Synthesis, Characterization, and Magnetically Controlled Release

Jun 22, 2009 - Derfus , A. M.; Maltzahn , G. V.; Harris , T. J.; Duza , T.; Vecchio , K. S.; Ruoslahti , E.; Bhatia , S. N. Adv. Mater. 2007, 19, 3932...
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Synthesis, Characterization, and Magnetically Controlled Release Behavior of Novel Core-Shell Structural Magnetic Ibuprofen-Intercalated LDH Nanohybrids Hui Zhang,* Dengke Pan, and Xue Duan State Key Laboratory of Chemical Resource Engineering, Beijing UniVersity of Chemical Technology, P.O. Box 98, Beijing 100029, China ReceiVed: February 5, 2009; ReVised Manuscript ReceiVed: May 15, 2009

LDH (layered double hydroxides)-based magnetic-sensitive drug-inorganic nanohybrids were assembled by a one-step co-precipitation method. The effect of a magnetic substance on the microstructure and drug release behavior of ibuprofen (IBU)-intercalated Mg-Al-LDH in magnetic nanohybrids was systematically studied via XRD, TEM, XPS, and VSM methods and in vitro release with and without an external magnetic field (MF). The results reveal a well-defined core-shell structure with a gray IBU-LDH shell coated onto the surface of a dark magnetic core and superior magnetic sensitivity of the magnetic nanohybrids. Compared with the clear platelets of the pure IBU-LDH, the IBU-LDH coatings in magnetic nanohybrids exhibit more like a compact stacking film fully covering the magnetic core and their particle sizes and thickness decrease with increasing core contents, explaining an enhanced release rate under no MF. While under a 1500 G MF, the release rate is greatly reduced with increasing core content due to the instant aggregation of the magnetic nanohybrid particles induced by the external MF. The release mechanism was discussed, and a primarily pulsatile drug release upon a consecutive MF “on-off” operation was also achieved. 1. Introduction The control of the drug release from drug carriers, embodying control of both the release rate of a drug and the delivery of this drug to a specific organ or location in the body (i.e., targeting), has been a major goal in drug delivery research over the last two decades.1,2 Magnetic nanoparticles have, thus, received much more attention for biomedical applications meeting the demand of versatile, high-performance controlledrelease systems,1-4 such as in magnetic drug targeting and remote magnetically controlled drug release aspects.5-9 An increasing number of works on magnetic nanocomposites have been published, including active carbon/Fe,5 starch/Fe3O4,6 dextran/Fe3O4,7 polymer/Fe3O4,8 silica/Fe2O3 or Fe3O4,9 magnetic collagen gels,10 and dendrimer/iron oxide.11,12 It is noticed that, among these magnetic nanocomposites, most are based on the bioorganic nanoparticulate systems but less on the inorganic nanoparticulate ones.9 Recently, Sokolova and Epple reviewed inorganic nanoparticles as carriers of nucleic acids into cells.13 As one class of inorganic nanoparticles, layered nanoparticles, especially the layered double hydroxides (LDH), have attracted considerable interest as effective drug release systems.14-17 LDH, also known as anion clays, can be represented by a general formula of [M2+1-xM3+x(OH)2]x+An-x/n · mH2O, where M2+ and M3+ designate the di- and trivalent cations, An- the interlayer anions, and x ()M3+/(M2+ + M3+)) the hydroxide layer charge density.18 Owing to the unique host-guest structure, many of the therapeutic drugs and biomolecules, such as nonsteroidal anti-inflammatory drugs,19,20 anticancer agents,21,22 and cardiovascular drugs,23,24 etc., can be readily intercalated into the LDH interlayer via anion exchange and co-precipitation routes to form the drug-intercalated LDH nanohybrids. The intrinsic advantages, such as good biocompatibility, ease of preparation, low * To whom correspondence should be addressed. E-mail: huizhang67@ gst21.com. Phone: +8610-6442 5872. Fax: +8610-6442 5385.

cost, high drug loadings, enhanced drug stability, low cytotoxicity, and protection for the intercalated drug molecules, make the LDH materials outstanding candidates for drug delivery systems.17,20,22,24 However, the use of bulk drug-LDHs, particularly those involving poor water-solubility anti-inflammatory drugs19,20and anticancer agents21,22 in drug delivery systems, has been profoundly restricted due to lack of specific affinity toward the pathological sites. With respect to drug targeting, aiming to enhance the effective applications of the drug-LDH in biomedicine, functional materials such as magnetic nanoparticles were introduced into the LDH materials to form a magnetic targeted drug matrix. We previously reported a novel magnetic solid base catalyst25 with a CO3-MgAl-LDH layer and a magnetic drug-clay composite26 with the 5-aminosalicylate-intercalated LDH layer over the magnesium ferrite nanoparticles, respectively, and the obtained magnetic products showed a plausible core-shell structure. Carja et al.27 reported a magnetic composite based on the aspirin-intercalated LDH for drug delivery and showed a coexistence of the magnetic nanoparticles and the fibrous drug particles on the surface of partially aggregated claylike particles. More recently, we first reported a novel core-shell structural magnetic nanohybrid based on diclofenac-intercalated LDH and its drug release behavior being primarily slowed down by an applied external magnetic field.28Actually, the modulation of the drug release behavior based on different stimuli, such as light,29 pH,30and electric field,31 has been reported extensively in polymer/polyelectrolyte systems. Especially, numerous studies have been conducted on applying an external magnetic field to control the drug release behavior of magnetic hydrogel7,32-34 and the permeability of polyelectrolyte microcapsules embedded with Co@Au nanoparticles.35 However, a rare investigation is reported on the effect of varied microstructures and varied external MF intensities on the magnetically controlled drug release behavior of LDH-based magnetic nanohybrid materials.

10.1021/jp901060v CCC: $40.75  2009 American Chemical Society Published on Web 06/22/2009

Core-Shell Ibuprofen-Intercalated LDH Nanohybrids

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Figure 1. XRD (A) and FT-IR (B) spectra of IBU-LDH and IBU-Mi (i ) 1-4).

In the present work, to enhance specific affinity to therapeutic sites of the drug-LDH nanohybrids by noncontact force, a series of magnetic ibuprofen (a typical anti-inflammatory drug)intercalated LDH nanohybrids containing varied magnetic ferrite content were elaborately synthesized. Different from our more recent publication28 on a novel core-shell-type diclofenac-LDH/ magnesium ferrite nanohybrid first showing magnetically controlled drug release behavior, this study systematically explores the relationships among the microstructure, the magnetic property, and magnetically controlled drug release behavior of as-prepared magnetic nanohybrids as a function of both the ferrite content and the intensities of the external magnetic fields applied. The release mechanism was discussed based on several kinetic models. A magnetically controlled pulsatile drug release property of these nanohybrids was also examined. 2. Experimental Section 2.1. Synthesis of the Magnetic Substance. The magnetic nanoparticles were prepared via a layered precursor method.18 Typically, a 300 mL aqueous solution containing Mg(NO3)2 · 6H2O (0.09 mol), Fe(NO3)3 · 9H2O (0.045 mol), and FeCl2 · 4H2O (0.045 mol) was adjusted to ca. pH 11 by slowly adding dropwise another 300 mL solution of NaOH (0.36 mol) and Na2CO3 (0.27 mol) under vigorous agitation in a N2 atmosphere. The resultant was subsequently aged at 70 °C for 24 h, then centrifuged and washed with deionized water, and dried at 70 °C for 24 h in vacuum, giving a CO3MgFeIIFeIII-LDH. After calcination of this precursor at 900 °C for 2 h, the magnesium ferrite particles were obtained with a chemical formula of MgFe1.03O2.54 based on ICP data and the particle size of ∼46 nm on XRD data (Figure 1). 2.2. Synthesis of the Magnetic Nanohybrids. An aqueous solution (100 mL) containing Mg(NO3)2 · 6H2O (0.02 mol) and Al(NO3)3 · 9H2O (0.01 mol) was first mixed with various amounts of the above ferrite particles, giving a set of suspensions in which the mass ratios of Mg(NO3)2 · 6H2O to ferrite are designed as 1:0.050, 1:0.100, 1:0.143, and 1:0.200. These suspensions were first treated under ultrasonic vibrations for 20 min, resulting in more uniform suspensions before the next steps. Another aqueous solution (100 mL) of NaOH (0.1 mol) and IBU (0.1 mol) was added dropwise into the above suspensions under vigorous stirring in N2 atmosphere until a final pH ca. 10.0. The resultant was aged at 60 °C for 24 h, then centrifuged, washed with degassed deionized water, and dried at 60 °C for 24 h in vacuum. After a small amount of

free IBU-LDH particles was magnetically separated, the magnetic IBU-LDH nanohybrids were obtained and denoted as IBU-Mi (i ) 1-4, referring to the products with sequentially increasing ferrite amounts). The pure IBU-LDH was prepared via a similar method for comparison. 2.3. Characterization. A powder X-ray diffractometer (Shimadzu XRD-6000, Cu KR radiation) was used to identify the crystallographic phase of the nanohybrids, at a scanning rate of 5° 2θ per min over a range of 2θ 3-70°. The magnetization of the magnetic nanohybrids was tested on a JSM-13 vibratingsample magnetometer (VSM) at 298 K and ( 12 kOe applied magnetic field. The TEM images were recorded on a Hitachi800 transmission electron microscope. The metal components were measured by inductively coupled plasma (ICP) emission spectroscopy (Shimadzu ICPS-7500). CHN microanalysis was carried out using an Elementarvario elemental analysis instrument. Surface chemical compositions of the samples at different depths were studied by means of argon (3 kV, 25 mA target current) sputtering on a VG ESCALAB-MK II X-ray photoelectron spectrometer. The sputtering rate is 2 nm/min, and the pressure in the analysis chamber during the experiments was 2 × 10-7 Pa. Spectra were obtained using a standard Al KR source at hν ) 1486.6 eV operating at 15 kV and 20 mA. The binding energy scale was referenced to the C 1s line of aliphatic carbon contamination set at 284.6 eV. The drug content in the nanohybrid was determined after dissolving 0.05 g of the nanohybrid in 250 mL of dilute hydrochloric acid solution (0.1 mol/L). UV-vis spectroscopy (Shimadzu UV-2501PC) was used for characterization of the absorption at 263 nm to quantitatively determine the IBU. 2.4. In Vitro Drug Release. The drug release profiles were obtained in a dissolution apparatus, Rong Hua SHA-CA (China). A solution of simulated gastrointestinal and intestinal fluid at pH 7.45 without pancreatine (phosphate buffer solution, Chinese pharmacopoeia 2005) was used as a release medium. A typical experiment used 0.05 g of the nanohybrid in 250 mL of buffer solution kept at 37 °C under a paddle rotation speed of 50 rpm. At specified time intervals, 3 mL of solution, which was replaced by the same volume of fresh buffer, was removed and centrifuged at 12 000 rpm, giving a clear supernatant for determining the concentration of IBU using a standard curve of known concentrations of IBU. To investigate the magnetic field (MF)-dependent drug release of the magnetic nanohybrids, a set of permanent magnets (Nd-Fe-B magnets of 385, 770, and 1500 G) is placed beside

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the magnetic nanohybrids to emulate the magnetic location and magnetically controlled release operation.6 In addition, a magnetically controlled pulsatile drug release behavior of the sample under MF “on-off” operation was examined through applying and removing a 1500 G MF alternatively for several cycles. For the MF “on” mode, the Nd-Fe-B magnet was placed just beside the flask and the position of the magnet relative to the flask is unchanged during the whole release process, whereas for the MF “off” mode, the Nd-Fe-B magnet was quickly removed from the release device, keeping other test conditions unchanged. In all release tests, a thermometer was immersed into the release medium to monitor the temperature, and a variation below 0.5 °C in temperature was observed, indicating that the heat generated during the release process can be negligible. To illustrate the kinetics for the release behavior of the drug from the magnetic nanohybrids, we fit the released data with the following kinetic models.23,24,36,37 (1) The zero-order model usually describes the dissolution process.

Mt - M0 ) -k0t (2) The first-order model describes the release from systems where the dissolution rate depends on the drug content in nanohybrids.

ln(Mt /M0) ) -k1t (3) The Bhaskar equation is extensively used to describe the release process where the diffusion through the particle, such as resinate particles, is the rate limiting step.

ln(Mt /M0) ) -kBt0.65 (4) The parabolic diffusion model describes the diffusioncontrolled event in clays.

(1 - Mt /M0)/t ) -kpt-0.5 + m (5) The modified Freundlich model is used to explain experimental data on ion exchange and diffusion-controlled process with clays.

(M0 - Mt)/M0 ) kFtn In the above equations, M0 and Mt are the amount of drug in the nanohybrid at time 0 and t, respectively, k the corresponding release rate constant, and m and n the constants whose chemical significance is not clearly resolved.23,36 3. Results and Discussion 3.1. Crystal-Phase Identification and Chemical Composition. The XRD patterns for magnetic nanohybrids, pure IBU-LDH, and magnesium ferrite are depicted in Figure 1A. All the IBU-Mi samples present characteristic lines of both the LDH and the magnesium ferrite phase. The three intense lines at low 2θ angles correspond to reflections by the (003), (006), and (009) planes, and one asymmetric one at ca. 60° by the (110) and (113) planes indexed to a typical hexagonal system

Figure 2. TEM images of (a) IBU-LDH and (b-e) IBU-Mi (i )1-4) as well as (f) XPS survey profiles for Fe 2p3/2 of IBU-M1 at different depths obtained by Ar+sputtering, along with a magnified TEM image for a single particle.

of the LDH materials, whereas those marked with (*) are ascribed to the ferrite phase.18,28 It is noticed that the peak intensities of the characteristic lines for both the LDH and the ferrite phases in nanohybrids are obviously weakened compared with those in pure IBU-LDH and single ferrite particles, respectively, indicative of a decrease in crystallinity of the drug-LDH phase and its possible coverage for the ferrite particles. On the basis of the XRD data analysis (Supporting Information, Table S1), the basal spacing d003 of pure IBU-LDH is 2.55 nm (x ) 0.316), which is larger than previously reported 2.17 nm (x ) 0.333)19 and smaller than another reported 2.85 nm (x ) 0.250)38 mainly due to a sequentially reduced LDH layer charge density x.39 However, as the magnetic particles were incorporated, the obtained nanohybrids reveal an orderly reduced d003 from 2.56 to 2.30 nm with increasing ferrite content (Table S1, Supporting Information), consistent with those found in the ASA-LDHs/MgFe2O4 system.26 Meanwhile, the derived x of the IBU-LDH phases in magnetic nanohybrids after subtracting the Mg content in ferrite also presents a decreased trend from 0.315 to 0.304 (Table S1, Supporting Information). This d003 versus x relationship, just opposite to that in both pure IBU-LDH19,38 and CO3-LDH,39 implies that the presence of the ferrite particles may affect the interlayer arrangement of IBU-LDH and a possible interaction between the IBU-LDH phase and the magnetic particles may occur. The mean crystal dimensions (D) corresponding to the size in the a-axis ((110) plane) and c-axis ((00l) plane) are derived according to the Scherrer formula (Table S1, Supporting Information). Quite similar to the d003 changes, a reducing trend is seen for both Da and Dc values, though the later ones to a lesser extent. The Da and Dc are decreased from 14.82 and 8.96 nm of IBU-M1 to

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Figure 3. (a) Magnetization curves of IBU-Mi (i ) 1-4) at 298K. (b) Photograph showing magnetic capture of the magnetic nanohybrids.

6.62 and 6.33 nm of IBU-M4, respectively, which are quite smaller than those of the ferrite particles, indicating an obvious hindrance in growth of the IBU-LDH crystallites in nanohybrids from the magnetic particles, especially in the case with high ferrite content. The FT-IR spectra (Figure 1B) reveal the common characteristic absorptions at ca. 1556 and 1398 cm-1 for all nanohybrids due to νas(COO-) and νs(COO-), demonstrating the successful intercalation of IBU anions in the LDH interlayer.19 A strong sharp band at ∼588 cm-1 can be ascribed to the Fe-O lattice mode of the ferrite phase.40 The Fe-O vibrations show increased relative absorption intensity for magnetic nanohybrids with increasing ferrite content, though these bands are relatively weak compared with that of the single ferrite phase, implying that the magnetic nanohybrids may have a core-shell structure and the absorption of the ferrite phase may be shielded by an exterior nonmagnetic LDH layer. The other common bands include the broadened ν(OH) (∼3456 cm-1), δ(H2O) (∼1620 cm-1), and M-O lattice modes (∼447 cm-1).18 Upon ICP and CHN analyses (Table S1, Supporting Information), the obtained magnetic nanohybrids possess considerable drug loadings of generally higher than 26 wt %, though these loadings are lower than that of pure IBU-LDH (40 wt %) due to both the introduction of the magnetic particles and the reduced LDH layer charge density in the magnetic nanohybrid system. 3.2. Core-Shell Nanostructure. The TEM images of IBU-Mi compared with pure IBU-LDH are shown in Figure 2. The pure IBU-LDH (Figure 2a) shows clear platelike particles with an average size of ca. 100 nm, similar to that previously reported.19,41 When the magnetic particles were incorporated, however, the typical platelet morphology of the LDH materials disappeared. Instead, all IBU-Mi samples reveal near spherical core-shell structure nanoparticles featured by a much darker core and light gray coherent coating shell made from fine IBU-LDH nanoparticles. In addition, there are a few free IBU-LDH platelets occasionally found scattered on or among the core-shell structure particles together with a little aggregation of the magnetic particles, making the nanohybrid composite present a capsule-like morphology. A possible explanation for this observation may be the different particle growing mechanisms. We do not clearly understand why the drug-LDH particles developed in such small dimensions, but the presence of the ferrite particles may have a profound effect since they are possibly developing Mg(Al)-O-Fe bonds in either a chemical or a physical nature during the synthesis

procedures, as in the case of ASA-LDHs/MgFe2O4,26 which inhibits the growth of the drug-LDH crystallites once being nucleated on the surface of the ferrite particles. It is also noticed that these nanohybrid particles have subtle varied dispersibility and reduced shell thickness with increasing ferrite content. Specifically, IBU-M1 and IBU-M2 (Figure 2b,c) present well-dispersed homogeneous particles with smooth surfaces. The dark core is ca. 50 nm in diameter, in good agreement with the XRD (Figure 1A) and TEM (Supporting Information, Figure S1) results of the single ferrite particles. IBU-M3 and IBU-M4 (Figure 2d,e) show an obviously increasing particle aggregation, which probably originated from their higher magnetic core content and relatively thin IBU-LDH coating layer. Believably, the thickness of the IBU-LDH shell can be tuned by varying the magnetic core content in magnetic nanohybrids. It can be actually estimated from TEM that the IBU-M1, IBU-M2, and IBU-M3 possess a shell thickness of 35-50, 20-30, and 15-20 nm with increasing core content of 6.6, 9.6, and 14%, respectively. Though showing considerable aggregation, the IBU-M4 still possesses core-shell structure (Figure 2e). The strong particle-particle interactions between the fine IBU-LDH crystallites and the partially aggregated ferrite particles may afford their coherent coating of the LDH nanoparticles onto the surface of the magnetic cores.42 It is noticed that the mean particle size of the these nanohybrids falls in the range of 90-180 nm, which readily meets the requirement for administration by injection and makes them possibly an effective drug carrier in drug targeting.13,22,23 To obtain more information on the core-shell structure of the magnetic nanohybrids, the Fe 2p3/2 XPS survey profiles for the sample IBU-M1 at different depths were obtained by using Ar+sputtering (sputtering rate of ca. 2 nm/min)26and are depicted in Figure 2f along with its magnified TEM image for a single particle with core-shell structure. It can be seen that, after 12 min of sputtering, equal to 24 nm in depth, no Fe 2p3/2 signal is observed in the profile, indicating that magnetic core is not located in the surface layer. However, after 22 min of sputtering, at the depth of 44 nm, the Fe 2p3/2 peak appears, although it seems to be a little weak but clearly visible, confirming the existence of the magnetic material at this depth, and the thickness of the shell can, thus, be estimated to be ca. 24-44 nm. It is noticed that the Fe 2p3/2 signal still exists at the depth of 90 nm when sputtering for 45 min, but at the depth of 130 nm, it disappears in the profile, suggesting that the sputtering has drilled through the magnetic core. Therefore, the magnetic

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Figure 4. Release profiles of IBU-Mi (i ) 1-4) samples and pure IBU-LDH in pH 7.45 PBS under no magnetic field.

core can be approximately deduced as 50 nm. Taking into account the thickness of the LDH shell, the particle size of IBU-M1 can be evaluated as ∼150 nm, in good agreement with the above TEM results. For this reason, the magnetic core is mostly situated in the interior rather than on the surface of the magnetic nanohybrid particles, revealing a core-shell structure involving a magnetic core embedded in a nucleus coated with the drug-LDH layer. 3.3. Magnetic Property. The room temperature magnetization curves (Figure 3a) for the magnetic nanohybrids show similar shape but different saturation magnetizations (σs) in the range of 2.2-8.2 emu/g being positively proportional to the mass of the ferrite particles entrapped. The lower σs of the magnetic nanohybrids compared with that of the ferrite core (28.9 emu/g, inset in Figure 3a) is mainly due to the contribution of the volume of the nonmagnetic LDH coatings to the total nanohybrid volume.26 The small detectable remanence and coercive force of the magnetic nanohybrids indicate the weak magnetic interaction between the particles and, therefore, expectably good dispersibility in solution. This approximate superparamagnetism of IBU-Mi samples is critical for the applications of the nanohybrid particles in targeted drug delivery. When the magnetic nanohybrids were placed in a strong magnetic field, the nanohybrids were magnetized and could be manipulated by changing the MF intensities. While the MF was removed, the magnetization decayed rapidly to zero and the nanohybrids could be readily redispersed in a medium. As shown in Figure 3b, when a magnet approached the dispersion of IBU-M1 in ethanol/water (1/1), the red-brown nanohybrid particles were attracted toward the magnet within 20 s and the dispersion became clear and transparent. The clear solution in Figure 3b showed no UV absorption, indicating no leakage of the drug and the ferrite nanoparticles after the enrichment by an external MF. When the MF was removed, the enriched nanohybrids redispersed well in the original solution. These processes can be repeated many times without any leakage of ferrite and IBU, demonstrating the stable incorporation of the ferrite particles and the IBU-LDH nanocrystals in magnetic core-shell nanohybrids. Their strong magnetic sensitivity will provide an easy and efficient way to separate the magnetic nanohybrid from a suspension system and to carry drugs to the targeted locations under an external MF. 3.4. Magnetically Controlled Drug Release. The in vitro drug release of IBU from the magnetic nanohybrids was primarily performed in pH 7.45 PBS under no MF compared

Figure 5. Release profiles of (a) IBU-M1 under an external magnetic field (MF) with varied strengths of 0, 385, 770, and 1500 G and (b) IBU-Mi (i ) 1-4) under a stable MF of 1500 G.

with that of pure IBU-LDH. As shown in Figure 4, all release profiles exhibit a fast release rate at the beginning, followed by a slower one with time until the equilibrium was attained, as in the case often observed in the drug-LDH intercalates.19,23,24 Clearly, the burst release (the release fraction in the initial 2 min) of IBU from the magnetic nanohybrids increases gradually from 25 to 54% with increasing core content, whereas the t0.5 and teq (the time for 50% release fraction and release equilibrium) present an opposite trend (Table S1, Supporting Information). It has been claimed by Gu et al.23 and Ambrogi et al.43 that the rate of drug diffusion out of the LDH is controlled mainly by the diffusion path length, depending on the LDH particle size. Gunawan et al.41 reported that the aggregation of the LDH particles has a profound effect on the release of IBU from the LDH matrix. However, it is noticed that, in these published works, the LDH particle size obtained upon TEM/ SEM obviously shows a considerably agglomerated platelike morphology.23,41,43 In the present study, the TEM images of the magnetic nanohybrids (Figure 2b-e) reveal the well-defined core/shell structure with a compact stacking IBU-LDH nanoparticle coating layer, which intimately attached to the surface of the ferrite core, instead of individual platelets of the pure IBU-LDH. Therefore, the derived D110 of IBU-LDH coating particles is considered here as the approximate primary particle size, which is reduced with increasing core content in nanohybrids. As the D110 decreases from 14.82 nm (IBU-M1) to 6.62 nm (IBU-M4), the t0.5 correspondingly reduces from 24 min

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TABLE 1: Linear Correlation Coefficient (R) of the Dissolution-Diffusion Kinetic Models Applied to IBU Release from IBU-Mi (i ) 1-4) Under an External Magnetic Field (MF)a first-order dissolution eq sample IBU-M1

IBU-M2 IBU-M3 IBU-M4

MF strength (G) relB (%)b T0.5 (min)c 0 385 770 1500 1500 1500 1500

25.7 13.4 10.3 8.2 5.5 10.3 11.6

24 55 90 149 156 245 380

Bhaskar eq

parabolic diffusion eq modified Freundlich eq

R2

k1

R2

kB

R2

kP

R2

kF

0.8677 0.9539 0.9682 0.9789 0.9832 0.9649 0.9817

0.4694 0.3405 0.2383 0.1539 0.1257 0.0741 0.0652

0.9669 0.9988 0.9990 0.9960 0.9950 0.9738 0.9799

0.7046 0.6311 0.4802 0.3954 0.3339 0.1954 0.1751

0.9728 0.9930 0.9942 0.9948 0.9938 0.9948 0.9817

1.1347 0.7228 0.5529 0.4435 0.3667 0.5901 0.6196

0.9958 0.9988 0.9936 0.9924 0.9944 0.9732 0.9902

0.6705 0.4968 0.4192 0.3421 0.2941 0.3989 0.3144

a For the Bhaskar eq, the IBU release fraction 0.99 obtained for the second stage for IBU-M3 (t > 7.3 h) and IBU-M4 (t > 5.3 h) (fitting lines not shown). The first-order model fits the release data a little better than the zero-order one under the MF with R2 ) 0.95-0.98 (Table 1),

but the modeling data points do not exactly fall in a straight line (Figure 6a). This result is quite different from the previously claimed suitable first-order model for the single ibuprofen-LDH.19 These findings suggest that the drug content dependent release may occur to some lesser extent under the MF applied in the present magnetic nanohybrid system. The Bhaskar model fits the release data much better (Figure 6b and Table 1) with R2 > 0.995 for IBU-M1 and IBU-M2 and R2 > 0.974 for IBU-M3 and IBU-M4, revealing a major diffusion through particle process in the present magnetic nanohybrid system.25,37,43 The release rate constant k is reduced gradually with increasing core content in nanohybrids, indicative of an enhancing inhibition of the MF on drug diffusion rate, especially for high core content samples. Furthermore, the parabolic and the modified Freundlich models also show quite better fitting data (Figure 6c,d) with R2 > 0.993 for IBU-M1 and IBU-M2 (Table 1). However, interestingly for IBU-M3 and IBU-M4 (R2 > 0.973), a detailed examination of the modified Freundlich modeling data point distribution in Figure 6d indicates that the whole release process consists of three linear stages, implying that the drug release from the magnetic nanohybrids under an external MF may undergo three diffusion routes. To better understand the release mechanism, we use the kinetic models as three separate stages: for IBU release from IBU-M3, with stage I in 0-0.3 h, stage II in 0.3-6.3 h, and stage III in 6.3-26.7 h and from IBU-M4, with stage I in 0-0.3 h, stage II in 0.3-3.3 h, and stage III in 3.3-26.7 h are best fitted with the modified Freundlich model, with R2 > 0.99. The modified Freundlich model describes heterogeneous diffusion from the flat surfaces, such as in clays via ion exchange. These fitting data suggest that the release in full process is diffusion-controlled, and the IBU release from the magnetic nanohybrids under the external MF may involve three different routes. The first one, within the first 20 min (stage I), can be identified as that when the drug anions on the surface of the nanohybrid particles on the exterior of the aggregated matrix release into the medium via ion exchange with phosphate anions in buffer solution upon intraparticle diffusion.23,24 Stage II is mainly ascribed to the interparticle diffusion between the LDH coating particles on the exterior of the aggregated matrixes. The following stage III is attributed to the interparticle diffusion between the aggregated magnetic nanohybrids, which markedly delayed the drug release of the magnetic nanohybrids. Furthermore, the drug release rate and the fitting data of IBU-M1 under various MF intensities (rows 2-5 in Table 1) strongly indicate that the aggregation extent plays an important role in controlling the drug release behavior of the magnetic nanohybrids under an applied external MF. To figure out what happened to the magnetic nanohybrids as an external MF was applied, the morphology of the IBU-M1

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Figure 6. Plots of kinetic models for the drug release data from IBU-Mi (i ) 1-4) in pH 7.45 PBS under a magnetic field of 1500 G: (a) first-order equation, (b) Bhaskar equation, (c) parabolic model, and (d) modified Freundlich model.

Figure 7. (a-c) Morphology of IBU-M1 in ethanol/water: (a) under no magnetic field (MF), (b) with an external MF of 1500 G, and (c) removing the MF. (d-e) The corresponding representative schemes of IBU-Mi dispersion in solution indicating various diffusion routes.

in ethanol/water (1/1) solution under no MF, MF applied, and MF removed modes was studied by SEM. As shown in Figure 7a, the IBU-M1 nanoparticles were dispersed well under no MF, indicating that the drug release rate can be controlled mainly by the particle size and the thickness of the coatings, as discussed above. However, when the MF of 1500 G was applied, the nanohybrid particles aggregated extensively (Figure 7b). In this case, the drug release from the nanohybrids may undergo the interparticle diffusion among the aggregations of the magnetic nanoparticles after diffusion out of a single magnetic nanohybrid particle, therefore, involving a longer diffusion path and higher diffusion resistance. For IBU-M1 and IBU-M2

with low magnetic core content, because of their relatively larger Da and thicker coatings of the LDH phase, the whole release processes proceed homogeneously, whereas for IBU-M3 and IBU-M4 with high magnetic core content, the drug release exhibits much faster in the initial phase and much slower in the long time due to their much smaller Da and quite thin coatings; thus, the heterogeneous diffusion phenomenon is revealed among the whole release processes, as shown in Figures 5b and 6. According to Figure 7(a-c), when the MF was applied, the magnetic nanohybrids aggregated into large-sized particles, providing much a longer diffusion path and higher diffusion

Core-Shell Ibuprofen-Intercalated LDH Nanohybrids

J. Phys. Chem. C, Vol. 113, No. 28, 2009 12147 characteristics of the LDH materials.46 In general, this magnetically tunable release rate implies a potential use of this novel magnetic nanohybrid for in-time drug release. 4. Conclusion

Figure 8. Quasi pulsatile release profile (a) and the relative release rate (b) of IBU from IBU-M1 on a consecutive “on-off” operation of a 1500 G MF.

resistance,33 resulting in a much slower drug release rate; when the MF was removed, the magnetic nanohybrids recovered back to the dispersed state (Figure 7c), and a higher release rate can be acquired in this case with a much shorter diffusion path and lower diffusion resistance. A representative scheme of IBU-Mi dispersion states in solution is, therefore, reasonably proposed in Figure 7(d-f). The repeat of this aggregation-redispersion cycle of the magnetic nanohybrids induced by the MF “on-off” operations may be utilized to achieve an approximate pulsatile drug release, as previously observed in ferrosponges.28,33,44 Figure 8 shows an approximately controlled pulsatile drug release from IBU-M1 achieved upon a quasi consecutive “on-off” operation of a 1500 G MF. The cumulative drug release amount is reduced while MF is switching “on” due to the particle aggregation, but it is increased again while the MF was removed (Figure 8a). Hence, the reduced drug release amount of the magnetic nanohybrids in an MF “on” mode may be used to explain the slow diffusion of the drug. Furthermore, the calculated release rate is depicted in Figure 8b, where a transition of the release rate was found in response to the “on-off” magnetization. Meanwhile, the so-called elastic fatigue behavior was not observed even after five cycles of consecutive MF “on-off” modes, being probably ascribed to the good dispersibility and proper particle-particle interaction due to the presence of magnetic cores and, consequently, triggered attraction-repulsion interactions among these magnetic nanohybrids, that is, nanomagnets. It should be noticed that a spongy gel-like LDH-alkaline phosphatase nanohybrid on a silica wafer was recently reported by Geraud et al.45 Considering the present quasi pulsatile drug release results, it is suggested that the magnetic drug-LDH nanohybrid composites possess certain elasticity, given the previously claimed semi-rigid layered structure

A series of novel magnetic ibuprofen (IBU)-LDH nanohybrids containing varied magnetic core content were fabricated by a one-step co-precipitation method. The obtained magnetic IBU-LDH nanohybrids possess a well-defined core-shell structure, homogeneous particle size distribution in the range of 90-180 nm, and superior magnetic responsive behavior, endowing them with the ability to meet the requirement for administration by injection and drug targeting. Under no applied external magnetic field (MF), the drug release rates of the nanohybrids increase with reducing particle sizes and the thickness of the IBU-LDH coatings, which can be tuned by the magnetic core content in nanohybrids. With a 1500 G MF applied, the drug release rate is reduced with increasing core content due to the differently aggregated extent induced by the MF. The release mechanism under the MF is a combination of the intraparticle diffusion of the drug-LDH particles, the interparticle diffusion between the drug-LDH nanoparticles in the coating layers, and interparticle diffusion between the magnetically triggered aggregated magnetic nanohybrids. The noncontact magnetically controlled drug pulsatile release upon a consecutive MF “on-off” operation was also achieved thanks to the reversible aggregation-redispersion ability of the magnetic nanohybrid particles. It is expected that these novel core-shell structural magnetic drug-LDH nanohybrids can be utilized in drug targeting and magnetically tunable drug delivery systems. Acknowledgment. We are thankful for the financial support from the National Nature Science Foundation of China (Grant No. 20776012), 111 Project (Project No. B07004), and 973 Program (2009CB939802). Supporting Information Available: Table S1 containing XRD parameters, the chemical compositions, and in vitro drug release parameters under no magnetic field of the as-synthesized magnetic IBU-LDH nanohybrids and pure IBU-LDH and Figure S1 showing the TEM image of the magnesium ferrite particles. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Pankhurst, Q. A.; Connolly, J.; Jones, S. K.; Dobson, J. J. Phys. D: Appl. Phys. 2003, 36, R167. (2) Edelman, E. R.; Kost, J.; Bobeck, H.; Langer, R. J. Biomed. Mater. Res. 1985, 19, 67. (3) Gupta, A. K.; Gupta, M. Biomaterials 2005, 26, 3995. (4) De, M.; Ghosh, P. S.; Rotello, V. M. AdV. Mater. 2008, 20, 1. (5) Rudge, S.; Peterson, C.; Vessely, C.; Koda, J.; Stevens, S.; Catterall, L. J. Controlled Release 2001, 74, 335. (6) Lubbe, A. S.; Alexiou, C.; Bergemanm, C. J. Surg. Res. 2001, 95, 200. (7) Derfus, A. M.; Maltzahn, G. V.; Harris, T. J.; Duza, T.; Vecchio, K. S.; Ruoslahti, E.; Bhatia, S. N. AdV. Mater. 2007, 19, 3932. (8) Arias, J. L.; Ruiz, M. A.; Garllado, V.; Delgado, A. V. J. Controlled Release 2008, 125, 50. (9) Hu, S. H.; Liu, T. Y.; Liu, D. M.; Chen, S. Y. Langmuir 2008, 24, 239. (10) De Paoli, V. M.; De Paoli Lacerda, S. H.; Spinu, L.; Ingber, B.; Rosenzweig, Z.; Rosenzweig, N. Langmuir 2006, 22, 5894. (11) Wang, S. H.; Shi, X.; Van Antwerp, M.; Cao, Z.; Swanson, S. D.; Bi, X.; Baker, J. R., Jr. AdV. Funct. Mater. 2007, 17, 3043. (12) Shi, X.; Wang, S. H.; Swanson, S. D.; Ge, S.; Cao, Z.; Van Antwerp, M. E.; Landmark, K. J.; Baker, J. R., Jr. AdV. Mater. 2008, 20, 1671.

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