Article Cite This: Chem. Mater. 2018, 30, 5770−5776
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Kinetically Controlled Dendritic Mesoporous Silica Nanoparticles: From Dahlia- to Pomegranate-like Structures by Micelle Filling Yue Wang, Hao Song, Yannan Yang, Yang Liu, Jie Tang, and Chengzhong Yu* Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
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S Supporting Information *
ABSTRACT: A unique dynamic structural transition from large-pore dendritic mesoporous silica nanoparticles (DMSNs) with a dahlia-like morphology to pomegranatelike mesoporous silica nanoparticles with small mesopores is reported. The structural evolution is accompanied by gradually filling the preformed dendritic large pores with silica-coated micelles, providing a series of DMSNs with kinetically controlled dual mesoporosity. The heterogeneous porous structure of DMSNs demonstrates advantages in the co-loading of two positively charged drug molecules, showing promising potential in cellular delivery applications.
S
ince their discovery in the early 1990s,1−3 mesoporous materials with ordered and controllable mesostructures,4−6 tunable compositions,7−11 and variable morphologies7 have attracted a great deal of attention for various applications.12−15 In particular, mesoporous silica nanoparticles (MSNs) with small particle sizes, good biocompatibility,16 and easy surface modification12 have been extensively studied with applications in drug delivery17 and adsorption.18 Moreover, MSNs have been used as templates in the preparation of soft polymer- and carbon-based materials with broad applications.19−23 Traditional MSNs such as SBA-1524 and MCM-4125 type materials have relatively small pore sizes. The successful synthesis of KCC-126 with both large dendritic pores (5−30 nm) and monodispersed uniform particle sizes (250−450 nm) has sparked significant interest in synthesis27−32 and applications of this new type of dendritic MSNs (DMSNs), specifically in the cellular delivery of various cargo molecules.27,28,33−38 Significant progress has been made in the structural control over DMSNs (e.g., particle size,30,33,38 pore size,29,32,36,37 and bimodal pores 29,31,36,39) and their assembly strategies, including biphasic synthesis,29 microemulsion templating,26,31,38 the aggregation of composite micelles in the presence of competing anions in aqueous systems,30,32 and the assembly from lamellar subunits.33,36,37 To date, these mechanisms are mainly focused on the formation of DMSNs as an end product. The structural heterogeneity of DMSNs controlled by reaction kinetics as well as its significance in the applications of DMSNs has rarely been reported. Herein, we report an unusual dynamic structural transition from DMSNs with a dahlia-like morphology (Scheme 1, A1) to pomegranate-like small-pore MSNs (A2) with the large dendritic pores gradually filled by silica-coated composite micelles (Scheme 1B). This new structural evolution © 2018 American Chemical Society
Scheme 1. From (A1) a Dahlia-like DMSN to (A2) a Pomegranate-like MSN and (B) a Kinetic Micelle Filling Mechanisma
a The dahlia-like DMSNs (B1) are first assembled by an anion-assisted approach through lamellar building blocks. By gradually filling the large dendritic pores with composite micelles, we obtained a series of intermediate structures (B2) and small-pore MSNs with the dendritic pores completely filled (B3). Objects are drawn not to scale.
mechanism has important implications. (1) DMSNs should be considered as a kinetically controlled product, with its structure changing with reaction time (B1 or B2). (2) B2 is not a “pure” structure either but represents a series of DMSNs, whose structure is dependent on not only the reaction time but also the structural evolution (from B1 to B3) time window that can be further controlled by other reaction parameters. In this Received: June 27, 2018 Revised: August 2, 2018 Published: August 3, 2018 5770
DOI: 10.1021/acs.chemmater.8b02712 Chem. Mater. 2018, 30, 5770−5776
Article
Chemistry of Materials
observed at a prolonged t of 5 h. The average particle sizes measured from TEM images are 129, 151, 163, and 166 nm for MSNs-80−1−0.3, MSNs-80−1−1, MSNs-80−1−2, and MSNs-80−1−5, respectively. Scanning electron microscopy (SEM) images of MSNs-80− 1−t shown in Figure 2 further confirm the observations from
regard, care should be taken with regard to the significant impact of reaction kinetics on the final structures of DMSNs to allow for reproducible synthesis and applications. (3) It is possible to generate DMSNs with similar particle sizes and dendritic pore sizes but different amounts of small-sized mesopores (due to the removal of micelles) within the large dendritic pores. Such a heterogeneous dual-pore structure, as we will demonstrate in this work, provides unique opportunities using bare DMSNs in the co-delivery of two positively charged drug molecules for enhanced cellular delivery applications. The structural transition from dahlia-like DMSNs to pomegranate-like MSNs was observed in an alkaline aqueous system utilizing tetraethyl orthosilicate (TEOS) as the silica precursor, cetyltrimethylammonium bromide (CTAB) as the surfactant, and trifluoroacetate anions (FC2) as co-templates. After being vigorously stirred at different temperatures (T, 60 and 80 °C) and FC2/CTAB molar ratios (R, 0.5−4) and for different periods of time (t, 0.3−24 h), samples denoted MSNs-T−R−t were collected by centrifugation. The final products were obtained by calcination at 550 °C for 5 h in air to remove surfactants. The influence of reaction time on the final structures was first studied at a fixed T of 80 °C and an R of 1. Transmission electron microscopy (TEM) images of MSNs-80−1−t samples (t = 0.3, 1, 2, or 5 h) are shown in Figure 1A−D. MSNs-80−
Figure 2. SEM images of MSNs-80−1−t, where t = 0.3, 1, 2, and 5 h (A−D, respectively).
TEM images. The large pore openings are observed directly in MSNs-80−1−0.3 (Figure 2A), MSNs-80−1−1 (Figure 2B), and MSNs-80−1−2 (Figure 2C), whereas the size of the pore opening is reduced with an increase in t. The small mesopores in MSNs-80−1−5 cannot be seen clearly in Figure 2D, showing a relatively smooth surface. The nitrogen sorption analysis was also conducted to characterize the pore structures of MSNs-80−1−t. The adsorption and desorption isotherms of MSNs-80−1−t are typical type IV. The major capillary condensation steps of MSNs-80−1−0.3, MSNs-80−1−1, and MSNs-80−1−2 (Figure S1A) occur at a high relative pressure (P/P0) of >0.85, indicating the existence of large pores. For MSNs-80−1−5, two obvious capillary condensation steps are observed, one at a P/P0 of 0.3−0.4 attributed to small mesopores and another at ∼0.9 attributed to the interparticle packing voids.41 The corresponding Barrett−Joyner−Halenda (BJH) pore size distribution curves of MSNs-80−1−t calculated from the adsorption branch are shown in Figure S1B. For MSNs-80−1− 0.3, MSNs-80−1−1, and MSNs-80−1−2, two peaks are observed, one centered at ∼2 nm and another at ∼20 nm from the center radial opening pores. The intensity of the peak at ∼2 nm increases with t, while that at ∼20 nm decreases with t. For MSNs-80−1−5, the mesopore distribution at 2 nm becomes the main peak; even the small mesopore volume is reduced to 0.06 cm3 g−1, suggesting that most of the small mesopores are closed.42 The physical properties of MSNs-80− 1−t are summarized in Table 1. With an increase in t, the pore size decreases from 26.7 to 2.3 nm, the BET surface area
Figure 1. TEM images of MSNs-80−1−t, where t = 0.3, 1, 2, and 5 h (A−D, respectively).
1−0.3, MSNs-80−1−1, and MSNs-80−1−2 (Figure 1A−C, respectively) all exhibit the typical center-radial dendritic pore structures reported in the literature.30,37 However, with the t increasing from 0.3 to 2 h, the mass thickness contrast in the TEM images appears to increase significantly and the porous voids (air) are less apparent, suggesting that the silica distribution density over the porous space is increased. Surprisingly, the radial dendritic pore structure cannot be observed in MSNs-80−1−5 (Figure 1D); instead, small mesopores similar to those of conventional MSNs40 are 5771
DOI: 10.1021/acs.chemmater.8b02712 Chem. Mater. 2018, 30, 5770−5776
Article
Chemistry of Materials Table 1. Physical Properties of MSNs-80−1−ta sample
D (nm)
d (nm)
S (m2 g−1)
V (cm3 g−1)
Vsp (cm3 g−1)
Vlp (cm3 g−1)
MSNs-80−1−0.3 MSNs-80−1−1 MSNs-80−1−2 MSNs-80−1−5
129 151 163 166
1.3, 26.7 2.7, 23.1 2.8, 21.9 2.3
488 373 334 207
1.28 0.78 0.69 0.25
0.12 0.15 0.23 0.06
0.67 0.33 0.21 0
a
D indicates the particle diameter, d the pore size, S the surface area, and V the total pore volume. Vsp and Vlp are the accumulated pore volume of small (∼2 nm) and large pores (∼20 nm), respectively.
decreases from 488 to 207 m2 g−1, and the total pore volume decreases from 1.28 to 0.25 cm3 g−1. To obtain information about the internal structures, electron tomography (ET) analysis was employed to compare MSNs80−1−0.3, MSNs-80−1−2, and MSNs-80−1−5. The tomogram sliced from the center of MSNs-80−1−0.3 (Figure 3A)
Figure 4. TEM images of (A−D) MSNs-80−0.5−t and (E−H) MSNs-80−4−t obtained at various t values of (A and E) 0.3, (B and F) 2, (C and G) 5, and (D and H) 24 h. Figure 3. ET slices of MSNs-80−1−t prepared for (A) 0.3, (B) 2, and (C) 5 h taken from the center of one particle. The scale bar is 50 nm.
H) while the small-pore structure could not be formed at this time point. The nitrogen sorption analysis of MSNs-80−4−24 supported the conclusion (Figure S2), where a bimodal pore size distribution (2.5 and 18.4 nm) is observed. Our study suggests that the time window of the structural transition from large-pore DMSNs to small-pore MSNs is positively correlated to the R values (a higher R for a longer transition time and vice versa). The structural transition was further studied in the MSNs60−1−t series (R = 1) when the reaction temperature was decreased to 60 °C. TEM images (Figure S3) revealed the formation of unilamellar vesicle-like subunits and then dendritic structures at 0.3−1 h (Figure S3A,B). However, small-pore MSNs could not be observed at prolonged reaction times of ≤24 h (Figure S3C,D) at 60 °C. In comparison to the studies performed at 80 °C [MSNs-80−1−t (Figures 1−3)], it is shown that a lower temperature favors a longer time window of the structural transition from large-pore DMSNs to smallpore MSNs. A dynamic composite micelle filling mechanism is proposed to explain the structural transition from large-pore DMSNs and small-pore MSNs (Scheme 1). In our synthesis, the fluorinated trifluoroacetate anions (FC2) and cetyltrimethylammonium cations (CTA+) as well as silicate species (from TEOS hydrolysis and condensation) could form silica-coated spherical micelles (Figure S4) and/or lamellar structures (Figure S3A), the latter being the building block for forming the DMSNs.36 However, even when the DMSNs were formed, e.g., in MSNs-80−1−1, composite micelles with an average diameter of ∼5 nm43 were still observed in the supernatant (Figure S4). The coexistence of DMSNs and spherical micelles at the same time is important for understanding our micelle filling mechanism. It is proposed that the gradual micelle filling of the void space of preformed large-pore DMSNs is responsible for the structural transition toward final smallpore MSNs. This mechanism can be used to explain the pore structure differences in various samples. For MSNs-80−1−0.3,
clearly presents the large dendritic and open pores. The wall thickness is measured to be 3.8 nm, indicating the formation of dendritic pores by lamellar structures, which is consistent with a previous literature report.36 The dendritic structure with a large pore opening for MSNs-80−1−2 is indicated by black arrows in Figure 3B. The wall is irregular and thicker than that of MSNs-80−1−0.3 and that in previous reports.29,36,37 There are small mesopores (∼2 nm) found on the wall indicated by red arrows, in accordance with nitrogen sorption analysis results. For MSNs-80−1−5, only small mesopores of ∼2 nm, not the large dendritic pores, are observed. However, some concave voids are observed at the boundary of particles (Figure 3C, black arrows) with a depth that is smaller than that of MSNs-80−1−2. It is noted that small mesopores of ∼2 nm cannot be clearly observed in MSNs-80−1−0.3, suggesting that the 1.3 nm micropores should have a different origin compared to those of ∼2 nm mesopores observed in MSNs80−1−2 and MSNs-80−1−5. The results presented above reveal a time-dependent structural transition from large-pore DMSNs to small-pore MSNs with the large dendritic pores gradually filled by small mesopores. The time window of the structural transformation from large-pore DMSNs to small-pore MSNs influenced by other parameters was further studied. The effect of R, which is one important parameter for inducing the formation of DMSNs,33,36,37 was investigated by adjusting R (R = 0.5 and 4) while keeping the reaction temperature at 80 °C. Surprisingly, the dendritic pore structure was observed for MSNs-80−0.5−0.3 at an early reaction time point (Figure 4A), while the completed structural transformation was observed at 2 h (Figure 4B), faster than that in the MSNs-80−1−t series (∼5 h at a higher R of 1). The small-pore structure was maintained for 24 h (Figure 4C,D). In contrast, when R was increased to 4, the large-pore dendritic structure was maintained in MSNs-80−4−t samples for 24 h (Figure 4E− 5772
DOI: 10.1021/acs.chemmater.8b02712 Chem. Mater. 2018, 30, 5770−5776
Article
Chemistry of Materials the ∼1.3 nm micropores should be attributed to amorphous silica because there is little micelle filling at this early time. With an increase in t to 1 and 2 h, the small mesopores (∼2.7 nm) with an increasing Vsp should come from the gradually filled silica-coated micelles after surfactant removal. When t is prolonged to 5 h, the large dendritic pores are almost fully filled by silica-coated micelles and possibly free silicate oligomers. Thus, even after calcination, most of the ∼2.3 nm mesopores embedded in the interior part of MSNs-80−1−5 are not accessible,42 leading to the smallest surface area and pore volume of the four samples. The micelle filling mechanism can also be used to explain the impact of the FC2/CTA+ ratio and reaction temperature on the structural transition, which will be discussed in the following section to compare our mechanism with reported formation mechanisms of DMSNs.29,32,36,37 (1) For kinetically controlled heterogeneous structures of DMSNs, there are several reported mechanisms of formation of DMSNs such as assembly by the silicate/surfactant/oil composites at the water−oil interface in biphasic29 and microemulsion systems,26,31,38 the competition effect of anions toward composite micelles in water systems,30,32 and the growth of lamellar conic structures in our previous studies.33,36,37 These mechanisms generally explain the final structures of DMSNs. The micelle filling mechanism proposed in this study reveals that DMSNs have dynamically changing structures. The silica-coated micelles are heterogeneously nucleated on a preformed large dendritic pore surface due to further condensation between silanol groups, in accordance with our observations that the pomegranate-like structures cannot be changed back to dahlia-like structures (data not shown). The extent of micelles filled into the dendritic large pores has consequences for the heterogeneous structures of DMSNs: not only bimodal mesopores (coexistence of large dendritic pores and small mesopores generated by removing micelles) but also the fractions of small mesopores deposited inside the large dendritic pores could be changed over reaction time; thus, DMSNs should not be considered as a thermodynamically stable product with a given structure. (2) The unique role of FC2 in our reaction system is described from two perspectives. First, as previously reported, the use of FC2 together with CTA+ favors the formation of DMSNs.33 Second, but more importantly, FC2 is less capable of inducing the formation of DMSNs than heptafluorobutyrate/perfluorooctanoate anions are (evidenced by the formation of DMSNs at lower anion/CTA+ ratios),33 leading to a reasonably short time window (e.g., 5 h) in which to observe the structural transition from DMSNs to small-pore MSNs. The impact of R (FC2/CTA+) and reaction temperature on the structural transition time window (Figure 4) can be explained by the micelle filling mechanism considering the interaction between FC2 and CTA+ micelles. A lower R value would result in fewer lamellar building blocks and more spherical micelles and, thus, a faster micelle filling kinetics (MSNs-80−0.5−t vs MSNs-80−1−t series). Similarly, a higher concentration of spherical micelles due to weakened electrostatic interaction between cationic and anionic molecules at elevated temperatures44 contributes to a faster structural transition (MSNs-80−1−t vs MSNs-60−1−t series). It is predicted that very high R values (e.g., >4), low temperatures, or the use of reagents with a strong ability to induce micelle structural change could result in further reduced concentrations of spherical micelles, which are insufficient to fill the
dendritic voids completely within the commonly selected reaction time ( 0.05) indicates no significant difference.
loading, MSNs-80−1−0.3 with a larger surface area exhibited a loading capacity (710 μg/mg) slightly higher than that of MSNs-80−1−2 (650 μg/mg), although there is no significant difference. In contrast, MSNs-80−1−5 possess the lowest loading capacity of 440 μg/mg limited by the small surface area. For single-RNase A loading, MSNs-80−1−0.3 possessed a loading capacity (374 μg/mg) higher than those of MSNs80−1−2 (247 μg/mg) and MSNs-80−1−5 (10 μg/mg) due to the large dendritic pore and large surface area (Table 1). For the co-loading of DOX and RNase A, DOX was loaded first followed by RNase A, and the DOX and RNase A contents were measured in the final co-loaded product. Among three samples, the DOX loading capacity of MSNs-80−1−0.3 decreased from 710 μg/mg (DOX single loading) to 585 μg/mg (co-loading). In contrast, the DOX loading capacity for MSNs-80−1−2 remained almost unchanged (∼650 μg/mg). For MSNs-80−1−5, similar to MSNs-80−1−0.3, there was also a decrease in the DOX loading capacity from 440 μg/mg (single loading) to 230 μg/mg (co-loading). The same trend was observed for RNase A loading. The RNase A loading capacity of MSNs-80−1−0.3 decreased from 374 μg/mg (single loading) to 258 μg/mg (co-loading), while there was no significant change for that of MSNs-80−1−5 (∼10 μg/mg). The RNase A loading capacity of MSNs-80−1−2, unlike those of the other two samples, increased from 247 μg/mg (single loading) to 386 μg/mg (co-loading), which is significantly higher than that of MSNs-80−1−0.3. To gain insight into the contribution of dual mesopores of MSNs-80−1−2 to the loading of two positively charged drugs, the loading study was conducted by incubation of MSNs-80− 1−2 either directly with a mixture of DOX and RNase A or with an RNase A solution first followed by DOX. As shown in Figure S6, the RNase A loading capacity decreased from 386 μg/mg (DOX loading first) to 134 μg/mg (mixture loading) and 192 μg/mg (RNase A loading first). Similarly, there is a decrease in DOX loading capacity from 650 μg/mg (DOX loading first) to 553 μg/mg for mixture loading and 134 μg/ mg for the RNase A loading first experiment. These results indicate that MSNs-80−1−2 with both large dendritic pores and small mesopores are advantageous for improving the coloading capacity of two positively charged drug molecules, and a sequential loading is essential for achieving this goal.
Figure 6. Orthogonal side views from z-stack confocal images of 4T1 cells incubated with (A−D) PBS only, (E−H) free DOX and RNase A, and (I−L) the MSNs-80−1−2−DOX−RNase A complex for 4 h. Blue indicates the DAPI-stained nucleus, green FITC-labeled RNase A, and red DOX. The scale bar is 20 μm. 5774
DOI: 10.1021/acs.chemmater.8b02712 Chem. Mater. 2018, 30, 5770−5776
Chemistry of Materials
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ACKNOWLEDGMENTS The authors acknowledge financial support from the Australian Research Council, the Queensland Government, the Australian National Fabrication Facility, and the Australian Microscopy and Microanalysis Research Facility at the Centre for Microscopy and Microanalysis and University of Queensland.
from side views indicated the existence of DOX inside the nucleus, while the green fluorescence (from FITC-labeled RNase A) was observed to be around the nucleus, which suggested the localization of FITC-RNase A inside the cytoplasm (Figure 6L). The overlap (yellow color) of green (from FITC-labeled RNase A) and red fluorescence (from DOX) confirmed the co-localization of DOX and FITC-RNase A in the cytoplasm. In contrast, the red fluorescence and green fluorescence were relatively weak for the free cells treated with DOX and RNase A (Figure 6F,G), indicating excellent cellular delivery performance of both DOX and RNase A by MSNs80−1−2. The cytotoxicity of DOX and RNase A delivered by MSNs80−1−2 was also evaluated using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The MSNs-80−1−2 without loading drugs exhibited good biocompatibility, maintaining >90% of cell viability at all tested doses. Both the MSNs-80−1−2−DOX−RNase A composite and free DOX and RNase A exhibited dosedependent cell viability with an increase in the concentration of DOX from 3 to 12 μg/mL (Figure S7). Furthermore, the MSNs-80−1−2−DOX−RNase A composite showed a high toxicity (20.1% viability) at a DOX concentration of 6 μg/mL compared with that of free DOX and RNase A (48.5%), suggesting the advantage of dual-mesopore DMSNs as the delivery system for the co-delivery of two positively charged anticancer drugs. In summary, the heterogeneity of DMSNs has been investigated and a micelle filling mechanism is proposed. The structural transition from large-pore DMSNs with a dahlia-like morphology to small-pore MSNs with a pomegranate-like morphology provides a new understanding of the morphology and structural controls of conventional MSNs and DMSNs. The heterogeneously structured DMSNs with partially deposited micelle composites have shown advantages in the intracellular delivery of two positively charged anticancer drugs. Understanding the kinetically controlled heterogeneous nature of DMSNs is important for the rational choice of silicabased nanocarriers for their bioapplications.
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REFERENCES
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.8b02712. Experimental section, nitrogen sorption results for MSNs-80−1−t and MSNs-80−4−24, TEM images of MSNs-60−1−t, freeze-dried supernatant for MSNs-80− 1−1 and MSNs synthesized at 80 °C using tosylate anions, Dox and RNase A loading capacity of MSNs80−1−2 with various incubation methods, and cytotoxicity results for 4T1 cells incubated with the DMSNs80−2−DOX−RNase A complex for 24 h (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hao Song: 0000-0002-6383-0605 Chengzhong Yu: 0000-0003-3707-0785 Notes
The authors declare no competing financial interest. 5775
DOI: 10.1021/acs.chemmater.8b02712 Chem. Mater. 2018, 30, 5770−5776
Article
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DOI: 10.1021/acs.chemmater.8b02712 Chem. Mater. 2018, 30, 5770−5776
