Preparation of Colloidal Mesoporous Silica Nanoparticles with

Article pubs.acs.org/cm

Preparation of Colloidal Mesoporous Silica Nanoparticles with Different Diameters and Their Unique Degradation Behavior in Static Aqueous Systems Hironori Yamada,† Chihiro Urata,† Yuko Aoyama,† Shimon Osada,†,⊥ Yusuke Yamauchi,‡,§ and Kazuyuki Kuroda*,†,⊥ †

Department of Applied Chemistry, Faculty of Science and Engineering, Waseda University, Ohkubo 3-4-1, Shinjuku-ku, Tokyo, 169-8555, Japan, ‡ World Premier International (WPI) Research Center, International Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, 305-0044, Japan, § Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan, ⊥ Kagami Memorial Research Institute for Material Science and Technology, Waseda University, Nishiwaseda 2-8-26, Shinjuku-ku, Tokyo, 169-0051, Japan S Supporting Information *

ABSTRACT: The degradation of colloidal mesoporous silica nanoparticles (CMPS) is quite important for the design of stable catalyst supports and biodegradable drug delivery systems carriers. The degradation of various silica nanoparticles in static aqueous systems was investigated. The condition was achieved through the use of a dialysis tube. Four types of CMPS with different particle diameters (ca. 20−80 nm) were newly prepared from tetraalkoxysilanes (Si(OR)4, R = Me, Et, Pr, and Bu) at different hydrolysis rates by a one-pot synthesis. Larger particles were formed by using tetraalkoxysilanes at slower hydrolysis rates because particle growth dominates nucleation. The degradation of CMPS is independent of diameter differences. The degradation rate of CMPS is higher than that of colloidal nonporous silica nanoparticles with smaller diameters because of the presence of mesopores. CMPS are also more degradable than aggregated CMPS because of colloidal dispersity. Moreover, it was confirmed for the first time that the degradation simultaneously proceeds from the outer as well as the inner surfaces of CMPS and that the mesostructure and morphology are partly retained even after more than half of the CMPS are degraded. The information on the degradation reported here is quite useful for the design of silica-based nanomaterials with tunable degradability/stability. KEYWORDS: colloidal mesoporous silica nanoparticles, degradation, behavior, aqueous systems

■

attribute in biomedical fields and industrial utilities. On the other hand, avoiding the problems of nanoparticle accumulation within an organism requires that nanoparticles be degradable in biological systems.4 Though the significance of studying the degradability of silica has been recognized,5,6 the number of such studies under conventional media, related to practical applications, is surprisingly small. An increase in the specific surface area of nanoparticles is quite effective in increasing the degradability of colloidal silica nanoparticles because of greater contact with water at the interfaces. Smaller amorphous silica particles are more soluble;5 however, they also have the disadvantages of higher cell toxicity

INTRODUCTION Colloidal silica nanoparticles have been used on an industrial scale and are one of the important materials in various technological fields including fiber treatment, silicon wafer polishing, and refractory products, etc. In addition, they have recently attracted keen interest because of their high potential as carriers for drug delivery systems (DDS) and probes for bioimaging owing to their dispersibility, biocompatibility, and easy surface modification incorporating various functionalities.1 In particular, the high controllability of colloidal silica nanoparticle size (14−550 nm)2 is quite useful for investigating the relationship of particle size to cytotoxicity or distribution of silica nanoparticles in living organisms.1a,3 The chemical stability of silica as a DDS carrier is higher than that of organic polymers; this has stimulated many studies on the application of silica for DDS.1 This higher stability is quite an important © 2012 American Chemical Society

Received: January 16, 2012 Revised: March 17, 2012 Published: March 22, 2012 1462

dx.doi.org/10.1021/cm3001688 | Chem. Mater. 2012, 24, 1462−1471

Chemistry of Materials

Article

and hemolytic activity.3 Therefore, nanoparticles with appropriate (not too small) particle diameters and large surface areas are required for achieving degradability and for medical applications such as DDS and bioimaging. The introduction of mesoporosity into colloidal silica nanoparticles creates functional nanoparticles possessing unique features owing to mesoporosity (large surface area, large pore volume, uniform and adjustable pore size, biocompatibility, etc.) and colloidal states (transparency, dispersibility, and mobility). Therefore, the application of mesoporous silica in the field of biomedicine has attracted great attention. Because mesoporous silica is not normally stable in water,7 it is expected to be usable as a biodegradable DDS carrier.7,8 Shi et al. investigated the degradation behavior of bulk MCM-41 type mesoporous silica in a simulated body fluid (SBF) and found that the presence of various inorganic species in a SBF affects its dissolution.7a Although SBF is usually used for the studies on human applications, mesoporous silica is applicable to wider fields including animal and plant imaging. Thus, we selected phosphate buffer saline (PBS), which is commonly used in biological fields, as a medium. The degradation behavior of colloidal mesoporous silica nanoparticles (CMPS) has recently been reported. Shi et al. prepared Ca-doped mesoporous silica nanoparticles ca. 100 nm in size and reported that their degradability in water at 37 °C is higher than that of undoped mesoporous silica nanoparticles.9 Bein et al. succeeded in suppressing the degradability of CMPS in a SBF by modifying nanoparticle surfaces with poly(ethylene glycol) (PEG).10 Haynes et al. showed the high stability of colloidal mesoporous silica nanoparticles less than 50 nm in size in phosphate buffer saline (PBS) by modifying their surfaces with PEG under hydrothermal treatment (The treatment probably contributes to the stability by affecting the degree of siloxane network condensation.).11 However, they investigated the degradability by analyzing the amount of substances dissolved in one continuous operation, which may have resulted in some uncertainties as to the amount of dissolved silica because both possible redeposition of dissolved silica and the stirring conditions may affect the amount measured. To circumvent this problem, it is necessary to investigate the degradability both in the system excluding dissolved silica continuously and under an unstirred condition. In addition, although it is known that smaller amorphous silica has higher degradability,5 previous studies have not paid much attention to the influence of particle size on the degradation behavior of mesoporous silica. Consequently, a study on the influence of particle size on the degradability of CMPS while retaining the colloidal state is quite important for applications of colloidal silica to biomedical fields. Herein, we focus on the following two points: (i) preparation of CMPS with different diameters using several tetraalkoxysilanes and (ii) investigation of the degradation behavior of CMPS in aqueous media, which is influenced by both the colloidal and mesostructural states. With regard to point i, four types of CMPS of different sizes (ca. 20−80 nm) were prepared by using different tetraalkoxysilane hydrolysis rates (Si(OR)4; R = Me, Et, Pr, and Bu). As previously reported by Yano et al. on the preparation of mesoporous silica particles, 0.52 to 1.25 μm in size,12 different tetraalkoxysilane hydrolysis rates are useable as a variable factor for controlled addition of the silica source. On the other hand, we have recently reported that the dialysis process is quite effective in removing surfactants and preparing mesoporous silica and ethenylene-bridged organosilsesquioxane

nanoparticles while retaining the colloidal states from tetramethoxysilane (TMOS) and bis(triethoxysilyl)ethenylene, respectively.13 Thus, by applying different tetraalkoxysilane hydrolysis rates to the present preparation of nanometer-sized mesoporous silica particles, we can easily prepare colloidal mesoporous nanoparticles with different diameters. In particular, we focus on the preparation of CMPS smaller than 100 nm, because CMPS larger than 100 nm tend to gradually precipitate even just after the dispersion by ultrasonication. In order to understand the significance of high dispersity of CMPS, the removal of surfactants was conducted by dialysis instead of calcination which inevitably results in condensation of silanol groups on the surface on silica nanoparticles. Besides, the dialysis process not only involves surfactant removal, but is essential for the study on the degradation behavior, as stated in point ii, which adopts a batch operation using a dialysis membrane (Scheme 1). Dialysis is a known means of separating Scheme 1. Degradation of CMPS with a Dialysis

or purifying colloidal suspensions and provides us with two advantages for investigating the degradation behavior of particles. (a) Dissolved silica in an inner solution of a dialysis membrane can be continuously separated from silica nanoparticles to an outer solution (the terms “inner” and “outer” are taken from conventional dialysis, where the colloid is enclosed inside a dialysis tube, floating in an outer solution). (b) The inner solution can remain unstirred by separating the inner region from the outer one. Because of these advantages, we can investigate how the physicochemical properties of nanoparticles themselves, including colloidal stability, affect degradability by excluding the possible effects caused by the redeposition of dissolved silica and the stirring conditions. Although there are many studies on the stability of various types of mesoporous silica (including nanoparticles) in aqueous systems,7−11 they have dwelled only on the low stability of mesoporous silica in aqueous systems and have not specifically shown how mesoporous silica is degraded. In this study, the degradation rate and degradation behavior of CMPS with different particle sizes were studied. The influences of the presence or absence of mesopores and colloidal stability were also surveyed. The findings reported here are quite essential for controlling the degradability of CMPS by varying their composition, mesostructure, and morphology, which will be quite useful in the design of silica-based nanomaterials.

■

EXPERIMENTAL SECTION

Materials. All materials were used without further purification. Hexadecyltrimethylammonium bromide (C16TMABr), triethanolamine (TEA), phosphate-buffered saline (PBS) powders, and acetic 1463



Article

Preparation of Colloidal Silica Nanoparticles (CS). Two types of CS without uniform mesopores were prepared as follows: First, TEA (0.420 g) was added to water (240 mL) and the solution was stirred at 60 °C for 2 h. Then 11 mmol of tetraalkoxysilane (TMOS or TEOS) was added to the solution and stirred vigorously at 60 °C for 12 h. Finally, the colloid was filtered with a filtering paper (No. 5). The molar ratio of the precursor solution was 1 tetraalkoxysilane:0.25 TEA:1200 H2O. Next, to match the pH value of the solution to that of the solution state of CMPS, we transferred 50 mL of the colloid to a dialysis membrane tube and dialyzed for 12 h against 250 mL of “diawater,” which was the last outer solution in the dialysis of CMPS. Degradation Behaviors of Various Silica Nanoparticles. Polypropylene containers were used to prevent contamination of the Si species. The concentration of Si in the solution outside the tube (Ci (i = 0− 15); the concentration on i-th day) was measured by ICP everyday (as described later, the outer solution was replaced with fresh PBS everyday). By assuming that the concentrations of solutions of both inside and outside the dialysis tube are same under equilibrium, we can calculate the total concentration of dissolved Si by analyzing the concentration of the solution outside the tube and measuring the volume of the solution inside the tube. We can not measure the concentration of dissolved Si species inside the tube because the solution inside the tube contains both dissolved species and undissolved CMPS. Therefore, the total amount of dissolved Si species up to day i is calculated by the eq 1.

acid were purchased from Wako Pure Chem. Ind., Ltd. Tetramethoxysilane (TMOS: Si(OCH3)4), tetraethoxysilane (TEOS: Si(OC2H5)4), tetrapropoxysilane (TPOS: Si(OC3H7)4), and tetrabutoxysilane (TBOS: Si(OC4H9)4) were purchased from Tokyo Kasei Co., Ltd. PBS powders were dissolved in deionized water and used as an outer solution for measuring degraded and/or dissolved nanoparticles. The pH value of the phosphate buffer saline used here was 7.3, and the concentration of the salt was 10 mM. Characterization. The UV−vis spectra of colloidal nanoparticles were obtained using a Shimadzu UV-2500PC spectrophotometer. Dynamic light scattering (DLS) measurements were performed with a HORIBA LB-550 Dynamic Light Scattering Nanoparticle Size Analyzer at 20 °C. The TEM images were obtained using a JEOL JEM-2010 microscope operating at 200 kV. The SEM images were obtained using a HITACHI S-5500 electron microscope operated at an acceleration voltage of 5−30 kV. The samples for TEM and SEM measurements were dropped and dried on a carbon-coated microgrid (Okenshoji Co.). The nanoparticle size was obtained by measuring the average size of 300 nanoparticles in TEM images. The X-ray diffraction (XRD) patterns of the dried powder samples were obtained on a RIGAKU Nano-Viewer. The dried samples were prepared by freezedrying colloidal mesostructured silica nanoparticles (CMSS) and CMPS in a vacuum to avoid degradation by heating. Nitrogen gas adsorption−desorption measurements were performed with an Autosorb-2 instrument (Quantachrome Instruments) at 77 K. The samples were preheated at 120 °C for 24 h under 1 × 10−2 Torr. The Brunauer−Emmett−Teller (BET) surface area was calculated from the adsorption data in a relative pressure range from 0.05 to 0.20. The pore volume was calculated at P/P0 = 0.95. The pore size distribution was evaluated using the adsorption branch with nonlocal density functional theory (NLDFT). CHN elemental analysis was performed with a Perkin-Elmer 2400 Series II. Thermogravimetry-differential thermal analysis (TG-DTA) was carried out with a RIGAKU Thermo Plus 2 instrument under a dry air flow at a heating rate of 10 °C min−1 up to 900 °C. Zeta-potential measurements were conducted with an Otsuka Electronics ELSZ-1 at 20 °C. The concentrations of Si species dissolved in PBS solutions were determined by an inductively coupled plasma (ICP) spectrometer with a Vista-MPX instrument (Varian Technology Japan Ltd.). Preparation of Various Silica Nanoparticles. Preparation of Colloidal Mesostructured Silica Nanoparticles (CMSS) with Different Diameters. Four types of CMSS were prepared according to a previous report on TMOS.13 First, 0.420 g of TEA and 2.00 g of C16TMABr were added to 240 mL of water and the solution (pH 9.5) was stirred at 80 °C for 30 min. Then 11 mmol of tetraalkoxysilane (TMOS, TEOS, TPOS, or TBOS) was added to the C16TMABr solution and the mixture was stirred vigorously at 80 °C for 6 h until a colloidal state was achieved. Finally, the colloidal suspension (pH 8.2) was filtered with a filtering paper (No. 5). The molar ratio of the precursor solution was 1 tetraalkoxysilane: 0.50 C16TMABr: 0.25 TEA: 1200 H2O. The samples are denoted as “X-Y-as”, in which X means the kind of tetraalkoxysilane, Y means the average particle size, and “as” means “as-synthesized” or “before removal of surfactants”. That is, the four types of CMSS prepared from TMOS, TEOS, TPOS, and TBOS are abbreviated as M-20-as, E-30-as, P-40-as, and B-80-as, respectively. Preparation of Colloidal Mesoporous Silica Nanoparticles (CMPS) from CMSS by Dialysis. To remove C16TMA ions, 50 mL of a colloidal suspension was transferred to a dialysis membrane tube composed of cellulose (molecular weight cut off = 12 000−14 000) and was dialyzed for 12 h against 250 mL of a mixture containing 2 M acetic acid and ethanol (1:1, v/v). This process was repeated five times, then, the tube containing CMPS was immersed in water for 12 h to remove acetic acid/EtOH. The process was repeated twice. The pH value of the final solution was 3.4. The sample names are denoted as X-Y-dia, where “dia” means “after dialysis” or “after removal of surfactants.” That is, the four types of CMPS prepared from TMOS, TEOS, TPOS and TBOS are abbreviated as M-20-dia, E-30-dia, P-40dia, and B-80-dia, respectively.

15

Mi = v ∑ Ci i=0

(1)

where Mi is the total amount of dissolved species, and v is the total volume of the solution of both inside and outside the dialysis tube, that is, 300 mL. On the other hand, the total amount of Si (Mtotal) in a colloidal solution introduced initially inside a dialysis tube was calculated from the mass of dried sample. By using the values of Mi and Mtotal the ratio of framework dissolution (Ri) by the i-th day is obtained by eq 2. Ri =

Mi M total

(2)

The Ri values were measured three times and the average was plotted with day. The reason why the Ri value does not reach 100% may be due to the low concentration of Si (about 300 ppm) in this degradation experiment containing a large amount of PBS. In fact, the concentration of Si is reduced by (i) the loss of Si species during washing of a dialysis tube on the replacement of PBS and (ii) trapping of Si species in a dialysis tube. Consequently, comparison among different CMPS, aggregates of CMPS, and nonporous colloidal silica is quite meaningful though the discussion is not completely quantitative. Effects of Diameter and Mesopore Presence on the Degradability of Colloidal Silica Nanoparticles. In order to investigate degradability, 50 mL of a colloid was put into a dialysis membrane tube and dialyzed for 24 h against 250 mL of PBS. After one day, the outer solution was replaced with 250 mL of fresh PBS, and the colloid was dialyzed again for a further 24 h. This process was repeated every 24 h for 15 days. Four kinds of CMPS, whose diameters ranged from ca. 20 to 80 nm, and two kinds of CS, whose diameters were ca. 5 and 10 nm, were used for the degradation experiments. Effect of CMPS Dispersibility on Degradability. The effect of CMPS dispersibility on degradability was examined in a similar way to that described above. In particular, aggregates of mesoporous silica (agMPS) were used for the degradation experiments. Two kinds of agMPS, M-20-agg or E-30-agg (“agg” means “aggregates”), were prepared by drying CMPS, M-20-dia, or E-30-dia, at 120 °C for 24 h, respectively. The degradability of agMPSs was compared with that of corresponding CMPS prepared with the same alkoxysilanes. Degradation Behavior of B-80-dia. To investigate the degradation behavior of B-80-dia (the selection of this material is discussed in the 1464



Article

Results and Discussion section), 50 mL of the B-80-dia colloid was put into a dialysis membrane tube, and a total of seven tubes was prepared and each tube dialyzed for 24 h against 250 mL of PBS. The dialysis times for the seven tubes were 1, 2, 3, 4, 5, 6, and 7 days. After 1 day, dialysis in one tube was finished and the outer solutions for the other six tubes were replaced with 250 mL of fresh PBS and the colloids were again dialyzed for one day. Likewise, this process was repeated every day for 7 days.

■

RESULTS AND DISCUSSION Preparation of CMSS and CS. Four types of CMSS are almost transparent with a clear Rayleigh scattering of the colloidal suspension, as shown in Figure S1 in the Supporting Information. The UV−vis transmittance spectra of CMSS (Figure S2 in the Supporting Information), particularly M-20-as and E-30-as, show high transparency in the visible light region. Besides, the ζ-potential values of M-20-as, E-30-as, P-40-as, and B-80-as are positive (see Table S1 in the Supporting Information), indicating dispersity of CMSS due to cationic electrostatic repulsion. The origin of the cationic states could be attributable to the presence of C16TMA layers on the surface of CMSS as a sort of “admicelle.”14 The hydrodynamic diameters of M-20-as, E-30-as, P-40-as, and B-80-as are 33, 47, 68, and 102 nm, respectively. The hydrodynamic diameters are often overestimated in comparison to those observed by electron microscopy15 because of the presence of a hydration layer and the stronger response of larger particles.16 In fact, the diameters measured by DLS are larger than those observed by TEM, as shown below. Each CMSS shows a monodispersed size distribution with an average particle size, as shown in Table S1. The fact that only single peaks were observed means that the four types of CMSS do not form aggregates. The XRD patterns (Figure S3 in the Supporting Information) of the dried samples (M-20-as, E-30-as, P-40-as, and B-80-as) prove the formation of mesostructures. The d values are 4.7, 5.1, 5.2, and 5.4 nm for M-20-as, E-30-as, P-40-as, and B-80-as, respectively, and this result shows that the different types of tetraalkoxysilanes have relatively little influence on the d values of CMSS. The TEM images (Figure 1) reveal that the mean particle diameter increases in the order TMOS, TEOS, TPOS, and TBOS. The mean diameters of M-20-as, E-30-as, P-40-as, and B-80-as are ca. 19 ± 10 nm, 30 ± 20 nm, 43 ± 25 nm, and 78 ± 50 nm, respectively. (The particle size distributions are shown in Figure S4 in the Supporting Information). In particular, in the case of TBOS, whose hydrolysis rate is the slowest,17 the particle diameter distribution (B-80-as) is somewhat broad. This can be explained as shown in Scheme 2. Tetraalkoxysilanes with fast hydrolysis rates, like TMOS (Scheme 2a), are easily hydrolyzed and soluble silica species are formed. Then, the CMSS nuclei are formed through an assembly of soluble silica and surfactants. In this case, small particles are formed because nucleation dominates particle growth. On the other hand, TBOS with a slow hydrolysis rate (Scheme 2b) is different from TMOS and TEOS in the following ways: (i) although tetraalkoxysilanes are hydrolyzed and CMSS nuclei are formed, an oily phase composed of unhydrolyzed TBOS remains in the system and (ii) tetraalkoxysilane should provide fewer soluble silica species to form fewer particles within a certain period. In general, when there are many nuclei in a system, most of the remaining dissolved species should be consumed for particle growth. However, as typical for TBOS, soluble species are consumed for both nucleation and particle growth when small numbers of nuclei are present. In short, the particle size

Figure 1. TEM images of (a) M-20-as, (b) E-30-as, (c) P-40-as, and (d) B-80-as.

distribution should be broadened owing to the simultaneous nucleation and particle growth during the reaction process. As a result, it is confirmed that four types of CMSS with different diameters are prepared by taking advantage of the differences in the hydrolysis rates of tetraalkoxysilanes. The mean particle diameter becomes larger and the particle size distribution becomes broader as the hydrolysis rate slows. In addition, all the CMSS prepared from the four types of tetraalkoxysilanes have wormhole-like mesostructures, as shown in the TEM images (Figure 1), and they retain colloidal stability even after one year. Rhee et al. reported that butanol affects the mesostructure,18 but the present study differs on the following points: (i) the use of a cationic surfactant as a structure directing agent (vs a triblockcopolymer for ref 18), (ii) reaction under basic conditions (vs acidic for ref 18), and (iii) the amount of alcohol generated from TBOS is small enough to be dissolved into an aqueous solution (vs excessive amounts for ref 18). In particular, we believe that point (iii) greatly influences the differences between the present study and the previous one. The amount of alcohols generated from tetraalkoxysilanes in this study is small enough to be dissolved into an aqueous solution and no oil-in-water emulsions should be formed, so the properties of CMSS are not greatly influenced by the differences in tetraalkoxysilanes, except for mean diameter and particle size distribution. Moreover, Yano et al. reported on the possibility of preparing mesoporous silica particles from various tetraalkoxysilanes at 30 °C in a mixture of water and ethanol (cosolvent) (75:25 = w/w) and that tetraalkoxysilanes with slow hydrolysis rates, such as TPOS and TBOS, did not sufficiently form spherical particles.12 According to the Stöber method,19 the cosolvent condition is effective at hydrolyzing tetraalkoxysilanes, whereas the report by Yano shows that the hydrolysis of TPOS and TBOS does not proceed sufficiently even under cosolvent conditions. On the other hand, TBOS formed spherical nanoparticles in the present study. The reaction conditions used here are a temperature of 80 °C and a solvent of water 1465



Article

Scheme 2. Formation Mechanism of CMSS Prepared from Tetraalkoxysilanes with (a) Faster and (b) Slower Hydrolysis Rates

with no added alcohol; these conditions are quite different from those reported in ref 12. The fact that spherical nanoparticles are formed from TBOS indicates its steady and sufficient hydrolysis. The achievement of appropriate hydrolysis even in the absence of a cosolvent like alcohol is quite important. Temperature should have a greater influence on the hydrolysis rate than the cosolvent. In fact, when alkoxysilanes are hydrolyzed, it is not necessary to add alcohol as a cosolvent, as previously reported.20 Therefore, a relatively high temperature, such as 80 °C, is essential when using tetraalkoxysilanes with slow hydrolysis rates, such as TBOS, as a Si source. Preparation of CMPS with Different Diameters. As shown in Figure 2 and Figure S1 in the Supporting

Figure 3. UV−vis transmittance spectra of M-20-dia, E-30-dia, P-40dia, and B-80-dia.

Table 1. Physicochemical Properties of CMPS sample M-20dia E-30dia P-40dia B-80dia

Figure 2. Appearances of (a) M-20-dia, (b) E-30-dia, (c) P-40-dia, and (d) B-80-dia.

Information, the four types of CMPS were more transparent than the corresponding CMSS with a clear colloidal suspension Rayleigh scattering (0.35 wt %). In fact, the UV−vis transmittance spectra of CMPS (Figure 3) showed higher transparency than those of CMSS because of the nearly complete removal of surfactants, described below. Besides, the ζ-potential values at pH 3.2 of M-20-dia, E-30-dia, P-40-dia, and B-80-dia were similar to those of silica (Table 1), indicating that the cationic layers composed of C16TMA on the surface of CMSS were efficiently removed by the dialysis process. The XRD patterns of the dried samples (M-20-dia, E-30-dia, P-40dia, and B-80-dia) are shown in Figure 4. The XRD patterns of

ζ-potential (mV)

hydrodynamic diameter (nm)

SBET (m2g−1)

Vtotal (cm3g−1)

DNLDFT (nm)

−7.0

31

960

1.1

4.3

−1.7

44

960

1.3

4.3

−6.0

62

980

1.3

4.3

−9.5

96

980

1.1

4.3

all the samples exhibit mesostructure retention. The d values of M-20-dia, E-30-dia, P-40-dia, and B-80-dia are 4.7, 5.0, 5.1, and 5.7 nm, respectively, and this result shows that the dialysis method has little influence on the d values of CMSS and CMPS. To investigate the effect of dialysis on the removal of the surfactants, thermogravimetry-differential thermal analysis (TGDTA) was carried out (see Figure S5 in the Supporting 1466



Article

Figure 5. TEM images of (a) M-20-dia, (b) E-30-dia, (c) P-40-dia, and (d) B-80-dia. Figure 4. XRD patterns of M-20-dia, E-30-dia, P-40-dia, and B-80-dia.

On the basis of all the results, it is confirmed that CMSS can be converted to CMPS by the removal of surfactants using dialysis, while preserving the difference in the particle diameters. More importantly, the diameter is not largely changed and both the mesostructure and the colloidal dispersity are preserved before and after dialysis. The weight ratio of CMPS in the colloids is ca. 0.35 wt % and there is little difference among the four types of tetraalkoxysilanes. Generally, it is well-known that the diameter of silica nanoparticles is controlled by continuously adding Si sources.2,22 The process is complex because of multiple steps. In contrast, our present method of taking advantage of the difference in hydrolysis rates among tetraalkoxysilanes is simpler because the diameters of the colloidal silica nanoparticles are varied in a one-pot synthesis. However, our method needs to be further improved in the aspect of particle size distribution when tetraalkoxysilanes with slower hydrolysis rates are used. This problem should be solved by adding TPOS or TBOS to prepared particles. This should suppress simultaneous nucleation and particle growth and make particle growth dominate nucleation. Further investigations of this problem are now under way. Degradation Behaviors of Various Silica Nanoparticles. Effect of Diameter and Mesoporosity on the Degradability of Colloidal Silica Nanoparticles. As shown in Figure 6, the CMPS frameworks were degraded by about 15% per day, and more than 90% of the CMPS framework was degraded after an immersion time of one week, independent of the particle diameter of CMPS. This results from the fact that the four types of CMPS had almost the same surface area. That is, regardless of diameter difference, the collision frequency between water molecules and siloxane frameworks must be nearly equal among the four types of CMPS because of the similar surface areas resulting from the presence of mesopores. To confirm the significant effect of mesopores on degradation, the degradation behavior of two types of CS (CS-5 and CS-10), possessing no ordered mesopores, was

Information). The TG curves of CMSS show three weight loss steps: 25−150 °C, 150−450 °C, and >450 °C. The first weight loss (ca. 2 wt %) is due to the desorption of water, whereas the second weight loss (ca. 65 wt %) is due to the desorption and decomposition of the surfactant species21 with possible overlap because of the dehydration of silanol groups. The third gradual weight loss (ca. 10 wt %) is due to further dehydration of the silanol groups to form siloxane bonds.21 On the other hand, the desorption and decomposition of the surfactant species are not confirmed in the TG curves of CMPS. The DTA curves (data not shown) also show the absence of exothermic peaks due to the oxidative decomposition of C16TMA ions. The nitrogen content was under the detection limit of CHN analysis. The TG curves of CMPS show two weight loss steps: 25−150 °C and >150 °C. The former corresponds to the first weight loss of CMSS and the latter corresponds to the gradual dehydration of the silanol groups. From these results, the removal of the surfactants was sufficiently achieved by the dialysis process for all the samples reported here, which is the same as in the previously reported case of TMOS.13 The N2 adsorption−desorption isotherms for dried CMPS show type IV isotherms, indicating the presence of mesopores (see Figure S6 in the Supporting Information). The surface areas, pore diameters, and pore volumes of the four samples were surprisingly similar, ca. 970 m2/g, ca. 4.3 nm, and ca. 1.2 cm3/g, respectively, and these values scarcely depended on the particle diameter (Table 1). The reason for the relatively large pore size, considering the use of C16TMA ions, is not clear at present although there may be some unidentified influences owing to such small nanoparticles. The TEM images (Figure 5) revealed that the mean particle size becomes larger, like CMSS, in the order M-20-dia, E-30-dia, P-40-dia, and B-80-dia. On the other hand, the TEM images of CS-5 and CS-10 revealed that the diameters of CS-5 and CS-10 were ca. 5 and 10 nm, respectively, and that they had no mesopores (see Figure S7 in the Supporting Information). 1467



Article

independent of the particle diameter. This can be explained as follows: the surface area of CMPS is higher than that of CS owing to the presence of mesopores. The presence of mesopores has a greater effect on surface area than the difference in particle diameters. As reported in ref 13a, the SEM image of CMPS shows the hollow of the outer surfaces, which means the real outer surfaces are much smaller than those of CS. Accordingly, the variation in the outer surface area with diameter is relatively small and the total specific surface areas should be less affected by this variation. Because four types of CMPS have similar surface areas, the degradability of CMPS does not depend on the particle diameter. Effect of Dispersibility of CMPS on Degradability of CMPS. To confirm the effectiveness of dispersibility on degradation, the degradation behaviors of two types of agMPS (M-20-agg and E-30-agg) and two types of CMPS (M-20-dia and E-30dia) were investigated in the same manner mentioned above. Figure 8 shows that the degradation percentage of agMPS

Figure 6. Degradation percentages of M-20-dia, E-30-dia, P-40-dia, and B-80-dia.

investigated in the same way as CMPS. The degradation behaviors of CMPS and CS prepared from TMOS or TEOS are shown in Figure 7. The degradation percentage of each CS

Figure 8. Degradation percentages of M-20-dia, E-30-dia, M-20-agg, and E-30-agg.

framework in a PBS system was ca. 5% per day, and that the rate was nearly constant up to 15 days. Besides, agMPS was not completely degraded even after 15 days. This means that silica nanoparticles in a colloidal state were more degradable than those in an aggregational state. This is because the Brownian motion of colloidal nanoparticles results in a much higher collision frequency between water molecules and nanoparticles. In addition, the surface area of silica nanoparticles in the aggregational state is lower than that in the colloidal state because of the fusion bonding of nanoparticles. The degradation rate of agMPS should be lower because the contact area with water molecules is lower. From these results, the degradation rate is slower in the order of CMPS, CS, and agMPS (cf. Figures 7 and 8). This tendency cannot be, and has not been, clarified under the previously reported stirred conditions. By using a dialysis tube, a colloidal solution inside the tube can remain nearly unstirred and the Brownian motion of intrinsic colloidal characteristics should be noticeable. Therefore, it is confirmed that the colloidal state is more

Figure 7. Degradation percentages of M-20-dia, E-30-dia, CS-5, and CS-10.

framework per day was less than 10%, and it took more than 10 days for CS to be almost completely degraded by immersion, in contrast to the CMPS cases, which were mostly degraded by immersion within one week. The difference should be attributable to the presence of mesopores in CMPS, which increase the contact area with water. In general, smaller silica nanoparticles are more degradable because degradability depends on the surface area of particles.5 It is clear that the degradability of CS is dependent on the particle diameter and surface area. On the other hand, the degradability of CMPS is 1468



Article

influential to degradation than the particle size and the presence of mesopores. Degradation Behavior of B-80-dia. B-80-dia was selected for investigation of the degradation behavior of CMPS in terms of structure and morphology because of the ease of observation of TEM and SEM images. Figure 9 shows the appearance of

Figure 11. Variation in the SEM images of B-80-dia with the immersion time in PBS: (a) 0, (b) 1, (c) 2, (d) 3, (e) 4, and (f) 5 days.

Figure 9. Variation in the appearances of B-80-dia with the immersion time in PBS.

colloidal solutions for the first seven days. The dispersion of each solution remained unchanged. Moreover, the white color of CMPS diminished day by day, which shows that a Rayleigh scattering of particles became weaker as the particles were degraded. The TEM images in Figure 10 show that the

Figure 12. Variation in the XRD patterns of B-80-dia with the immersion time in PBS.

Figure 10. Variation in the TEM images of B-80-dia with the immersion time in PBS: (a) 0, (b) 1, (c) 2, (d) 3, (e) 4, and (f) 5 days.

mesostructure and the particle morphology of B-80-dia remained to some extent, although more than half of the B80-dia was degraded after 3 days (ICP) from the beginning of the measurement. As the degree of degradation increased, the mesostructure and the particle morphology were gradually degraded. Degradation should proceed even on the inner sides of the particles because the contrast there was lowered. Moreover, the SEM images (Figure 11) show that the B-80-dia particle morphology remained intact to some extent during degradation. As shown in Figure 11b, there was some undulation on the surfaces of CMPS. This infers that CMPS are degraded in the forms of soluble monomeric/oligomeric silicate species and also some fragmentary species. Therefore, it is confirmed that the degradation proceeds from the outer surfaces of particles not homogeneously, but heterogeneously. Figures 12 and 13 show how the mesostructure periodicity of B-80-dia changed. The XRD patterns in Figure 12 show that

Figure 13. Variation in the pore size distributions of B-80-dia with the immersion time in PBS. 1469



Article

“active” control would be possible by introducing stimuliresponsive groups into the framework.

the mesostructure periodicity decreased as the degradation of CMPS proceeded, judging from the decreased intensity of the XRD peaks. On the other hand, it is suggested that the mesostructure was partly retained even after a 70% degradation of CMPS because the peak due to the mesostructure was observed even after 4 days from the beginning of the measurement. The pore size distributions shown in Figure 13 reveal that the pore size centered at 4.3 nm is broadened as the degradation of CMPS proceeds. On the other hand, CMPS were heterogeneously degraded because the presence of another pore of approximately 8.0 nm was shown. In addition, the surface areas of B-80-dia before degradation and after immersion for five days are ca. 980 and ca. 410 m2/g, respectively (data not shown). The morphology and the mesostructure of CMPS are not clear after immersion for 5 days and the surface area decreases as the degradation proceeds. However, this relatively large surface area after degradation infers that CMPS are heterogeneously degraded and the mesostrucuture is partly retained. Thus, both the structure and morphology of CMPS are heterogeneously degraded. On the basis of appearance, TEM images, SEM images, XRD patterns, and pore size distributions of CMPS as mentioned above, it was confirmed that the mesostructure of CMPS remained despite a degradation percentage of more than 70%, even after 4 days from the beginning of the investigation, although the morphology was largely changed. It is thought that water molecules and dissolved silica species can diffuse adequately in mesopores because degradation proceeds from the outer and inner surfaces of CMPS. These findings, obtained using a dialysis tube under an unstirred condition, are meaningful because diffusivity cannot be confirmed under a stirred condition.9−11 However, the degradation study was performed in a PBS system and these results are not directly applicable to in vivo degradation. Even in vitro, it is reported that hydroxyapatite is formed on the surface of mesoporous silica in a SBF system known as bioglasses,23 and the phenomenon is different from that found for PBS. Therefore, it is necessary to account for the degradability caused by the interactions of metal salts and proteins with the surfaces of mesoporous silica. Barbe et al. reported that the degradation of silica microparticles can be suppressed by adding serum in a PBS system.24 Besides, in the study conducted in vivo, Wu et al. reported that mesoporous silica nanoparticles were bioaccumulated in the liver after one month of aqueous exposure.25 Tamanoi et al. also reported that mesoporous silica nanoparticles were released by renal excretion with retention of the particle morphology.26 This means that the in vivo environment is quite different from the in vitro one. Therefore, this work is particularly useful for in vitro experiments. In particular, CMPS may be useful as a DDS carrier which encapsulates drugs or growth-promoting substances and can sustainably release them, because the mesostructure and morphology of CMPS are partly retained even after more than half of the CMPS are degraded. A sustained-release drug carrier system would be realizable using CMPS because of its degradability, as the entire dosage could be administered. Mesoporous ethenylene-bridged silsesquioxane nanoparticles are highly resistant to hydrolysis,13 whereas mesoporous silica nanoparticles are highly degradable. Therefore, degradability could be tuned by arranging the framework ratio of siloxane to organosiloxane. This is “passive” degradability control, but

■

CONCLUSIONS Four types of CMPS with different diameters (ca. 20−80 nm) were prepared using tetraalkoxysilanes with different hydrolysis rates. Nucleation and particle growth can be controlled by using the different hydrolysis rates of alkoxy groups. This method is quite simple and useful because multiple steps are not needed. Nucleation and particle growth should be controlled by combining the present method with a so-called seed-growth method for further finely tuned particle size distribution. CMPS are uniquely degraded while retaining colloidal stability in systems that can continuously exclude dissolved silica. The degradation rates of CMPS are (i) independent of the difference in diameters, (ii) higher than those of CS, probably because of large surface areas, and (iii) higher than those of aggregates of CMPS because of high colloidal mobility. CMPS heterogeneously degrade from its outer and inner surfaces, which means that the morphology and the mesostructure are partly retained even after most of the CMPS has degraded. The fact that the degradation of colloidal mesoporous silica nanoparticles is independent of the diameter is quite important for the design of DDS carriers. The four types of CMPS with different diameters have almost the same surface areas but different outer surface areas. The outer surface area affects contact with living substances, such as cells and cytotoxicity. CMPS have attractive characteristics because their outer surface areas are different and they degrade at a nearly constant rate. Moreover, colloidal solutions inside tubes can remain unstirred by using a dialysis tube for the degradation experiments, and it is confirmed that particles in the dispersion state are more easily degraded than in the aggregational state. Therefore, high colloidal mobility should prove advantageous in catalysis applications as well as in DDS carriers. Future achievements in both “passive” and “active” controls of degradability will be quite useful for silica-based nanomaterials design.

■

ASSOCIATED CONTENT

S Supporting Information *

Additional table and figures (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Fax: +81-3-5286-3199. Tel: +81-3-5286-3199. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors thank Mr. M. Fuziwara (Waseda University) for his kind assistance in TEM measurement. This work was supported in part by Elements Science and Technology Project, “Functional Designs of Silicon−Oxygen-Based Compounds by Precise Synthetic Strategies” and the Global COE program, ‘Practical Chemical Wisdom’ from MEXT, Japan.

■

REFERENCES

(1) (a) Barbé, C.; Bartlett, J.; Kong, L.; Finnie, K.; Lin, H. Q.; Larkin, M.; Calleja, S.; Bush, A.; Calleja, G. Adv. Mater. 2004, 16, 1959−1966. (b) He, X.; Nie, H.; Wang, K.; Tan, W.; Wu, X.; Zhang, P. Anal. Chem.

1470



Article

2008, 80, 9597−9603. (c) Yang, J.; Lee, J.; Kang, J.; Lee, K.; Suh, J.-S.; Yoon, H.-G.; Huh, Y.-M.; Haam, S. Langmuir 2008, 24, 3417−3421. (d) Chauhan, V. P.; Popovic, Z.; Chen, O.; Cui, J.; Fukumura, D.; Bawendi, M. G.; Jain, R. K. Angew. Chem., Int. Ed. 2011, 50, 1−5. (e) Nakamura, M.; Shono, M.; Ishimura, K. Anal. Chem. 2007, 79, 6507−6514. (f) Hayashi, K.; Nakamura, M.; Ishimura, K. Chem. Commun. 2011, 47, 1518−1520. (g) Nakamura, M.; Ishimura, K. Langmuir 2008, 24, 12228−12234. (h) Nakamura, M.; Ozaki, S.; Abe, M.; Doi, H.; Matsumoto, T.; Ishimura, K. Colloids Surf., B 2010, 79, 19−26. (i) Nakamura, M.; Ozaki, S.; Abe, M.; Matsumoto, T.; Ishimura, K. J. Mater. Chem. 2011, 21, 4689−4695. (2) Watanabe, R.; Yokoi, T.; Kobayashi, E.; Otsuka, Y.; Shimojima, A.; Okubo, T.; Tatsumi, T. J. Colloid Interface Sci. 2011, 360, 1−7. (3) (a) Napierska, D.; Thomassen, L. C. J.; Rabolli, V.; Lison, D.; Gonzalez, L.; K.-Volders, M.; Martens, J. A.; Hoet, P. H. Small 2009, 5, 846−853. (b) Lu, F.; Wu, S.-H.; Hung, Y.; Mou, C.-Y. Small 2009, 5, 1408−1413. (c) He, Q.; Zhang, Z.; Gao, Y.; Shi, J.; Li, Y. Small 2009, 5, 2722−2729. (d) Rabolli, V.; Thomassen, L. C. J.; Princen, C.; Napierska, D.; Gonzalez, L.; K.-Volders, M.; Hoet, P. H.; Huaux, F.; Kirschhock, C. E. A.; Martens, J. A.; Lison, D. Nanotoxicology 2010, 4, 307−318. (e) Kumar, R.; Roy, I.; Ohulchanskky, T. Y.; Vathy, L. A.; Bergey, E. J.; Sajjad, M.; Prasad, P. N. ACS Nano 2010, 4, 699−708. (f) Thomassen, L. C. J.; Aerts, A.; Rabolli, V.; Lison, D.; Gonzalez, L.; K.-Volders, M.; Napierska, D.; Hoet, P. H.; Kirschhock, C. E. A.; Martens, J. A. Langmuir 2010, 26, 328−335. (g) Napierska, D.; Thomassen, L. C. J.; Lison, D.; Martens, J. A.; Hoet, P. H. Particle Fibre Toxicol. 2010, 7, 1−32. (h) Ariano, P.; Zamberlin, P.; Gilardino, A.; Mortera, R.; Onida, B.; Tomatis, M.; Ghiazza, M.; Fubini, B.; Lovisolo, D. Small 2011, 7, 766−774. (4) (a) Langer, R. Nature 1998, 392, 5−10. (b) Lendlein, A.; Langer, R. Science 2002, 296, 1673−1676. (c) Radin, S.; E.-Bassyouni, G.; Vresilovic, E. J.; Schepers, E.; Ducheyne, P. Biomaterials 2005, 26, 1043−1052. (d) Nair, L. S.; Laurencin, C. T. Prog. Polym. Sci. 2007, 32, 762−798. (5) (a) Alexander, G. B. J. Phys. Chem. 1957, 61, 1563−1564. (b) Iler, R. K. The Chemistry of Silica; Wiley: New York, 1979; pp 49−56. (6) (a) Roelofs, F.; Vogelsberger, W. J. Phys. Chem. B 2004, 108, 11308−11316. (b) Miyata, K.; Gouda, N.; Takemoto, H.; Oba, M.; Lee, Y.; Koyama, H.; Yamasaki, Y.; Itaka, K.; Nishiyama, N.; Kataoka, K. Biomaterials 2010, 31, 4764−4770. (7) (a) Landau, M. V.; Varkey, S. P.; Herskowitz, M.; Regev, O.; Pevzner, S.; Sen, T.; Luz, Z. Microporous Mesoporous Mater. 1999, 33, 149−163. (b) Czuryszkiewicz, T.; Ahvenlammi, J.; Kortesuo, P.; Ahola, M.; Kleitz, F.; Jokinen, M.; Lindén, M.; Rosenholm, J. B. J. NonCryst. Solids 2002, 306, 1−10. (c) Dunphy, D. R.; Singer, S.; Cook, A. W.; Smarsly, B.; Doshi, D. A.; Brinker, C. J. Langmuir 2003, 19, 10403−10408. (d) Burleigh, M. C.; Markowitz, M. A.; Jayasundera, S.; Spector, M. S.; Thomas, C. W.; Gaber, B. P. J. Phys. Chem. B 2003, 107, 12628−12634. (e) Bass, J. D.; Grosso, D.; Boissiere, C.; Belamie, E.; Coradin, T.; Sanchez, C. Chem. Mater. 2007, 19, 4349−4356. (f) He, Q.; Shi, J.; Zhu, M.; Chen, Y.; Chen, F. Microporous Mesoporous Mater. 2010, 131, 314−320. (g) I.-Barba, I.; Colilla, M.; V.-Regí, M. Microporous Mesoporous Mater. 2010, 132, 442−452. (8) (a) V.-Regi, M.; Rámila, A.; del Real, R. P.; P.-Pariente, J. Chem. Mater. 2001, 13, 308−311. (b) Andersson, J.; Rosenholm, J.; Areva, S.; Lindén, M. Chem. Mater. 2004, 16, 4160−4167. (c) Dai, C.; Guo, H.; Lu, J.; Shi, J.; Wei, J.; Liu, C. Biomaterials 2011, 32, 8506−8517. (9) Li, X.; Zhang, L.; Dong, X.; Liang, J.; Shi, J. Microporous Mesoporous Mater. 2007, 102, 151−158. (10) (a) Cauda, V.; Schlossbauer, A.; Bein, T. Microporous Mesoporous Mater. 2010, 132, 60−71. (b) Cauda, V.; Argyo, C.; Bein, T. J. Mater. Chem. 2010, 20, 8693−8699. (11) Lin, Y.-S.; Abadeer, N.; Haynes, C. L. Chem. Commun. 2011, 47, 532−534. (12) Yano, K.; Fukushima, Y. J. Mater. Chem. 2003, 13, 2577−2581. (13) (a) Urata, C.; Aoyama, Y.; Tonegawa, A.; Yamauchi, Y.; Kuroda, K. Chem. Commun. 2009, 5094−5096. (b) Urata, C.; Yamada, H.; Wakabayashi, R.; Aoyama, Y.; Hirosawa, S.; Arai, S.; Takeoka, S.; Kuroda, K. J. Am. Chem. Soc. 2011, 133, 8102−8105.

(14) (a) Atkin, R.; Craig, V. S. J.; Wanless, E. J.; Biggs, S. Adv. Colloid Interface Sci. 2003, 103, 219−304. (b) Tyrode, E.; Rutland, M. W.; Bain, C. D. J. Am. Chem. Soc. 2008, 130, 17434−17445. (15) (a) Möller, K.; Kobler, J.; Bein, T. Adv. Funct. Mater. 2007, 17, 605. (b) Möller, K.; Kobler, J.; Bein, T. J. Mater. Chem. 2007, 17, 624− 631. (c) Kobler, J.; Möller, K.; Bein, T. ACS Nano 2008, 2, 791−799. (d) Kobler, J.; Bein, T. ACS Nano 2008, 2, 2324−2330. (e) Lin, Y.-S.; Tsai, C.-P.; Huang, H.-Y.; Kuo, C.-T.; Hung, Y.; Huang, D.-M.; Chen, Y.-C.; Mou, C.-Y. Chem. Mater. 2005, 17, 4570−4573. (f) Lu, F.; Wu, S.-H.; Hung, Y.; Mou, C.-Y. Small 2009, 5, 1408−1413. (16) (a) Helden, A. K. V.; Jansen, J. W.; Vrij, A. J. Colloid Interface Sci. 1981, 81, 354−368. (b) Persson, A. E.; Schoeman, B. J.; Sterte, J.; Otterstedt, J.-E. Zeolites 1994, 14, 557−567. (c) Schoeman, B. J.; Sterte, J.; Otterstedt, J.-E. J. Porous Mater. 1995, 1, 185−198. (17) Brinker, C. J.; Scherer, G. W. Sol−Gel Science: The Physics and Chemistry of Sol−Gel Processing; Elsevier: Amsterdam, 1990 pp 96− 233. (18) Kang, K.-K.; Rhee, H.-K. Microporous Mesoporous Mater. 2005, 84, 34−40. (19) Stöber, W.; Fink, A.; Bohn, E. J. Colloid Interface Sci. 1968, 26, 62−69. (20) Avnir, D.; Kaufman, V. R. J. Non-Cryst. Solids 1987, 192, 180− 182. (21) (a) Chen, C.-Y.; Li, H.-X.; Davis, M. E. Microporous Mater. 1993, 2, 17−26. (b) Zhao, D.; Huo, Q.; Feng, J.; Chmelka, B. F.; Stucky, G. D. J. Am. Chem. Soc. 1998, 120, 6024−6036. (22) Lin, Y.-S.; Haynes, C. L. J. Am. Chem. Soc. 2010, 132, 4834− 4842. (23) (a) I-Barba, I.; Arcos, D.; Sakamoto, Y.; Terasaki, O.; L-Noriega, A.; V.-Regí, M. Chem. Mater. 2008, 20, 3191−3198. (b) I-Barba, I.; Colilla, M.; V.-Regí, M. J. Nanomater. 2008, 2008, 1−14. (c) García, A.; Cicuendez, M.; I-Barba, I.; Arcos, D.; V.-Regí, M. Chem. Mater. 2009, 21, 5474−5484. (24) Finnie, K. S.; Waller, D. J.; Perret, F. L.; K.-Heuer, A. M.; Lin, H. Q.; Hanna, J. V.; Barbé, C. J. J. Sol−Gel Sci. Technol. 2009, 49, 12−18. (25) Lin, W.-C.; Chiang, C.-W.; Hong, C.-Y.; Chen, P.-J.; Wu, K. C.W. Chem. Lett. 2011, 40, 533−535. (26) Lu, J.; Li, Z.; Zink, J. I.; Tamanoi, F. Nanomedicine 2011, 8, 212−220.

1471


Preparation of Colloidal Mesoporous Silica Nanoparticles with

Recommend Documents