Mesoporous silicas templated by heterocyclic amino acid derivatives: Biomimetic synthesis and drug release application

Materials Science & Engineering C 93 (2018) 407–418

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Mesoporous silicas templated by heterocyclic amino acid derivatives: Biomimetic synthesis and drug release application

T

Heran Lia,b, Jia Keb, Haiting Lib,c, Chen Weib, Xueqian Wub, Jing Lib, Yang Yangb, Lu Xub, ⁎ ⁎⁎ Hongzhuo Liub, Sanming Lib,c, , Mingshi Yangd, Minjei Weia, a

School of Pharmacy, China Medical University, Shenyang, 110122, P.R. China School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China c School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China d Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark b

A R T I C LE I N FO

A B S T R A C T

Keywords: Mesoporous silica Biomimetic synthesis nanomaterial Drug delivery Dynamic self-assembly

The present paper reported a biomimetic synthesis of mesoporous silicas (BMSs) at room temperature by using synthesized polymers (C16-L-His, C16-L-Pro and C16-L-Trp) which derived from amino acid with ring structures as template under basic condition via co-structural-directing-agent method. The formation mechanism of BMSs and effect of initial synthesis conditions (such as surfactant structure, pH and co-solvents) on morphology and structure of BMSs were systematically studied. Synthesized BMSs were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and nitrogen adsorption/desorption isotherms. The results showed that the surfactant structure was the dominant factor to direct the final mesostructure of BMSs, since the structure of surfactant affected the structure and size of clusters. Meanwhile the generation of BMSs required very rigorous alkaline condition which controlled the ionization degree of the surfactant and thus contributing to adequate stacking energy. Higher pH resulted in construction of channels with higher curvature. The presence of ethanol was found to facilitate the formation of BMSs with larger particle size. In application, aspirin can be loaded into BMSs with high efficiency, and the drug crystalline state of aspirin transformed from crystalline state to amorphous state during this process, which undoubtedly lead to the improvement of drug dissolution from 72.8% to 100% within 90 min. It is convincible that the biomimetic method presented here provided novel insight on precisely control of mesoporous silica and undoubtedly promoted the application of mesoporous silica materials.

1. Introduction Since mesoporous silica M41S family was first discovered in the early 1990s, silica-based mesoporous materials with controlled nanostructures has attracted considerable interest in a wide range of applications, such as separation, catalysis, adsorption, sensing and drug delivery [1–11]. Precisely control of structure is crucial to practical application and usually accomplished by top-down synthetic process (e.g. chemical vapor deposition and lithography/etching processes) [12,13]. Compared to traditional methods, biomineralization which occurs at ambient temperature and neutral pH in aqueous solution provides novel synthetic routes to fabricate hybrid materials. It is a nontrivial bottom-up approach and exists widely in nature [13–15].

Biominerals such as marine diatoms, sponges and radiolarians often exhibit excellent optical, biocompatible and mechanical properties, and possess intricate structures and hierarchical organizations ranging from nanoscale to macroscale [16]. Furthermore, in biosilicification process, the deposition of silica precursors is actively catalyzed by amines [14]. Biomacromolecules including polyamine, polypeptides, proteins, and amino acid derivatives can effectively catalyze the condensation of silica precursors in biological systems of silica generation [13–17]. Many types of biomacromolecules are easily available and can be used to form a great variety of structures [18]. Multiple morphogenesis of silicas including nanoribbons, twisty nanorods, helical nanofibers, nanoflakes, nanospheres, curved films and large aggregates can be obtained by using biomacromolecules as template [18,19]. According

⁎

Correspondence to: S. Li, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua RD 103, 110016 Shenyang, China. Correspondence to: M. Wei, School of Pharmacy, China Medical University, 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, Shenyang, China. E-mail addresses: [email protected] (S. Li), [email protected] (M. Wei). ⁎⁎

https://doi.org/10.1016/j.msec.2018.07.081 Received 22 September 2017; Received in revised form 4 June 2018; Accepted 30 July 2018 Available online 02 August 2018 0928-4931/ © 2018 Elsevier B.V. All rights reserved.

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Fig. 1. Synthesis route of C16-L-aminoacid. a, dehydration–condensation reaction; b. ester hydrolysis reaction.

entirely composed of water. Therefore the establishment of waterethanol or water-methanol system was of great importance. Furthermore, aspirin was selected as model drugs, and was incorporated into BMSs according to the solvent deposition method. The drug loading capacity, controlled release behavior and the crystalline conversion effect of BMSs were deeply studied to evaluate the functionalities of BMSs as drug carrier. We believe that this study will make contributions to the further understanding of the BMSs formation and provide promising silica-based mesoporous materials for the practical application.

to Atluri et al., a naturally occurring folate supramolecular was able to use as templates to create functional ordered mesoporous particles as a result of self-assembly of folates monomer into rotated tetramers within the pores [20]. Besides, mesoporous silica with spiral fiber nanostructures had been constructed by Che et al. via the self-assembling of anionic amphiphile (N-acyl-L-alanine) with the use of costructure-directing-agent. By tuning the reaction conditions, such as pH, temperature, solvent and stirring rate, the mesostructure of the mesoporous silica are controllable [21–23]. Furthermore, in the report of Wu et al., nanoflakes with perpendicular mesoporous channels and nanoworms with horizontal channels were synthesized using the self-assemblies of alanine acid derivatives L-18Ala6PyBr and L-18Ala11PyBr, respectively. The results demonstrated that the hydrophobic effect of the bridging alkylene chains affected the morphology of mesoporous silicas [24]. Not too long ago, bimodal nanoporous silica was synthesized by Li et al., using amino acid derivative of serine as template. Both mesoporous and macroporous can be detected in the obtained mesoporous silicas due to the dynamic behavior of serine template [25]. Mesoporous silica has received great attention because of their unique properties, such as non-toxic nature, good physicochemical stability, high surface area, large pore volume, tunable pore size and excellent biocompatibility, make them promising candidates to be used in the field of drug delivery [8,26–29]. The efficacy of silica materials as drug carriers is strongly related to the particle size, morphology, mesostructure and dispersibility [28,30]. For example, spherical mesoporous silica carrier was served as immediate drug delivery systems by Barba and co-workers. After being loaded into the MCM-48, the dissolution rate was significantly improved, 90% of the drug can be released within 5 min due to the highly accessible pore network [31]. Zhu et al. exploited mesoporous silica with 3D face-centered cubic structure as a carrier for a poorly water soluble drug, and studied the influence of pore size on drug delivery rate. The study indicated the pore size of mesoporous silica was an important factor to control the drug-loading/releasing behavior as it affected the drug diffusion. Larger diffusion resistance was encountered for drugs to diffuse in the smaller pores [32]. Besides, Wang et al. utilized both MCM-48 with interconnected pore networks and MCM-41 with unconnected pore structures as cilostazol carriers. The results demonstrated that MCM-48 had a faster dissolution rate than MCM-41, because the interconnected pore networks and MCM-48 facilitated the transport path [33]. Inspired by biosilicification, in the present study, synthesized polymers derived from heterocyclic amino acids (proline, histidine and tryptophan) were prepared for the first time and employed as templates to build up mesoporous silicas. Meanwhile, 3-aminopropyltriethoxysilane (APTES) was used as co-structural-directing-agent and tetraethoxysilane (TEOS) was served as main silica source. Besides, the effects of the initial synthesis conditions on the structure and morphology of the BMSs were also systematic studied. It should be noticed that the biomimetic mineralizations in nature always took place in an inexact aqueous medium which contained a large portion of water but was not

2. Materials and methods 2.1. Materials 4-(Dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4Hpyran (DCM), dimethylformamide (DMF), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT) were obtained from Shanghai Jinjinle Industrial Co., Ltd. (Shanghai, China). 3-Aminopropyltriethoxysilane (APTES) and tetraethoxysilane (TEOS) were purchased from Chengdu Xiya Chemical Technology Co., Ltd. (Chengdu, China). Palmitic acid, L-histidine methyl ester, L-proline methyl ester and L-tryptophan methyl ester were purchased from Yangzhou Baosheng Biochemical Co., Ltd. (Yangzhou, China). All other chemicals were commercially available and used without any further purification. 2.2. Synthesis of C16-L-aminoacids The amino acid derivatives, C16-L-aminoacid methyl esters were synthesized by dehydration condensation of L-aminoacid methyl easers with palmitic acid, and the synthesis route was listed in Fig. 1. Briefly, 0.25 g L-tryptophan methyl ester hydrochloride was dissolved in 5 ml TMF, and 0.3 ml triethylamine was added dropwise to the mixture under stirring. Then the mixture was transferred to an ice-water bath and stand for 10 min. After introducing of EDCI (0.23 g), HOBT (0.16 g) and palmitic acid (0.26 g), the mixture was transferred to a water bath at room temperature and was stirred for 5–6 h. Subsequently, the obtained mixture was carefully washed by a saturated solution of NaHCO3 configured using water and DMF (5:1, v/v). After precipitation, crude product was filtered, dried and weighted. The product was named as C16-L-tryptophan methyl ester (see Fig. 2). C16-L-tryptophan (C16-L-Trp) was prepared by hydrolyzing C16-Ltryptophan methyl ester. In details, 6 g NaOH was dissolved in a mixed solution of water and ethanol (3:7, v/v), and the obtained alkaline liquid (100 ml) was utilized to dissolve C16-L-tryptophan methyl ester at room temperature. After 6 h, the product was separated out by rotatory evaporation, transferred to an ice-water bath, adjusted pH to 2–3 by HCl, filtered, washed and dried to get C16-L-Trp. C16-L-proline (C16-L-Pro) and C16-L-histidine (C16-L-His) were 408

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Fig. 2. Schematic illustration of cooperative self-assembly formation of BMSs.

TEOS was added, and the pH after 24 h of statically treating were measured and recorded as pH 1, pH 2 and pH 3, respectively. BMSs prepared with C16-L-Pro, C16-L-Trp and C16-L-His were denoted as ProBMS, Trp-BMS, and His-BMS, respectively.

synthesized using the same method. In particular, C16-L-histidine methyl ester was recrystallized by the mixture of n-hexane and ethyl alcohol (4:1, v/v) and C16-L-proline was prepared without recrystallization due to its low melting point. 2.3. Preparation of BMSs

2.4. Drug loading procedure Typically, 1.1 mmol of synthesized anionic surfactant was dispersed to 20 ml mixture solution of water, NaOH (0.1 mol/l), HCl (0.01 mol/l), and organic alcohol at 60 °C. The solvent composition and the dosage of additives were listed in Table 1. Here, methanol and ethanol were added as co-solvent, NaOH and HCl were used to adjust pH, leading to a wide pH range from 6.05 to13.05. After that, the system was cooled to room temperature, and was stirred mildly for 80 min. Then a mixture of APTES (0.24 ml) and TEOS (1.57 ml) was added dropwise to the solution and the system was stirred for a few minutes at room temperature. After 24 h of statically treating, the obtained precipitation was recovered by centrifuge, meticulous washed with deionized water and ethanol, dried overnight in an oven, and finally calcined at 550 °C for 6 h. The initial pH before APTES was added, the pH after APTES and

Aspirin was selected as a model drug, and was loaded into BMSs according to the solvent deposition method. A certain amount of BMSs was added into an ethanol solution of drug (10 mg/ml) at the drug/ carrier ratio of 1:3 (w/w). After soaked for 24 h under stirring, aspirin loaded BMS (aspirin-BMS) was separated from the mixture by vacuum drying. To measure the loading content of drug, an accurately weighed amount of aspirin-BMS was extracted completely using ethanol under ultrasound, and then aspirin content was determined by using ultraviolet spectroscopy (UV-1750, Shimadzu, Japan) at a wavelength of 225 nm.

Table 1 Solution composition of BMSs samples before silica deposition. Sample

Surfactant (g)

NaOH (ml)

HCl (ml)

H2O (ml)

Methanol (ml)

Ethanol (ml)

Pro-BMS1 Pro-BMS2 Pro-BMS3 Pro-BMS4 Trp-BMS1 Trp-BMS2 Trp-BMS3 Trp-BMS4 Trp-BMS5 His-BMS1 His-BMS2 His-BMS3 His-BMS4

0.388 0.388 0.388 0.388 0.484 0.484 0.484 0.484 0.484 0.434 0.434 0.434 0.434

10 10 5 10 10 20 10 10 10 10 20 10 10

0 10 0 0 0 0 0 0 0 0 0 0 0

10 0 15 5 10 0 5 7.5 5 10 0 5 5

0 0 0 0 0 0 5 0 0 0 0 5 0

0 0 0 5 0 0 0 2.5 5 0 0 0 5

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2.5. Characterizations

3. Results and discussion

The size distribution of the micelles formed by surfactants before APTES and TEOS added was evaluated using a Zeta-Potential/Particle Sizer (3000 HAS, UK). The morphology and porous structures of the synthesized BMSs were obtained by TEM (TEM, Tecnai G2 F30, FEI, Netherlands) operated at 200 kV. Prior to examination, low-dose of calcined samples were dispersed in ethyl alcohol through sonication and placed on carbon-coated copper grids. The N2 adsorption/desorption isotherms of BMSs were obtained at a liquid nitrogen temperature (77 K) using a surface area and pore size analyzer (Vsob-2800P, China). Before the study, samples were outgassed at 60 °C for 8 h under vacuum. The specific surface areas were evaluated by the BrunauerEmmett-Teller (BET) method using experimental nitrogen adsorption data at the relative pressure range from 0.05 to 0.2. The pore volume (Vt) and pore size distributions (DBJH) were calculated by the BarrettJoyner-Halenda (BJH) method from the corresponding adsorption branch. FTIR spectra of C16-L-aminoacids, C16-L-aminoacid micelles (extracted by freeze-drying), BMSs and aspirin-BMSs were performed on a FTIR spectrometer (Spectrum 1000, Perkin Elmer, USA). Spectra of samples were obtained from 400 to 4000 cm−1 wavenumber range in transmittance mode with a resolution of 1 cm−1. Samples were prepared by smashing and mixing with dried KBr in an agate mortar and pestle to prepare a suitable-size pellet. XRD patterns of BMSs and drug loaded samples were obtained using an X-ray diffractometer (EMPYREAN, PANalytical B.V., Netherlands). Data was recorded from 2θ 0.7° to 10° and 2θ 5° to 40°, respectively. Differential scanning calorimetry (DSC) analysis was performed on a thermal analyzer (HCT-1, China). Samples were heated from 20 to 250 °C with a heating rate of 5 °C/min under nitrogen flow.

3.1. Formation mechanism of BMSs In the present work, BMSs were synthetized on various initial synthesis conditions through the sol–gel reaction by using three kinds of synthesized heterocyclic amino acid derivatives (C16-L-His, C16-L-Pro and C16-L-Trp) as templates, TEOS as the main silica source and APTES as co-structural-directing-agent. As indicated in Fig. 2, initially, synthesized anionic surfactants (C16-L-aminoacids) self-assembled in aqueous solution to form micelles. As a kind of amphiphile, the hydrophilic head groups of C16-L-aminoacids were in contact with the surrounding solvent, sequestering the hydrophobic long carbon chain regions in the micelle centre. After that, they can self-assemble into supramolecular aggregation through H-bondings (evidenced by the FTIR results) [34]. Then alkaline environment favored the transformation of surfactants from protonation to non-protonation [18]. After addition of APTES, direct electrostatic interaction was occurred between the positively charged amino group of APTES and the negatively charged hydrophilic head group of C16-L-aminoacids. Meanwhile, in the mixture of APTES and TEOS, polymerization reaction occurred between the alkoxysilane sites of APTES and TEOS led to the formation of silica framework [25]. It is worth pointing out that, interactions occurred on the organic/inorganic hybrid interface (including interaction between C16-L-aminoacid and APTES and interaction between APTES and TEOS) favored the helical packing of surfactants. Thereby, twisty mesoscopic structure was imprinted along with the deposition of silica precursor [25,35]. Besides, monodispersed spherical particles were formed to minimize the surface free energy since the particle aggregation was driven by global surface tension forces [36]. The whole process conducted at ambient condition, in which amines effectively catalyzed the condensation of silica precursors. These all coincided with the unique features of biomineralization, therefore synthesis of BMSs can be classified to biomimetic method [15].

2.6. In vitro release Dissolution studies of samples were performed by USP paddle method in a dissolution apparatus (ZRS-8G, China) at 37 °C and 50 rpm using 250 ml of deionized water as dissolution medium. Pure aspirin (5 mg) and aspirin-BMS samples (containing 5 mg aspirin) were respectively exposed to the dissolution medium. At a predetermined time interval, 5 ml of the dissolution medium was collected, and the release system was complemented by an equivalent amount of fresh medium immediately. After filtered by 0.22 μm membrane filters, the aspirin content was measured by using ultraviolet spectroscopy (UV-1750, Shimadzu, Japan) at the wavelength of 225 nm. All in vitro studies were carried out in triplicate.

3.2. Influence of synthesis conditions Surfactant structure is the dominant factor to form BMSs, due to the fact that surfactant packing played a key role in directing the final nanostructure, and the matching of the interfacial charge density between the surfactant hydrophilic groups and hydrophobic groups controlled the kinetics of mesophase transition [25]. However, the surfactant packing was not only depended on the molecular geometry of surfactant, but the ionization degree of the surfactant. It was greatly influenced by pH, which controlled the ionization degree. In details, higher alkalinity led to higher ionization degree and higher negative charge density of surfactants, thus enhancing the electrostatic interaction between surfactant and APTES [35]. Therefore, a stronger packing energetics of the surfactants was caused by the higher electrostatic

Table 2 pH, micelle size, mesopore properties, and drug loading capacity of samples. Sample

pH 1

pH 2

pH 3

SBET (m2/g)

Vt (cm3/g)

DBJH (nm)

Average size of micelle (nm)

ASP loading content (%)

Pro-BMS1 Pro-BMS2 Pro-BMS3 Pro-BMS4 Trp-BMS1 Trp-BMS2 Trp-BMS3 Trp-BMS4 Trp-BMS5 His-BMS1 His-BMS2 His-BMS3 His-BMS4

9.25 7.86 6.05 8.66 11.09 13.05 9.72 10.02 9.45 10.20 12.21 9.81 10.76

11.25 10.34 9.25 10.18 11.42 12.56 11.28 11.29 10.88 10.96 11.88 10.54 10.75

10.45 9.74 8.74 9.06 11.24 12.12 11.07 10.88 10.35 10.06 11.42 10.36 10.35

509.14 598.89 748.11 369.23 99.78 196.23 206.79 246.14 307.02 651.28 409.08 59.02 18.18

0.63 0.68 0.75 0.48 0.26 0.85 0.68 0.45 0.41 0.94 0.46 0.35 0.14

3.42 3.03 2.71 3.43 5.47 3.75 3.66 3.84 3.03 3.23 3.63 3.51 22.37

3.85 3.76 3.52 3.75 / 4.13 3.83 3.89 3.32 3.30 3.56 / /

26.02 27.29 24.46 22.54 / 26.41 27.10 26.02 27.29 28.49 26.70 / /

410

± ± ± ±

0.98 0.57 0.33 0.52

± ± ± ± ± ±

0.11 0.78 0.29 0.24 0.53 1.05

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3.3.2. TEM The morphology of BMSs was mainly analyzed by TEM. As shown in Fig. 4, Pro-BMSs were well-formed spheres with a large number of curved mesoporous. The synthesis conditions could affect the morphology of silica delicately. Pro-BMS1 (Fig. 4(1)) was well-formed spherical nanoparticles with plenty of twisty wormlike channels, which curvature degree was largest. This was mainly because in higher pH condition, the higher ionization degree of the surfactant resulted in stronger packing energetics. In the images of Pro-BMS2, a mixture of straight and curved channels can be seen. The tortuous channels appeared partly at the outer layer of the particles and the others emerged randomly. When the synthesis process operated under even lower pH (Pro-BMS3), a feature of lattice fringes can be observed in the central of spherical particles (detailed image in Fig. 4(3)a), and few curved disordered channels were found at the edge of the particles. BMSs with uniform wormhole arrangement of curved channels can only be obtained in a narrow range of pH. It can be sketchily considered, the curvature degree of channels was increased with increasing pH. Among them, Pro-BMS1~Pro-BMS3 samples were about 200 nm in diameter, while Pro-BMS4 (Fig. 4(4)) was 200–400 nm in diameter. With ethanol as co-solvent, larger particles were obtained with many long and curved radially oriented channels. It seemed that, the decrease of cluster numbers was predominated over the slower aggregation rate in this case. TEM results of the calcined Trp-BMSs samples were presented in Fig. 5. It confirmed that Trp-BMS1 sample (Fig. 5(1)) was irregular in morphology with less-ordered mesoscopic structure, due to the huge indole group in the amino acid side chain of C16-L-Trp provided large steric hindrance for the formation of micelles. The silica yield of TrpBMS1 was extremely low (< 10%), indicated that the formulation of BMSs was hard to accomplish under this synthesis condition. With increasing pH, spherical particles were obtained with rough disordered curved channels, which were about 100 nm in diameter (Trp-BMS1, Fig. 5(2)). As can be seen from Fig. 5(3), the present of methanol as cosolvent can improve the shape of silica nanoparticles to some extent (compared to Trp-BMS1), disordered layered architecture with curved mesostructure can be detected, which were derived from the disorganized packing of C16-L-Trp. In particular, the present of ethanol can significantly improve the morphology of silica nanoparticles. As can be seen in Fig. 5(4) and (5), after using ethanol as co-solvent, monodispersed core-shell structure spherical nanoparticles with curved mesoporous were successfully prepared. Among them, Trp-BMS4 (Fig. 5(4)) was about 200 nm in diameter with a thick wall, and TrpBMS5 (Fig. 5(5)) was about 250–300 nm in diameter with a thin layer at the outside edge of the nanoparticle, indicated that the increasing of ethanol amount resulted in increase in particle size and decrease in wall thicknesses. Meanwhile, some enlarged honeycombed nanopores (pointed at in yellow square box) can be observed on the external space of the particle. Therefore, in this case, the decrease of cluster numbers caused by ethanol overcame the problem of slower aggregation rate. As can be seen in Fig. 6(1), His-BMS1 was regular spheres with uniformed size. The diameter of nanoparticles was about 200 nm with a large number of twisty nanopores. After addition of an excess amount of NaOH, less-uniformed nanospheres (His-BMS2, Fig. 6(2)) were obtained as a resulted of the uncontrolled packing energetics. Using methanol and ethanol as co-solvent conducted improvement in shape and size distribution of silica. Both His-BMS3 (Fig. 6(3)) and His-BMS4 (Fig. 6(3)) were uniformed spherical particles with smooth boundary. The diameters of these particles were about 70 nm, which were much smaller than the other His-BMSs. However, no nanopore was detected in the TEM images of His-BMS3 and His-BMS4. Herein, problems were mainly brought from the excellent dissolution of C16-L-His in methanol and ethanol, which increased the critical micelle concentration and restricted the formation of micelle, thus caused failure in self-assembly. In C16-L-His templated mesoporous silica, the effect of organic solvent on solubilization and aggregation rate was predominant over the

interaction, which commanded higher micellar curvature to build up twisty supramolecular entities [8]. What's more, as indicated in Table 2, the size of micelle which functioned as templates to determine the final mesostructures of BMSs became larger at higher pH, because the strongly non-protonation occurred at higher alkaline weakened the hydrogen bondings formed between C16-L-aminoacids, and the strongly electrostatic repulsion favored the formation of looser micelles. It should be noticed that, the formulation of mesoporous silica nanoparticle started from small disordered clusters which aggregated into large particles, and the particle size of mesoporous silica nanoparticle was determined by the nucleation number of disordered clusters and their aggregation rate [36]. The sphere diameter was increased with smaller nucleation numbers and faster the aggregation rate. When the surfactant aggregates were exposed to alcohol-water system, a much slower alcoholysis process was occurred on the hydrophilic part of C16L-aminoacids, which provided gentler packing energy and consumed longer time for surfactant packing. Meanwhile, the presence of ethanol and methanol as co-solvents significantly slowed down the condensation of silica precursors on the clusters and the hydrolysis reaction of TEOS, which impeded both the cluster formation and aggregation [36,37]. In that sense, organic co-solvents were unfavorable for the formation of micelles because of their higher dissolving capacity for the synthetized surfactants, which caused reduction in both the numbers and size of micelles (Table 2). In fact, the influence of ethanol on the mesostructure and particle size of BMSs depends on the conflict between the modulation of silica deposition and the suppression of micellization.

3.3. Characterization of BMSs 3.3.1. FTIR The FTIR spectra of samples were shown in Fig. 3. In the FTIR spectra of C16-L-aminoacids, two particular bands of –CH2 stretching were respectively found around 2919 cm−1 and 2850 cm−1, and characteristic bands of the long carbon chain were found around 720 cm−1 [8]. Stretching vibration of carbonyl groups assigned to carboxylic acid appeared at 1732.1 cm−1, 1713.1 cm−1 and 1721.5 cm−1 for C16-L-Pro, C16-L-Trp and C16-L-His specimens, respectively. Meanwhile, stretching vibrations of carbonyl groups were shown around 1642 cm−1 for all the synthesized polymers. However, symmetrical stretching vibration of eNH group was not detected in spectrograms of C16-L-Pro, demonstrating the absence of secondary amide, because amines cyclized and existed in forms of tertiary amines in C16-LPro. In the FTIR spectra of the micelle samples, the bands corresponding to the carbonyl groups were shifted to lower wavenumbers (C16-L-Pro micelles: from 1732.1 cm−1 to 1728.3 cm−1, C16-L-Trp micelles: from 1713.1 cm−1 to 1709.5 cm−1 and C16-L-His micelles: from 1714.5 cm−1 to 1711.3 cm−1). Meanwhile, red shift was also observed in the bands relative to –OH groups (C16-L-Pro micelles: from 3442.3 cm−1 to 3423.8 cm−1, C16-L-Trp micelles: from 3417 cm−1 to 3411 cm−1, C16-LHis micelles: from 3438.5 cm−1 to 3425.1 cm−1). The red shifts of –OH group and C]O group bands suggested that hydrogen bonds were formed during the formation of supramolecular aggregation. After NaOH was added, the bands around 1720.2 cm−1 belonging to carbonyl groups were disappeared and replaced by two new bands around 1560.5 cm−1 and 1400.5 cm−1 characterized for carboxylate (C16-L-Pro micelles: at 1559.2 cm−1 and 1397.7 cm−1, C16-L-Trp micelles: 1562.1 cm−1 and 1400.0 cm−1, C16-L-His micelles: 1560 cm−1 and 1400 cm−1), which strongly confirmed the successful non-protonation of surfactants. After calcination, BMSs were successfully synthesized evidenced by Si–O–Si bending vibration at 465.1 cm−1 and Si–O–Si antisymmetric stretching vibration at 1099.6 cm−1, which were characteristic bands of silica [28].

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Fig. 3. A, FTIR spectra of C16-L-Pro, C16-L-Pro micelles, C16-L-ProNa micelles and Pro-BMS; B, FTIR spectra of C16-L-Trp, C16-L-Trp micelles, C16-L-TrpNa micelles and Trp-BMS; C, FTIR spectra of C16-L-His, C16-L-His micelles, C16-L-HisNa micelles and His-BMS; D, FTIR spectra of aspirin, the physical mixture of aspirin and BMSs (1:3, w/w), aspirin-BMSs and BMSs.

Furthermore, the large hindrance of indole group hindered the formation of H-bondings, and disorganized the orientation arrangement of micellar aggregation which functioned as templates to determine the final mesostructure of BMSs. As a result of the less-ordered arrangement of micelles, Trp-BMSs possessed disordered architecture. It can be speculated that the structure of Trp-BMSs were not well-ordered and the pore channels were randomly arranged (Fig. 5). The XRD patterns of the samples based on histidine-derivative were shown in Fig. 7C. In the XRD pattern of His-BMS1, the first peak was observed at 2θ 1.60°, the second peak was observed at 2θ 2.76°, suggesting the formulation of mesostructure. Besides, His-BMS2 synthesized at higher pH had less ordered structure according to the rearward shift of diffraction peak and the decrease of peak intensity. However, in the XRD patterns of His-BMS3 and His-BMS4, no well-resolved peak appeared in the 2θ range of 0.7–6.0°, which cannot be indexed to any mesostructure.

decrease of cluster numbers.

3.3.3. XRD Fig. 7A showed the XRD patterns of these template-free Pro-BMSs. In the XRD pattern of Pro-BMS1, the main peak appeared at 2θ 1.7°, and the second peak appeared at 2θ 2.9°, implying the successful forming of mesostructure using C16-L-Pro as template. In XRD patterns of Pro-BMS2 and Pro-BMS3, the main peaks moved to 2θ 1.60° and 2θ 1.52° respectively, and were increased in intensity, implying the order degree of the mesostructure was increased with decreasing basicity and the dspacing was also increased with decreasing basicity. According to the TEM observation, it can be sketchily considered that with increasing pH, the pore structure of BMSs tended to change from ordered lattice fringes arrangement to disordered worm-like arrangement as a result of a stronger packing energetics of the surfactant, and the order degree decreased during this process due to the shorter time consumption for energy transfer. Besides, with the presence of ethanol as co-solvent, the XRD pattern showed a single broad peak at 2θ 1.58°, demonstrating a low long-range ordered porous arrangement existed in Pro-BMS4. As can be seen in Fig. 7B, no high ordering peaks were detected in the 2θ range of 0.7–6.0° from the XRD patterns of calcined Trp-BMSs samples. In the self-assembly of C16-L-Trp, the indole group in the amino acid side chain provided large steric hindrance for the gather of hydrophilic head groups, and was adverse for the formation of micelles.

3.3.4. Nitrogen adsorption/desorption isotherms Nitrogen adsorption–desorption isotherms and pore size distribution curves of the samples were displayed in Fig. 8, and the calculated parameters were presented in Table 2. Typical type IV isotherms were shown for Pro-BMSs samples with pronounced capillary condensation steps, implying the presence of uniform mesopores. As shown in Table 2, with decreasing pH, a significant increase in SBET and Vt, and 412

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Fig. 4. TEM images of Pro-BMS1 (1-a and 1-b), Pro-BMS2 (2-a and 2-b), Pro-BMS3 (3-a and 3-b) and Pro-BMS4 (4-a and 4-b).

and 307.02 m2/g, while the average pore diameter was respectively decreased to 3.84 nm and 3.03 nm as a result of the attenuation of micelle size caused by ethanol. The nitrogen adsorption/desorption isotherms of His-BMS1 and HisBMS2 were both representative type IV isotherms with clear capillary condensation steps, confirming the presence of uniform mesopores. With increasing pH, the SBET and Vt were reduced, while the pore diameter was increased. Meanwhile, the capillary condensation step of His-BMS1 sample was sharper than His-BMS2 sample, indicated that mesopores became less uniform with increase pH, which was in good consistency with the XRD results. It was worth pointing out that, among the three kinds of BMSs synthesized under the same condition, HisBMS1 templated by C16-L-His had the largest SBET and Vt compared to Pro-BMS1 and Trp-BMS1, due to the existence of imidazole which contributed to the transformation between protonation and non-protonation. In the nitrogen adsorption/desorption isotherms of His-BMS3

decrease in pore size were observed. The pore size of BMSs was positively correlated with the size of micelle, which became larger at higher pH. After the addition of ethanol, the SBET and Vt of Pro-BMS4 sample were respectively reduced to 369.23 m2/g and 0.48 cm3/g, while the average pore diameter was controlled in almost constant level. As shown in Fig. 8C, the nitrogen adsorption–desorption isotherms of the all template-free Trp-BMSs exhibited the type IV pattern, indicating the presence of mesopores. In the nitrogen adsorption–desorption isotherm of Trp-CMS5, the capillary condensation step at a relative pressure of 0.55–0.95 strongly confirmed the presence of macopores in the shell. Besides, the SBET and Vt of Trp-BMS2~TrpBMS5 were all much larger than that of Trp-BMS1. In conjunction with the TEM and XRD results, it is reasonable to estimate that, in the synthesis of Trp-BMSs, both NaOH and organic alcohol favored the forming of mesopores. For samples synthesized with increasing amount of ethanol, the surface area was respectively increased to 246.14 m2/g

Fig. 5. TEM images of Trp-BMS1 (1-a and 1-b), Trp-BMS2 (2-a and 2-b), Trp-BMS3 (3-a and 3-b) and Trp-BMS4 (4-a and 4-b). 413

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Fig. 6. TEM images of His-BMS1 (1-a and 1-b), His-BMS2 (2-a and 2-b), His-BMS3 (3-a and 3-b) and His-BMS4 (4-a and 4-b).

Fig. 7. XRD patterns of samples. A, XRD patterns of template-free Pro-BMSs; B, XRD patterns of template-free Trp-BMSs; C, XRD patterns of template-free His-BMSs; D, XRD patterns of (a), BMSs; (b) aspirin-BMSs; (c) physical mixture of aspirin and BMSs (1:3 w/w); d, aspirin. 414

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Fig. 8. A, Nitrogen adsorption/desorption isotherms of Pro-BMSs; B, Pore size distribution curves of Pro-BMSs; C, Nitrogen adsorption/desorption isotherms of TrpBMSs; D, Pore size distribution curves of Trp-BMSs; E, Nitrogen adsorption/desorption isotherms of His-BMSs; F, Pore size distribution curves of His-BMSs.

3.4. Functionalities of BMSs as aspirin carrier

and His-BMS4, no capillary condensation step was observed, and the values of SBET and Vt were extremely low. Based on the results of TEM, XRD and N2 adsorption/desorption isotherms, it is reasonable to speculate that no mesostructure was existed with the presence of organic alcohol as co-solvent, and the problem was caused by the excellent dissolving capacity of organic alcohol.

3.4.1. Aspirin loading content Aspirin was loaded into BMSs by using solvent deposition method and the drug loading contents of aspirin-BMSs were measured and summarized in Table 2. As shown in Table 2, aspirin can be successfully loaded into BMSs and the drug loading content was within the range of 22.54% to 28.01%. The results indicated that aspirin could be loaded into BMSs with high efficiency, and only a small quantity of aspirin was 415

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BMS1 and aspirin-His-BMS2 released extremely fast (Fig. 9B and C), > 99% drug dissolved out within 20 min. Particularly, aspirin-TrpBMS4 and aspirin-Trp-BMS5 released much gradually, the accumulative release percentage could reach 100% within 60 min. As a key strategy for drug release improvement, the mesoscopic channels of mesoporous silica carriers favored the amorphization of the drug (confirmed by XRD and DSC studies), due to the geometrical space confinement on drug crystallization. To further analysis the release kinetic, the obtained release data was fitted into Ritger-Peppas equation (data not shown). For all aspirin-BMSs, the R2 values obtained for Ritger-Peppas model were all within the range of 0.937–0.998, and the values of exponent n in Ritger-Peppas model (which defined the release mechanism) were all within the range of 0.011–0.103, corresponding to the Fickian diffusion [40–42]. This finding was in accordance with many previous studies that drug release from mesoporous carriers was a mainly diffusion-controlled process [31–34,43]. It had been verified that, the release behaviors of mesoporous silica were controlled by their mesostructure. In this case, the prominent release performance of BMSs can be attributed to the architectures, in which the short interconnected and curved mesoporous channels could reduce the mass transfer resistance during diffusion process. It should be noticed that, the release behaviors of drug loaded samples can be regulated by the architectures of carrier. In details, the cumulative release amounts within 20 min followed the sequence: aspirin-Pro-BMS1 > aspirin-Pro-BMS2 > aspirin-Pro-BMS3, which was consistent with the pore diameter sequence. Pro-BMS1 with the largest pore size possessed smallest diffusion resistance and fastest release rate. Compared to Pro-BMS1~ProBMS3, Pro-BMS4 had larger particle size, longer internal channels and more distinct shell structure, resulting in longer diffusion distance and higher diffusion resistance for aspirin to dissolve in the bulk solution. As a result, the release rate of aspirin-Pro-BMS4 was the slowest among all Pro-BMSs. This tendency became even more pronounced in the case of aspirin-Trp-BMS4 and aspirin-Trp-BMS5, Trp-BMS5 with larger particle size and thicker shell structure had slower release rate. In conclusion, based on the beneficial pore architectures, BMSs could provide controllable favorable dissolution-promoting functionality.

lost during the drug loading process. The high drug loading capacity of BMSs was a necessary precondition for its application as carrier of sustained-release and controlled-release formulations. The drug loading capacity was a combination function of pore volume, pore diameter and pore morphology [30]. In this study, most of drug loading capacity of BMSs was positively correlated with pore volume the drug the loading capacity of BMSs was positively correlated with their total pore volume. For example, His-BMS1, with the largest pore volume, possessed the highest drug loading capacity. In particular, the smaller pore size and the separated long lattice fringes networks of Pro-BMS3 limited the accessibility of pores, provided larger steric hindrance for drug loading. In this case of Trp-BMS3, most of the drug was loaded into the highly accessible outer layer of Trp-BMS3, resulting in a larger drug loading content. 3.4.2. FTIR Fig. 3D displayed the FTIR spectra of aspirin and aspirin-BMSs. For aspirin, the characteristic bands at 1690.4 cm−1 and 1605.5 cm−1 were attributed to the C]O vibration of carbonyl group and C]C vibration of benzene ring, respectively [38]. The FTIR spectra of the physical mixture was just the superposition of the two components. After drug loading, most of the aspirin characteristic bands disappeared, implying that aspirin was successfully loaded into BMSs. Moreover, bands in the region of 3300–2300 cm−1 relative to eOH stretching vibration disappeared gradually with red shift of C]O stretching vibration of carbonyl group from 1704.2 cm−1 to 1690.4 cm−1, suggesting that hydrogen bonds were formed between the carbonyl groups of aspirin and silanol groups of BMSs during the drug loading process [39]. 3.4.3. XRD and DSC The crystalline state of aspirin before and after drug loading can be determined by XRD and DSC. As shown in Fig. 7D, the XRD pattern of aspirin was highly crystalline in nature as indicated by multiply classic peaks. The pattern of BMSs was amorphous as characterized by a broad band between 2θ 5° to 40°, and the pattern of the physical mixture of aspirin and BMSs (1:3 w/w) was crystalline with reduction of peak intensity. However, after drug loading, no crystalline aspirin was detected in aspirin-BMSs, demonstrating that aspirin was loaded into BMSs in amorphous state due to the space confinement. Fig. 9D showed the DSC curves of aspirin, BMSs and aspirin-BMSs. Among them, the DSC curve of BMSs was almost a smooth line, suggesting that BMSs was a kind of amorphous materials. DSC curve of aspirin showed a single endothermic peak at 141.7 °C. Besides, the endothermic peak of crystallographic aspirin in the DSC curve of physical mixture can be easily detected with reduction of peak intensity. However, after being loaded into BMSs, no melting peak for drug was detected in the DSC curve of aspirin-BMSs, suggesting that aspirin was existed in amorphous state, which was in good agreement with the XRD result. It should be noticed that, the suppression of drug crystallization can be attributed to the limited nanoporous space and the curved mesoscopic structure of BMSs.

4. Conclusion Mesoporous silica nanospheres with curved mesoscopic channels were biomimetic synthesized based on three kinds of heterocycle-containing amino acid derivatives via co-structural-directing-agent method. Systematic studies were carried out to investigate the effect of the surfactant structure, pH and co-solvent on the formulation of the BMSs. Among them, the molecular structure of amphiphiles was the dominant factor to direct the final morphology of BMSs and the arrangement mode of nanopores due to the fact that the structures of the surfactant played important roles in the formation of micelles. Besides, the mesostructure of silica were extremely sensitive to pH, which controlled the ionization degree. It seemed that BMSs with uniform wormhole arrangement of curved channels can only be obtained in a narrow range of pH. Meanwhile, the presence of ethanol can significantly increase the particle size and reduce the pore diameter of BMSs. By tuning the reaction conditions, the morphologies of the final products are controllable. Then, BMSs were successfully developed as nanocarriers to improve the dissolution rate of aspirin. Aspirin can be loaded into BMSs with high efficiency, and drug effectively transformed to amorphous state due to the space confinement. On account of the correlations between the synthesis condition, the silica morphology and the controlled release function, the biomimetic method presented here is competent for the synthesis of BMSs and is promising to be impelled in practical application of drug delivery.

3.4.4. In vitro drug release study A series of aspirin-Pro-BMSs, aspirin-Trp-BMSs and aspirin-HisBMSs samples were prepared, their release behaviors were investigated, and the release profiles were presented in Fig. 5A–C, respectively. It turned out that, the functionality of BMSs for aspirin-release was significant. By loading into BMSs, aspirin presented extremely fast dissolution rate, and the dissolution increased from 72.8% to 100% within 90 min. As shown in Fig. 5A, all aspirin-Pro-BMSs samples released much faster than pure aspirin. Among them, best result came out from aspirin-Pro-BMS1 which could release 100% of aspirin within 20 min, compared to that of pure aspirin which released only 54.9%. Meanwhile, aspirin released 97.9%, 96.3% and 92.1% within 20 min for aspirin-Pro-BMS2, aspirin-Pro-BMS3 and aspirin-Pro-BMS4, respectively. Similarly, aspirin-Trp-BMS2, aspirin-Trp-BMS3, aspirin-His-

Acknowledgements This work was supported by the National Natural Science 416

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Fig. 9. A-C, In vitro release profiles of samples in water, A, aspirin-Pro-BMSs; B, aspirin-Trp-BMSs; C, aspirin-His-BMSs; D, DSC curves of (a) BMSs; (b) aspirin-BMSs; (c) physical mixture of aspirin and BMSs (1:3 w/w); d, aspirin.

Foundation of China (No. 81773672) and China Postdoctoral Science Foundation (No. 2016M590235).

[10]

References [11]

[1] S. Fekete, M. Rodriguez-Aller, A. Cusumano, R. Hayes, H. Zhang, T. Edge, Prototype sphere-on-sphere silica particles for the separation of large biomolecules, J. Chromatogr. A 1431 (2016) 94–102. [2] G. Jin, D. Yu, Z. Guo, D. Yang, H. Zhang, A. Shen, Preparation of glyco-silica materials via thiol-ene click chemistry for adsorption and separation, RSC Adv. 6 (11) (2016) 8584–8587. [3] C. Chen, L.W. Finger, R.C. Medrud, C.L. Kibby, P.A. Crozier, I.Y. Chan, Synthesis, structure, and physicochemical and catalytic characterization of the novel highsilica large–pore zeolite ssz–42, Chem-Eur. J. 4 (7) (2015) 1312–1323. [4] K. Lim, J. Che, J. Lee, Experimental study on adsorption characteristics of a water and silica-gel based thermal energy storage (tes) system, Appl. Therm. Eng. 110 (2017) 80–88. [5] M.I. Zaki, M.A. Hasan, A.S. And, L. Pasupulety, Surface chemistry of acetone on metal oxides: IR observation of acetone adsorption and consequent surface reactions on silica−alumina versus silica and alumina, Langmuir 16 (2) (2016) 430–436. [6] M.L. Delacour, E. Gailliez, M. Bacquet, M. Morcellet, Poly(ethylenimine) coated onto silica gels: adsorption capacity toward lead and mercury, J. Appl. Polym. Sci. 73 (6) (2015) 899–906. [7] B. Wang, L. Zhang, B. Li, Y. Li, Y. Shi, T. Shi, Synthesis, characterization, and oxygen sensing properties of functionalized mesoporous silica SBA-15 and MCM4141 with a pt(II)–porphyrin complex, Sensors Actuators B Chem. 190 (190) (2014) 93–100. [8] H. Li, J. Wang, J. Cong, C. Wei, J. Li, H. Liu, S. Li, M. Yang, Biomimetic synthesis of proline-derivative templated mesoporous silica for increasing the brain distribution of diazepam and improving the pharmacodynamics of nimesulide, Drug Deliv. 24 (1) (2017) 1086–1098. [9] J. Liu, C. Wang, X. Wang, X. Wang, L. Cheng, Y. Li, Mesoporous silica coated single-

[12]

[13] [14]

[15]

[16] [17] [18] [19] [20]

[21] [22]

417

walled carbon nanotube served as drug carrier used for cancer combination therapy, Nanomedicine 12 (2) (2016) 522–523. S. Hashemikia, N. Hemmatinejad, E. Ahmadi, M. Montazer, Antibacterial and antiinflammatory drug delivery properties on cotton fabric using betamethasone-loaded mesoporous silica particles stabilized with chitosan and silicone softener, Drug Deliv. 23 (8) (2016) 2946–2955. D. Ling, L. Gao, J. Wang, M. Shokouhimehr, J. Liu, Y. Yu, A general strategy for sitedirected enzyme immobilization by using nio nanoparticle decorated mesoporous silica, Chemistry 20 (26) (2014) 7916–7921. S. Matsunaga, R. Sakai, M. Jimbo, H. Kamiya, P-283 long-chain polyamines from marine sponge: implication in the silicon biomineralization in sponges, J. Infect. Dis. 203 (12) (2017) 1784–1790. R.R. Naik, P.W. Whitlock, F. Rodriguez, Controlled formation of biosilica structures in vitro, Chem. Commun. 9 (2) (2003) 238–239. K. Motomura, T. Ikeda, S. Matsuyama, M.A. Abdelhamid, T. Tanaka, T. Ishida, The c-terminal zwitterionic sequence of cotb1 is essential for biosilicification of the bacillus cereus spore coat, J. Bacteriol. 198 (2) (2015) 276–282. J. Ford, S. Yang, Directed synthesis of silica nanoparticles on micropatterned hydrogel templates tethered with poly(ethyleneimine), Chem. Mater. 19 (23) (2007) 5570–5575. R.H. Jin, J.J. Yuan, Shaped silicas transcribed from aggregates of four-armed star polyethyleneimine with a benzene core, Chem. Mater. 18 (2006) 3390–3396. E. Licsandru, E. Petit, S. Moldovan, O. Ersen, M. Barboiu, Biomimetic autocatalytic synthesis of organized silica hybrids, Eur. J. Inorg. Chem. 22 (2015) 3637–3641. T. Yokoi, T. Tatsumi, Synthesis of mesoporous silica materials by using anionic surfactants as template, J. Jpn. Pet. Inst. 50 (6) (2007) 299–311. Z. Xue, Y. Zhao, L. Wu, Y. Li, B. Li, M. Wang, A chirality indicator for the surfaces of the silica nanotubes, J. Nanosci. Nanotechnol. 13 (8) (2013) 5732–5735. R. Atluri, M.N. Iqbal, Z. Bacsik, N. Hedin, L.A. Villaescusa, A.E. Garcia-Bennett, Selfassembly mechanism of folate-templated mesoporous silica, Langmuir 29 (38) (2013) 12003–12012. S. Che, L. Zheng, O. Tetsu, S. Kazutami, T. Osamu, T. Takashi, Synthesis and characterization of chiral mesoporous silica, Nature 429 (2004) 281–284. H. Jin, H. Qiu, C. Gao, S. Che, Synthetic design towards targeted chiral anionic surfactant templated chiral mesoporous silica, Microporous Mesoporous Mater. 116

Materials Science & Engineering C 93 (2018) 407–418

H. Li et al.

insoluble cilostazol, Drug Dev. Ind. Pharm. 40 (6) (2014) 819–828. [34] Y. Zhao, Z. Huang, Z. Yan, S. Wang, B. Li, Y. Li, Preparation of frustule-like 1,2ethylene-silica nanospheres through a chiral amphiphile/organic solvent dualtemplating approach, Mater. Res. Bull. 48 (2) (2013) 367–371. [35] J. Li, L. Xu, B. Yang, Z. Bao, W. Pan, S. Li, Biomimetic synthesized chiral mesoporous silica: Structures and controlled release functions as drug carrier, Mater. Sci. Eng. C 55 (2015) 367–372. [36] Q. Chen, L. Han, C. Gao, S. Che, Synthesis of monodispersed mesoporous silica spheres (mmsss) with controlled particle size using gemini surfactant, Microporous Mesoporous Mater. 128 (1–3) (2010) 203–212. [37] O.I. Lebedev, G. Van Tendeloo, O. Collart, P. Cool, E.F. Vansant, Structure and microstructure of nanoscale mesoporous silica spheres, Solid State Sci. 6 (2004) 489–498. [38] S. Huang, C. Li, Z. Cheng, F. Yong, P. Yang, C. Zhang, Magnetic Fe3O4 @mesoporous silica composites for drug delivery and bioadsorption, J. Colloid Interface Sci. 376 (1) (2012) 312–321. [39] L. Gao, J. Sun, Y. Li, Functionalized bimodal mesoporous silicas as carriers for controlled aspirin delivery, J. Solid State Chem. 184 (8) (2011) 1909–1914. [40] E.S. Dolinina, M.I. Vlasenkova, E.V. Parfenyuk, Effect of trehalose on structural state of bovine serum albumin adsorbed onto mesoporous silica and the protein release kinetics in vitro, Colloids Surf. A Physicochem. Eng. Asp. 527 (2017) 101–108. [41] S. Jangra, P. Girotra, V. Chhokar, V.K. Tomer, A.K. Sharma, S. Duhan, In-vitro drug release kinetics studies of mesoporous sba-15-azathioprine composite, J. Porous. Mater. 23 (3) (2016) 679–688. [42] V. Venkateswarlu, M. Kopparam, Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles, J. Control. Release 95 (3) (2004) 627–638. [43] H. Li, H.T. Li, C. Wei, J. Ke, J. Li, L. Xu, Biomimetic synthesis and evaluation of histidine-derivative templated chiral mesoporous silica for improved oral delivery of the poorly water-soluble drug, nimodipine, Eur. J. Pharm. Sci. 117 (2018) 321–330.

(1) (2008) 171–179. [23] S. Che, Y. Sakamoto, O. Terasaki, T. Tatsumi, The structure and morphology control of mesoporous silica under acidic conditions, Microporous Mesoporous Mater. 85 (3) (2005) 207–218. [24] L. Wu, Y. Shan, Y. Chen, Y. Li, B. Li, Preparation of mesoporous silica nanoflakes and nanospheres with perpendicular pore channels, J. Nanosci. Nanotechnol. 12 (3) (2012) 2037. [25] J. Li, L. Xu, N. Zheng, H.Y. Wang, F.Z. Lu, S.M. Li, Biomimetic synthesized bimodal nanoporous silica: bimodal mesostructure formation and application for ibuprofen delivery, Mater. Sci. Eng. C 58 (2016) 1105–1111. [26] Y. Zhu, S. Kaskel, J. Shi, T. Wage, K.H.V. Pée, Immobilization of trametes versicolor laccase on magnetically separable mesoporous silica spheres, Chem. Mater. 19 (26) (2017) 6408–6413. [27] A. Goux, M. Etienne, E. Aubert, C. Lecomte, J. Ghanbaja, A. Walcarius, Oriented mesoporous silica films obtained by electro-assisted self-assembly (easa), Chem. Mater. 21 (4) (2009) 731–741. [28] Y. Wang, Q. Zhao, N. Han, L. Bai, J. Li, J. Liu, Mesoporous silica nanoparticles in drug delivery and biomedical applications, Nanomedicine 11 (2) (2015) 313–327. [29] L. Bai, Q. Zhao, J. Wang, Y. Gao, Z. Sha, D. Di, Mechanism study on ph-responsive cyclodextrin capped mesoporous silica: effect of different stalk densities and the type of cyclodextrin, Nanotechnology 26 (16) (2015) 165704. [30] R.A. Perez, R.K. Singh, T.H. Kim, H.W. Kim, Silica-based multifunctional nanodelivery systems toward regenerative medicine, Mater. Horiz. 4 (2017) 772. [31] I. Izquierdo-Barba, E. Sousa, J.C. Doadrio, A.L. Doadrio, J.P. Pariente, A. Martínez, Influence of mesoporous structure type on the controlled delivery of drugs: release of ibuprofen from mcm-48, sba-15 and functionalized sba-15, J. Sol-Gel Sci. Technol. 50 (3) (2009) 421–429. [32] W. Zhu, L. Wan, C. Zhang, Y. Gao, X. Zheng, T. Jiang, Exploitation of 3d facecentered cubic mesoporous silica as a carrier for a poorly water soluble drug: influence of pore size on release rate, Mater. Sci. Eng. C 34 (1) (2014) 78–85. [33] Y. Wang, L. Sun, T. Jiang, J. Zhang, C. Zhang, C. Sun, The investigation of mcm-48type and mcm-41-type mesoporous silica as oral solid dispersion carriers for water

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