Mesoporous silica nanoparticles with manipulated microstructures for drug delivery

Mesoporous silica nanoparticles with manipulated microstructures for drug delivery

Colloids and Surfaces B: Biointerfaces 95 (2012) 274–278 Contents lists available at SciVerse ScienceDirect Colloids and Surfaces B: Biointerfaces j...

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Colloids and Surfaces B: Biointerfaces 95 (2012) 274–278

Contents lists available at SciVerse ScienceDirect

Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb

Mesoporous silica nanoparticles with manipulated microstructures for drug delivery Zhongdong Chen, Xiang Li ∗, Haiyan He, Zhaohui Ren, Yong Liu, Juan Wang, Zhe Li, Ge Shen, Gaorong Han ∗ State Key Laboratory of Silicon Materials, Department of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, PR China

a r t i c l e

i n f o

Article history: Received 2 February 2012 Received in revised form 5 March 2012 Accepted 19 March 2012 Available online 28 March 2012 Keyword: Silica nanoparticle Controlled mesoporous structure Drug releasing kinetics

a b s t r a c t A range of mesoporous silica nanoparticles (MSNs) with controlled microstructural characteristics were successfully prepared via the binary surfactant templated synthesis approach with varied concentration of triblock copolymer Pluronic F127. The relationship between the MSNs structural evolution and the surfactant concentration was extensively discussed. Ibuprofen (IBU) was loaded as drug model to uncover the in vitro drug releasing kinetics. It was found that the quantity of the drug loaded mainly depended on the specific surface area, while the drug releasing rate was dominantly determined by the length and curvature of the mesopores. This study has uncovered the core influential factors of MSNs system on its drug releasing properties, and thus demonstrated a facile approach to prepare MSNs with manipulated structural characteristics for drug delivery applications. Crown Copyright © 2012 Published by Elsevier B.V. All rights reserved.

1. Introduction In the past decades, the mesoporous silica nanoparticles (MSNs) have been widely investigated for biomedical purposes. Due to their various advantages, such as tunable pore size and geometry, high specific surface area and biocompatibility [1–5], MSNs have been highly regarded as a promising drug carrier material with the easecontrol of drug releasing characteristic. The interaction between the substances with topological features at nanoscale in the biological system is of high complexity. Many studies have documented that the surface chemistry and dimension of carrier materials had a big impact on the biodistribution, the biocompatibility, and the clearance in vitro [6–9] and in vivo [10–13]. Tsai et al. found that some rod-like MSNs presented great potential in monitoring the cell trafficking, cancer cell metastasis, and drug/DNA delivery compared with the spherical ones [14]. In addition, numerous evidences have shown that the drugloading and releasing characteristics depend on the specific surface area and pore structure (size, geometry and volume) of MSNs [15–17]. The synthesis methodology of the nanoparticles with different size and geometry was investigated [18]. Furthermore, the effect of MSNs geometry and size on the drug release kinetics was also extensively studied [19,20]. However, the core influentials of such various inter-linked structural characteristics on their

∗ Corresponding authors. Tel.: +86 571 88276240; fax: +86 571 88276240. E-mail addresses: [email protected] (X. Li), [email protected] (G. Han).

biomedical performance were hardly investigated in an isolated manner, and thus remained a challenge, which limits the research of MSNs with the defined drug releasing properties. This is mainly due to the restriction of the current MSNs preparation techniques, which normally use the surfactant aggregates or block polymers as structure-directing agent [21,22]. Therefore, an appropriate synthesis approach to prepare MSNs with structural characteristics manipulated isolatedly during the synthesis is needed to pursue for the more advanced MSNs drug carrier material. There are a number of nanoscale drug carrier materials synthesis techniques, such as hydrothermal method [1], sol–gel method [15], electrospining [23], etc. Compared with such various synthesis methodologies, the binary surfactant template method has been widely studied to synthesize MSNs with different morphology due to its unique advantages of low-cost, flexible synthesis conditions and ease-control of microstructures [24–26]. In a double template system of triblock copolymer Pluronic F127 and cetyltrimethylammonium bromide (CTAB), it was found that CTAB mainly contributed to the pore structure of MSNs while F127 influenced the particle size and the pore structure integrity [27]. Therefore, in this study, F127 and CTAB were used as binary templates to engineer the microstructure of MSNs during the preparation. In such method, the F127 surfactant concentration was controlled to manipulate the MSNs microstructural characteristics isolatedly. Subsequently, an in vitro study using Ibuprofen was used as a drug model to uncover the core influentials among the various MSNs structural parameters on the drug loading and releasing behavior.

0927-7765/$ – see front matter. Crown Copyright © 2012 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfb.2012.03.012

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2. Materials and method

3. Results and discussion

2.1. The synthesis of mesoporous silica nanoparticles

3.1. The structural characteristics

MSNs were synthesized via the binary surfactant template method. In a typical synthesis procedure, 0.05 g F127 (EO106 PO60 EO106 , AR, Sigma Aldrich), 0.2 g CTAB (AR, Sigma Aldrich), and 1.5 ml aqueous ammonia solution (28%vol, Hangzhou Chemical Co.) were dissolved in 30 ml deionized water, and subsequently 0.5 ml TEOS (Beijing Yili chemical Reagent Co.) was added in the solution under vigorous stirring. The concentration of CTAB, F127, TEOS, and ammonia was set at 18.3 mM, 0.17 mM, 0.6 mM, and 0.1 mM, respectively. After stirring for 30 min, the mixture was allowed to sedimentate under static condition at room temperature for 5 h, leading to a white suspension. The sedimentation obtained was collected by centrifugation, and washed with deionized water, followed by drying at 60 ◦ C under vacuum condition. The surfactant templates were removed by heating at 550 ◦ C for 5 h. For comparison, the same procedure was carried out with the F127 concentration increased to 0.34 mM, 0.51 mM and 0.68 mM, respectively, to investigate the pore structural evolution of MSNs.

The morphology of MSNs plays a crucial role in the drug delivery carrier applications. In our case, as shown in Fig. 1a, continuous morphology evolution was observed while F127 concentration was increased. When the concentration was 0.17 mM, MSNs were of an average length of 550 nm with the standard deviation of 21 nm. While F127 content was increased to 0.34 mM, 0.51 mM and 0.68 mM, respectively, the length of MSNs was found to decrease to 500 ± 14 nm, 400 ± 15 nm and 200 ± 23 nm, respectively. The particle geometry was found to vary from rod-like to spherical shape. In addition, when the concentration of F127 was 0.51 mM, the particles with curvature of certain degree were observed (Fig. 1c). To uncover the inter-link of such morphological evolution with the microstructural characteristics, the mesopores of MSNs were further studied using TEM. It was found that the ordered mesopores were formed and uniformly distributed within the particles. As shown in the insets (Fig. 2a and b), it has clearly shown that the pores formed present straight characteristic. This is due to the regular rod-like geometry of the silica nanoparticles prepared when the concentration of F127 was set at 0.17 mM and 0.34 mM. When F127 concentration was increased to 0.51 mM, the silica nanorods curved (Fig. 2c). Such phenomenon induced the mesopores formed with a certain curvature of a similar degree to the silica nanorods. With the increase of the F127 concentration to 0.68 mM, the aspect ratio of silica nanorods decreased further, and thus the particles presented a spherical shape. As shown in the inset of Fig. 2d, the mesopores formed present as numerous hexagonal dots in the surface which is perpendicular to the axial direction. The mechanism of such structural evolution due to the varied F127 concentration was also studied as shown in the schematic diagram (Fig. 3). Initially, a few monolayers of silicate species covered on the isolated surfactant micellar rods due to the electrostatic force, and thus formed the surfactant silicate rods. Subsequently, the long surfactant-silicate rods spontaneously aggregated and packed in a long-range ordered hexagonal manner [28]. While the polarity decreased with the assembly of the anionic and cationic species, the nonionic surfactant F127 surrounded the hexagonally ordered silica-CTA composites. When the concentration of F127 was at a lower degree, the F127 molecules intended to aggregate on the axial surface of the silica-CTA composites nanoparticles, and formed an incontinuous coverage. Therefore, the nanoparticles dimension in radial direction decreased while no distinguishable dimension changes presented in the axial direction. When F127 was increased to 0.51 mM, a higher concentration, the coverage of the F127 molecules increased, and presented a transitional stage of curved silica nanorods. This might be due to the incontinuous F127 coverage, of which the molecule distribution near the rod’s end with higher surface energy is denser than other parts. Thus, the curvature phenomenon took place owing to the interaction of the F127 aggregations at two ends. When F127 concentration was further increased, the density of F127 molecules reached a certain magnitude, and formed a continuous coverage on the cross-sectional surface and the axial surface of the silica-CTA composite. Such phenomenon restricted the particle growth in the axial direction. Therefore, the spherical MSNs were formed. Such scenario was found to be consistent with the previous work that CTAB mainly contributed to the pore structure of MSNs while the grain growth of nanoparticles was suppressed by the surrounding F127 micelles [27].

2.2. Drug loading 1 g as-prepared SiO2 power was suspended in 50 ml Ibuprofen (IBU, 99 wt%) hexane solution of 40 mg/ml at ambient temperature. The mixture was subsequently stirred for 3 days to induce the drug diffusion into the mesopores. The silica particles were separated from this solution by centrifugation, and subsequently washed with hexane to remove the adsorbed ibuprofen on the surface. MSNs were subsequently dried under vacuum condition at 60 ◦ C, 1 ml Filtrates was sucked and diluted to 10 ml for particle drug loading characterization using UV–Vis spectroscopy at a wavelength of 264 nm.

2.3. In vitro study 0.5 g drug-loaded MSNs were suspended in 200 ml simulated body fluid (SBF) at 37 ◦ C under stirring at 150 r/min to allow the drug extraction from the mesopores. 2 ml medium was collected for analysis at each specific time point. The IBU concentration variation of such medium was referred as the drug releasing kinetics of different MSNs groups. The 2 ml medium extracted was diluted to 10 ml with SBF, and analyzed with UV–Vis spectroscopy at a wavelength of 264 nm. The measurement was performed in triplicate for each sample to ensure the accuracy.

2.4. The structural characterization The morphology of MSNs was observed via a field emission scanning electron microscope (Hitachi S4800) at 5.0 kV. 50 particles were chosen stochastically for each dimensional measurement. Transmission electron microscopy and high resolution transmission electron microscopy were performed using a Philips Tecnai G2 F30 S-Twin electron microscope operated at 200 kV to uncover the mesoporous structure at high magnification. The surface area, the pore size and volume were examined via N2 adsorption–desorption isotherms using a micromeritics adsorption analyzer (ASAP 2010M) under a continuous adsorption condition. The releasing characteristic was investigated using ultraviolet and visible spectrophotometer (Shimadzu UV-3100PC).

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Fig. 1. The field emission scanning electron micrographs of as-synthesized MSNs with the F127 concentration of (a) 0.17 mM; (b) 0.34 mM; (c) 0.51 mM and (d) 0.68 mM.

The specific surface area and pore characteristics of MSNs were examined using the nitrogen adsorption/desorption measurements. As shown in Fig. 4a, MSNs present typical IV isotherm characteristics with well-defined step at a relative pressure of close to 0.4. The isotherms revealed distinguishable difference in the surface area of MSNs with the increase of F127. The nitrogen adsorption with the F127 concentration increase did not present

a linear change. When the F127 concentration was 0.17 mM, it presented the highest specific surface area of 1300 m2 /g and a large pore volume of 0.99 cm3 /g. When the concentration was further increased to 0.34 mM, 0.51 mM and 0.68 mM, the specific surface area of MSNs decreased to 840 m2 /g, 760 m2 /g and 1100 m2 /g, respectively, and the total pore volume changed to 0. m3 /g, 0.47 m3 /g and 0.95 m3 /g. Generally, the size reduction

Fig. 2. The transmission electron micrographs of MSNs prepared with the F127 concentration of (a) 0.17 mM; (b) 0.34 mM; (c) 0.51 mM and (d) 0.68 mM. The inserts show the microstructure of MSNs at high magnification.

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Fig. 3. The schematic illustration of MSNs formation.

increases the particle specific surface area. In the meantime, for the mesoporous particles, the particle size reduction would decrease the pore volume which is proportional to the surface area. Thus, the competition of such two phenomena for the MSNs results in a ‘V’ shape evolution of the specific surface area. Furthermore, in our case, the specific surface area was found to be influenced more dominantly by the nanoparticle pore volume than the particle size, and thus the highest surface area of MSN was obtained at low F127 concentration. Furthermore, the marginal hysteresis loop presented in the N2 -adsorption isotherm (Fig. 4a) implies that the mesopores in MSNs prepared with the F127 concentration of 0.51 mM are not of straight geometry but corrugate of the onedimensional pores. As shown in Fig. 4b, it reveals that the pore size of approximate 2.5 nm, which coincides with the TEM observation. 3.2. In vitro study 3.2.1. The drug storage It has been reported that the quantity of the drug loaded depends on the specific surface areas, pore size and surface properties of mesoporous silica [8]. The amount of Ibuprofen drug

was determined by quantitative analysis of the relative intensity of ultraviolet and visible light. The UV absorption spectrum of filtrates from 40 mg/ml Ibuprofen hexane solutions of the asprepared MSNs are shown in Fig. 5a. The amount of the drug loaded exhibited significant diversity on the different MSNs carriers, which were 69.25 wt%, 44.15 wt%, 36.75 wt% and 63.61 wt%, respectively. The quantity of the drug loaded presented a similar trend of the specific surface area examined. As summarized in Table 1, the pore size, geometry and volume of MSNs prepared are of the similar magnitude. Therefore, the amount of the drug loaded was proved to mainly depend on the surface area rather than the others. 3.2.2. The drug release The drug release occurs only after the medium has diffused into the channels, followed by drug molecules extraction along aqueous pathways into the medium. As shown in Fig. 5b, the MSNs prepared with the F127 concentration of 0.68 mM present the highest drug release rate. The mesopores formed in such MSNs are of the shortest length and straight elongation, which induced the ease of the SBF diffusion and thus the drug releasing. For the rodlike MSNs, the release rate presented a decrease trend that the

Fig. 4. (a) The N2 adsorption–desorption isotherms and (b) the pore size distribution of MSNs prepared with different F127 concentration.

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Fig. 5. (a) The UV absorbance spectra of filtrates from 40 mg/ml ibuprofen hexane solutions and (b) the mean cumulative release rates ibuprofen of MSNs prepared with different F127 concentration.

Table 1 Structural parameters of MSNs. F127 concentration

Pore geometry

Particle morphology

Mean particle size (nm)

0.17 0.34 0.51 0.68

Hexagonal Hexagonal Hexagonal Hexagonal

Rod Rod Rod-like Sphere-like

550 500 400 200

Length ± ± ± ±

21 14 15 23

releasing periods were 15 h, 38 h and 40 h, respectively. Since the pore size and surface chemistry of such MSNs used are similar, the varied drug releasing behavior is attributed to the pathway characteristics, such as the pore length and curvature of MSNs. The pore of MSNs prepared with F127 content of 0.17, 0.34 and 0.51 mM are of higher magnitude in length compared with MSNs prepared with 0.68 mM F127, which restricted the release of drug molecules from the mesopores. In addition, the flexuous structure of mesopores prevented the release of drug. Therefore, the length and the curvature of mesopores had also shown considerable influence on the drug releasing profiles, similarly to the effect of the mesopore size and geometry [13]. 4. Conclusions The mesoporous silica nanoparticles with the manipulated microstructures have been successfully prepared with controlled F127 concentration using the binary surfactant templated method. With the increase of F127 concentration, MSNs were found to vary from rod-like shape to spherical shape. The pore length and curvature were found to vary with the F127 concentration increase, while the cross-sectional geometry and diameter of the mesopores remained. The total mass of the drug loaded was mainly determined by the specific surface area. In addition, the in vitro study has shown that MSNs prepared were of sustained-releasing property, and the length and the curvature of the mesopores were found to play a crucial role in the drug releasing characteristics. This study has therefore paved the way to the further investigation of the more advanced MSNs drug carrier materials. Acknowledgments This work was financially supported by the National Natural Sciences Foundation of China (grant code: 51103128) and Fundamental Research Funds for the Central Universities (grant code: 2011QNA4004).

Diameter

L/D

± ± ± ±

2.2 3.3 3 1

250 150 130 200

29 5 23 23

Surface area (m2 /g)

Drug loaded amount (wt%)

1300 840 760 1100

69.25 44.15 36.75 63.61

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