCL
Magnetically Triggered Release From Giant Unilamellar Vesicles: Visualization By Means Of Confocal Microscopy Silvia Nappini,† Tamer Al Kayal,† Debora Berti,† Bengt Norden,‡ and Piero Baglioni*,† † ‡
Department of Chemistry & CSGI, University of Florence, Via della Lastruccia 3 - Sesto Fiorentino, 50019 Florence, Italy Department of Chemical and Biological EngineeringPhysical Chemistry, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
bS Supporting Information ABSTRACT: Magnetically triggered release from magnetic giant unilamellar vesicles (GUVs) loaded with Alexa fluorescent dye was studied by means of confocal laser scanning microscopy (CLSM) under a lowfrequency alternating magnetic field (LF-AMF). Core/shell cobalt ferrite nanoparticles coated with rhodamine B isothiocyanate (MP@SiO2(RITC)) were prepared and adsorbed on the GUV membrane. The MP@SiO2(RITC) location and distribution on giant lipid vesicles were determined by 3D-CLSM projections, and their effect on the release properties and GUV permeability under a LF-AMF was investigated by CLSM timeresolved experiments. We show that the mechanism of release of the fluorescent dye during the LF-AMF exposure is induced by magnetic nanoparticle energy and mechanical vibration, which promote the perturbation of the GUV membrane without its collapse. SECTION: Nanoparticles and Nanostructures
T
he ability to achieve spatial and temporal control over drug release from artificially designed drug carriers is one of the core challenges in biomedical research.13 The most common methods to favor drug leakage from vectors (polymeric or polyelectrolyte microcapsules and liposomes) are based on the destabilization of the system induced by an external stimulus such as pH change,4 temperature increase (hyperthemia),58 ultrasound application,9,10 ionic strength variations,11,12 enzymatic digestion,13,14 or reductive intracellular environment.15 Lipid vesicles, since their discovery, have attracted growing interest for their potential application as drug delivery16,17 vehicles, magnetic resonance imaging (MRI) contrast agents,18,19 and primitive models for cellular membrane permeability investigation.2022 Their main advantages in comparison with other well-studied systems, such as polyelectrolyte microcapsules,2325 are mainly related to a high biocompatibility, flexibility in terms of size and composition, the easy modification of surface properties, and their ability to encapsulate both hydrophilic molecules26 into the aqueous pool or hydrophobic molecules within the lipid bilayer.27 Thanks to their submicrometer diameter, large unilamellar vesicles (LUVs or liposomes) are commonly used for in vivo applications, while giant unilamellar vesicles (GUVs), with a diameter ranging between 1 and100 μm but with identical local arrangement of lipid bilayers, can be used as models28 to visualize with optical microscopic techniques the membrane perturbations occurring after the application of an external stimulus.2931 The responsive agents are magnetic particles, which can be easily encapsulated inside of lipid vesicles and steer their r 2011 American Chemical Society
host to specific locations of the body under an external magnetic force.21,32 Once the drug carrier has reached the specific target, an alternating magnetic field (AMF) can be applied to trigger the drug leakage.6,17,33 A number of reports in the literature address the investigation of drug release under an alternating magnetic field; in most cases, a high-frequency magnetic field (HF-AMF), 10500 kHz, was used to promote local heating.8,17,23,34 However, a low-frequency alternating magnetic field (LF-AMF), with oscillating frequencies < 10 kHz, is generally preferred for in vivo applications, and the hyperthermic effect is minimized. In previous works,35,36 we have studied how magnetoliposomes (liposomes loaded with cobalt ferrite nanoparticles) release a fluorescent molecule entrapped in the aqueous pool upon exposure to LF-AMF. The release behavior of the dye has been studied as a function of different parameters, that is, field frequency, exposure time, and magnetic fluid concentration, showing that either hyperthermic effect or nanoparticle motions, both driven by LF-AMF, alter the bilayer structure, promoting the drug release. However, mechanistic insight into the perturbations locally acting on the bilayer cannot be obtained with the previous investigation. In this study, we gain further structural details on the interaction of magnetic nanoparticles with their liposomal host and on the release process through CLSM visualization of the carriers Received: January 20, 2011 Accepted: March 1, 2011 Published: March 10, 2011 713
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during and after the application of the external stimulus. The use of micrometer-sized magnetic GUVs allows a direct observation of the location of magnetic nanoparticles in the lipid vesicle and thus provides a better understanding of the permeation properties of lipid bilayers in the presence of an external magnetic field of 200 Hz. The use of magnetic and fluorescent particles encapsulated in GUVs is a well-suited system for locating their position, and the use of a fluorescent dye entrapped in the internal lumen of the vesicle as a mimic of a drug enclosed in the aqueous pool of a liposome allows study of the release process through CLSM acquisition.3739 Moreover, magnetic GUVs can be used as models to study shape deformation and membrane perturbation when a magnetic field is applied.37 Recently, GUVs loaded with fluorescent maghemite nanoparticles tagged with rhodamine B were used to study vesicle deformations in the presence of a static magnetic force at different salt concentrations, evidencing an important elongation of GUVs and a fluorescence intensity increase at higher salt concentration in the rhodamine magnetic fluid.12,37,40 The aim of the present work is to detect the location and distribution of fluorescent superparamagnetic particles in magnetic GUVs and to study the effect of a LF-AMF on the permeability of magnetic vesicles. For the first time, to the best of our knowledge, we report a detailed CLSM investigation on magnetic particles' location in GUVs and a study of controlled drug release from magnetic fluorescent vesicles upon LF-AMF exposure. Cobalt ferrite nanoparticles incorporating rhodamine B isothiocyanate MP@SiO2(RITC) were synthesized by a solgel method4143 in order to allow for their observation by fluorescence and confocal microscopy. Magnetic GUVs were prepared using the electroformation method44 by means of a homemade conducting chamber (see the procedure in Supporting Information, Figure S1) in the presence of MP@SiO2(RITC). Drug release experiments were carried out by CLSM time series acquisition, measuring the varation in fluorescence emission of Alexa 488-C5-maleimide dye loaded in the aqueous pool of GUVs, in order to check the vesicle permeability changes or their structural deformations during and after the LF-AMF exposure. MP@SiO2(RITC) was prepared by a solgel method (see Supporting Information), introducing some modifications to the standard procedure.41 Cobalt ferrite nanoparticles were first prepared according to the Massart45,46 method, introducing minor modifications as previously reported,35,47,48 and then, APTESRITC, aminopropyltriethoxysilane covalently coupled to the fluorescent dye rhodamine B,49 was added to the magnetic fluid to have a fluorescent coating of nanoparticles. The growth of APTES-RITC shells on a cobalt ferrite NP involved the hydrolysis of TEOS and the condensation of silica on cobalt ferrite cores. Cobalt and iron contents in MP@SiO2(RITC) were checked by an inductively coupled plasma atomic emission spectrometer (ICP-AES), indicating 950 and 1920 mg/mL of Co and Fe, respectively. MP@SiO2(RITC) particles were observed with an inverted optical microscope (Nikon Diaphot 300) and with a DMIRE2 confocal laser scanning microscope (CLSM, Leica TCS SP2). Microscopy images of MP@SiO2(RITC) are reported in Supporting Information (Figure S4), evidencing the presence of fluorescent microstructures resulting from the aggregation of smaller primary particles, which easily align in a given direction because of magnetic anisotropy effects. MP@SiO2(RITC) particles were also characterized by dynamic light scattering (DLS) measurements. The size distribution of the particles extracted
from CONTIN analysis indicates the presence of three different populations (see Supporting Information, Figure S5). In particular, the number-weighted size distribution highlights the presence of a dominant population of 50 nm nanoparticles and the occurrence of some larger aggregates of about 180 and 350 nm of diameter, as shown in Figure S5(b) in Supporting Information. The fluorescence emission spectra of MP@SiO2(RITC) were compared to those obtained for an identical concentration of APTES-RITC aqueous solution, excited at λ = 546 nm (corresponding to the maximum fluorescence emission) and λ = 514 nm (corresponding to the laser line used for confocal microcopy acquisition), indicating a red shift for MP@SiO2(RITC) due to the interaction of the dye with cobalt ferrite particles or inclusion of the dye in the silica shell of the particles with respect to noninteracting dye molecules in solution. The fluorescence intensity of MP@SiO2(RITC) was at least twice lower than that for free APTES-RITC (see Supporting Information, Figure S6). The differences in fluorescence emission for MP@SiO2(RITC) and APTES-RITC aqueous solutions indicates that APTES-RITC dye is effectively bound to magnetic particles. Magnetic GUVs, prepared by the electroformation method,44 have diameters that range from 10 to 50 μm, and their images were acquired by CLSM using a water immersion objective 63/ 1.2 W (Zeiss). The water-soluble probe Alexa 488-maleimide was excited at λ = 488 nm and detected between 525 and 540 nm by the first detector (PMT1), while MP@SiO2(RITC) particles were excited at λ = 514 nm and detected between 560 and 650 nm by a second detector (PMT2). All leakage experiments were quantitatively analyzed by measuring the change in fluorescence intensity of the probe in the aqueous pool inside of the GUVs during the exposure to a LF-AMF generated by a broken ferrite ring carrying a solenoid through which an alternating electric current (AC) from a tone generator was delivered.36 For the application of a LF-AMF, the samples were placed in the middle of the gap in 1 cm cylindrical quartz cells. Due to the design of the experimental apparatus, the magnetic field inside of the cell is not isotropic. As a consequence, the sample undergoes magnetic field gradients that cannot be avoided (see Supporting Information, Figures S2 and S3). CLSM images of magnetic GUVs prepared in the presence of MP@SiO2(RITC) are reported in Figure 1. The localization of the magnetic particles onto the bilayer membrane results in the staining of the bilayer itself, showing that most particles are adsorbed on the surface of GUVs’bilayer. Three-dimensional projection obtained by assembling with Leica software confocal slices (thickness 0.366 μm) of magnetic GUVs indicates that generally, MP@SiO2(RITC) particles are not homogeneously distributed on the membrane surface of the vesicles (Figure 2) but rather tend to concentrate in magnetic patches. Intensity line profiles of different regions of the GUV membrane (see Supporting Information, Figure S7) confirm that the magnetic nanoparticles are not evenly distributed on the lipid bilayer of vesicles, evidencing larger profiles (ranging between 1 and 4 μm) and higher fluorescent intensities where MP@SiO2(RITC) particles are adsorbed. Moreover, confocal xyλ-scans of magnetic GUVs were performed to analyze the fluorescence spectra in different regions of the membrane, depending on MP@SiO2(RITC) adsorption, evidencing higher fluorescent intensity (maximum emission around λ = 586 nm) in the 714
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Figure 1. CLSM images of magnetic GUVs prepared by electroformation in the presence of MP@SiO2(RITC).
The leakage behavior was studied by means of CLSM, loading GUVs with the water-soluble fluorophore Alexa 488-C5-maleimide. To detect the vesicle permeability changes under LF-AMF, magnetic GUVs in the presence of MP@SiO2(RITC) and control samples (GUVs without magnetic particles) were analyzed by measuring the change in fluorescence intensity of the Alexa dye located inside of the GUVs. Time series scans were carried out before, during (15 min), and after (15 min) the LFAMF application at 200 Hz of oscillating field frequency. Alexa-loaded GUV (without magnetic particles) acquisitions indicated no changes in the fluorescence intensity over time. Therefore, we can exclude any leakage mechanisms due to the LF-AMF exposure of nonmagnetic GUVs and any photobleaching effects of the Alexa dye.36 On the other hand, Alexa-loaded GUVs in the presence of MP@SiO2(RITC) showed a pronunced release of the dye, monitored as a decrease of fluorescence emission, due to the LF-AMF exposure, as reported in the time series pictures in Figure 3. During the LF-AMF application, we observed a progressive reduction of the fluorescent intensity of Alexa inside of the vesicles, and this trend proceeded even after field removal as a consequence of an increased Alexa diffusion through the vesicles membrane. It is interesting to note that even if the distribution of MP@SiO2(RITC) onto the membrane is not homogeneous, the Alexa dye leakage from the GUVs is uniform, evidencing no preferential paths in the membrane. Release curves of Alexa dye from magnetic and nonmagnetic GUVs are shown in Figure 4, where the relative fluorescence intensity, calculated as the ratio between the measured fluorescence intensity at time t and the fluorescence intensity of the untreated sample at time zero, were monitored over time. Magnetic GUV samples exposed to the field have shown a strong decrease (around 50%) of the fluorescence intensity during the experiments. Therefore, the permeability of GUVs, negligible in the absence of LF-AMF, strongly increased after the field exposure. These results indicate that the application of a LF-AMF induces an alteration of the lipid bilayer structure (promoting the formation of pores) that enhances the Alexa release, without the rupture of the vesicles. This behavior is similar to what we have previously reported for uncoated and citrate-coated nanoparticles36 loaded in the aqueous pool of lipid vesicles. In order to better understand the mechanism involved in the Alexa leakage, the release kinetics, reported as a decrease of the normalized fluorescence intensity of the dye inside of GUVs over
Figure 2. Three-dimensional projection (max fix treatment) of magnetic GUVs prepared by electroformation in the presence of MP@SiO2(RITC).
presence of larger amounts of adsorbed nanoparticles (see Supporting Information, Figure S9). These results were compared to the ones obtained with GUVs hydrated with a solution with an identical concentration of APTES-RITC. Differently from magnetic GUVs, RITC-labeled GUVs images show a uniform distribution of the fluorescent dye on the lipid bilayer of vesicles, evidencing the same membrane thickness (around 0.5 μm, close to the instrumental resolution limit) over the entire surface of GUVs (see Intensity line profiles in Supporting Information, Figure S8). Confocal xyλ-scans of RITC-labeled GUVs (reported in the Supporting Information, Figure S10) showed a fluorescence emission spectrum centered around λem = 576 nm, confirming that the red-shift effect observed by spectrofluorimetric analysis of MP@SiO2(RITC) aqueous solution is also present for MP@SiO2(RITC)-adsorbed GUVs (λem = 586 nm). Empty and nonfluorescent GUVs were mixed to MP@SiO2(RITC) in the ratio [CoFe2O4]/[lipid] = 2 and analyzed by CLSM in order to detect the effect of the external addition of magnetic particles to preformed GUVs. Confocal images reported in the Supporting Materials (Figure S11) show the adsortpion of fluorescent MP@SiO2 particles on the bilayer, whose results are visible to confocal microscopy, and the occurrence of large aggregates of magnetic particles, whose presence induces shape deformations in nearby vesicles. 715
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Figure 3. CLSM images of Alexa-loaded GUVs over time. In the first line, Alexa is colored in green, and MP@SiO2(RITC) is in red: magnetic GUV (a) in the absence of AMF at time zero, (b) exposed for 15 min to 200 Hz AMF, and (c) 15 min after the field application. Magnetic GUV again exposed to 200 Hz AMF for (d) 15 min and (e) 15 min after the last field application. In the second line are CLSM pictures obtained by removing the nanoparticle fluorescent contribution from the first line pictures.
Figure 4. Alexa release profiles from GUVs decorated (a) and not decorated (b) with MP@SiO2(RITC) during and after LF-AMF applications.
Figure 5. Alexa release kinetics from GUVs decorated with MP@SiO2(RITC) exposed to LF-AMF. The solid curve is the fitting obtained by means of eq 1.
time, was studied by the Ritger and Peppas equation.5053 The Ritger and Peppas equation is widely used to analyze the release behavior of various drug delivery systems5456 and can be written as ðIð0Þ IðtÞÞ ¼ Kt n Ið¥Þ
erosion contribute to the overall release mechanism (“anomalous transport”). The experimental curve and the corresponding fitting obtained with magnetic GUVs exposed to the LF-AMF are reported in Figure 5. The curve is well-fitted by eq 1 for n equal to 0.67 ( 0.01, indicating an anomalous transport mechanism of release; that is the combination of Fickian diffusion and membrane perturbation of GUV. This kinetics of release suggests an alteration of the lipid bilayer structure followed by the formation of pores promoting the fluorescent dye leakage. Moreover, a kinetic constant, K, of (2.37 ( 0.31) 103 indicates a high rate of release, which confirms the drug leakage through formation of pores. In summary, magnetic and fluorescent GUVs decorated with MP@SiO2(RITC) were successfully prepared, evidencing a
ð1Þ
where [I(0) I(t)]/I(¥) is the drug fraction release at time t, K is the kinetic constant, and n is the diffusion exponent that can be related to the drug transport mechanism. The power law equation can be seen as the superposition of Fickian diffusion and zero-order kinetics; when the n value is near 0.5, Fickian diffusion control is indicated, while an n value of near 1.0 indicates erosion or relaxation control, which lead to a zero-order release (“case II transport”). Intermediate n values between 0.5 and 1.0 suggest that diffusion and 716
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nonhomogeneous adsorption of magnetic nanoparticles on the membrane of the vesicles. The effect of a LF-AMF on the release properties and GUVs' permeability was investigated by acquisition of CLSM images over time, evidencing a progressive reduction of Alexa fluorescent intensity. The experimental results have indicated an increase of Alexa leakage through the vesicle membrane as a consequence of the formation of pores induced by LF-AMF exposure. The system exposed to the LF-AMF follows an anomalous transport mechanism of release. The equipment that we have set up for the acquisition of CLSM time series images during the application of a LF-AMF and the successful preparation of magnetic and fluorescent GUVs open the opportunity for the real observation of membrane perturbations due to an external stimulus and the possibility to gain understanding of the drug release mechanism. For biomedical applications in drug delivery, the size of the vesicles and particles could be decreased and easily visualized and located by MRI or optical imaging without the requirement of invasive methods.
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’ ASSOCIATED CONTENT
bS
Supporting Information. Experimental procedure of MP@SiO2(RITC) synthesis and GUV preparation by electroformation chamber, LF-AMF setup, MP@SiO2(RITC) characterization (microscopy images, DLS size distribution, and fluorescent spectra), intensity line profiles and fluorescent spectra of the magnetic GUV membrane, and CLSM images of empty GUVs mixed to MP@SiO2(RITC). This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Fax: þ39 055 4573032. Tel: þ39 055 4573033. E-mail:
[email protected]fi.it.
’ ACKNOWLEDGMENT Financial support from CSGI, MIUR-PRIN (2008-20087K9A2J), and FIRB (RBPR05JH2P ITALNANONET) is acknowledged. B.N. acknowledges a King Abdullah University of Science and Technology Award making this project possible. Dr. Tore Eriksson is acknowledged for building the alternating magnetic field generator. ’ REFERENCES (1) Woodle, M. C. Sterically Stabilized Liposome Therapeutics. Adv. Drug Delivery Rev. 1995, 16, 249–265. (2) Allen, T. M.; Cullis, P. R. Delivery Systems: Entering the Mainstream. Science 2004, 303, 1818–1821. (3) Torchilin, V. P. Recent Advances with Lipososmes As Pharamceutical Carriers. Nat. Rev. 2005, 4, 145–160. (4) Mills, J. K.; Eichenbaum, N.; Case, N.; Needham, D. Effect of Bilayer Cholesterol and Surface Grafted Poly(ethylene glycol) on PhInduced Release of Contents from Liposomes by Poly(2-ethylacrylic acid). J. Liposome Res. 1999, 9, 275–290. (5) Needham, D.; Dewhirstb, M. W. The Development and Testing of a New Temperature-Sensitive Drug Delivery System for the Treatment of Solid Tumors. Adv. Drug Delivery Rev. 2001, 53, 285–305. (6) Viroonchatapan, E.; Sato, H.; Ueno, M.; Adachi, I.; Tazawa, K.; Horikoshi, I. Release of 5-Fluorouracil from Thermosensitive 717
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