Design and preparation of mesoporous silica carriers with chiral structures for drug release differentiation

Materials Science & Engineering C 103 (2019) 109737

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Design and preparation of mesoporous silica carriers with chiral structures for drug release differentiation ⁎

Yumei Wanga, Wei Lia, Tiaotiao Liua, Lu Xua, Yingyu Guoa, Jia Kea, Sanming Lia, , Heran Lib, a b

T

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School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China School of Pharmacy, China Medical University, Shenyang 110122, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Release differentiation Biomimetic synthesis Chiral mesoporous silica Induced circular dichroism Ibuprofen

In this study, twisted rod-like chiral mesoporous silicas (CMSs) with discriminating chiral characteristics (D/L) were designed and biomimetic synthesized by using L- and D-alanine derivatives as templates, and employed as poorly water-soluble chiral drug ibuprofen (IBU) carriers. The morphology and mesoscopic characteristics of CMSs were determined by transmission electron microscope (TEM) and small-angle X-ray scattering (SAXS). Meanwhile, the physicochemical properties of CMSs before and after drug loading were systematically characterized by infrared spectroscopy (IR), nitrogen adsorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and induced circular dichroism (ICD). The results suggested that, the CMSs exhibited local chiral characteristics, which were successfully endowed by the alanine-derivative surfactants templates with a reversal of chirality. The crystalline state of IBU was effectively converted to amorphous state after being incorporated into CMSs, and the drug delivery systems shared the chiral characteristic of carriers. Besides, in vitro drug release experiments were respectively performed in simulated gastric fluid (SGF, pH 1) and simulated intestinal fluid (SIF, pH 6.8) medium, and the results demonstrated that both L-CMS and D-CMS could improve the dissolution of IBU in SGF medium, which could be explained by the amorphization of IBU. Particularly, due to the different pore geometry of these two materials, CMSs with different chirality (D/L) could be applied as carriers to accomplish drug release differentiation.

1. Introduction Since the discovery of M41S with mesoscale structures in the early 1990s, mesoporous silica nanoparticles (MSNs) have attracted much attention because of the emerging applications in adsorption, catalysis, separations, sensors and drug delivery [1,2]. In recent decades, the design and preparation of MSNs with a novel mesostructure has become a new fashion because of their prominent characteristics including relatively large specific surface area and pore volume, controlled pore size, excellent pore structure, morphological diversity, easily modified surface, in vivo degradability and biosafety [3]. Many efforts have focused on the control of morphologies, hierarchical structures, pore orientations and pore sizes of MSNs [4–6]. Compared to traditional topdown fabrication methods, biosilicification inspired by beautiful silica skeletons has become one of the hottest topics among material science, because it involves unprecedented characteristics including efficient cascade reactions and mild synthesis conditions [7–9]. Additionally, it is reported that biosilicification can be achieved by adding catalysts to

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effectively promote the condensation of silica precursors [10,11]. Therefore, MSNs synthesized with this method have many advantages such as hierarchical structures, multiple morphologies and adjustable nanopores, which are mainly attributed to the complex and diverse organization of Si-O-Si framework [12,13]. Chiral mesoporous silica (CMS) is an important branch of MSNs since chirality is one of the fundamental issues in the related fields of biology, physics, materialogy and medicine [14,15]. Especially, in solid minerals and inorganic materials, chirality which arises from the geometric properties and the atomic structure of surfaces is always associated with a helical structure on both the microscopic and macroscopic levels [16,17]. Therefore, chiral materials, such as periodic mesoporous organosilicas [18,19], functionalized mesoporous silicas [20,21] and chiral imprinting polymers [22], have attracted increasing attention on account of their potential applications in heterogeneous asymmetric catalysis [23,24], chiral adsorption and separation [25–27], chemical sensors and drug delivery [28,29]. Kim and Yang firstly reported mesoporous silica with helical channels by using the cationic surfactant as

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

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https://doi.org/10.1016/j.msec.2019.109737 Received 6 August 2018; Received in revised form 21 March 2019; Accepted 8 May 2019 Available online 10 May 2019 0928-4931/ © 2019 Elsevier B.V. All rights reserved.

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ester. Myristic acid (2.851 g, 1.0 mmol), HOBT (1.350 g, 1.0 mmol) and EDCI (1.917 g, 1.0 mmol) were introduced into the above solution with 5 ml DCM as catalyst. After that, the mixture was agitated in 0 °C ice bath for 1 h and transferred to a 45 °C oil bath for 6 h. Thin layer chromatography (TLC) was used to supervise the reaction until yellow liquid was obtained. The reaction solution was placed under reduced pressure to remove DCM and then mixed with the saturated aqueous solution of NaHCO3 to acquire the precipitates. Afterwards, the crude product (C14-L-Ala methyl ester) was filtered, sufficiently washed with water and dried at 37 °C. In order to further purification, the crude product was processed with crystallization using ethyl acetate/nhexane (3/1, v/v). Afterwards, the above precipitates were refluxed with 1.5 mol/l NaOH composed of 70% ethyl alcohol and 30% water(v/ v) under stirring in 70 °C oil bath for 1.5 h. Then ethyl alcohol was removed using reduced pressure distillation. The remaining solution was acidified to pH 2–3 by 0.1 M HCl. Finally, the solution was filtered, carefully washed, and dried to obtain N-myristyl-L-alanine (C14-L-Ala). 1 H NMR (400 MHz, CDCl3) δ 12.32 (m, 1H), 8.06 (d, 1H), 4.18 (m, 1H), 2.10 (t, 3H), 1.47 (d, 2H), 1.24 (d, 22H), 0.86 (t, 3H). N-myristyl-D-alanine (C14-D-Ala) was prepared by the same method, except that D-alanine methyl ester hydrochloride was used instead of Lalanine methyl ester hydrochloride. 1H NMR (400 MHz, CDCl3) δ 12.35 (m, 1 H), 7.98 (d, 1 H), 4.14 (m, 1 H), 2.12 (t, 3 H), 1.46 (d, 2 H), 1.25 (d, 22 H), 0.85 (t, 3 H).

templates [30]. Che et al. employed chiral amino acid as templates to synthesize single chiral mesoporous silica and successfully transferred chirality from organic chemistry to inorganic materials [31]. Izutsu et al. skillfully designed spherical chiral mesoporous silica by impregnating the internal cavity with L-tartaric acid, and applied it to separate chiral Co complexes successfully [32]. Li et al. prepared chiral functionalized MSN by using a novel silane coupling agent (APTTES) synthesized with 3-aminopropyl-triethoxysilane (APTES) and L-tartaric acid [33]. Comparing to naked non-functionalized MSN, chiral functionalized MSN favored the sustained release of famotidine and doxorubicin due to its long mesoporous channels [34]. The design and preparation of novel CMSs continues to be a promising research field due to the growing demands in the pharmaceutical industry. However, few attention have been paid on the drug delivery system based on CMSs and the drug release differentiation of materials with different chiral characteristics. Ibuprofen (IBU) is a long-term nonsteroidal anti-inflammatory drug used for relieving symptoms of pain and inflammation in a variety of rheumatoid arthritis and musculoskeletal [35]. Due to its safety and effectiveness, IBU is also employed as the child medication for the treatment of acute pain and fever [36]. As one of the chiral drugs, the metabolism of IBU involves chiral transformation from the relatively inactive R-enantiomers to its active S-antipodes in vivo, and the pharmacological activity of IBU is mainly produced by the corresponding (S)-enantiomer, while the (R)-enantiomer is unexpected enantiomer as it can give rise to the side effects or toxicity [37]. Actually, IBU was commercially available in form of racemate, and it is an excellent candidate to study the drug control-release function of chiral carriers [38]. In this study, twisted rod-like CMSs were successfully prepared by using biomimetic method. In the synthesis process, L- and D-alanine derivatives were selected as templates, 3-aminopropyl-triethoxysilane (APTES) was used as co-structure directing agent (CSDA), and tetraethoxysilane (TEOS) was employed as inorganic silica source. The morphology and mesoscopic characteristics of CMSs were determined by using TEM and SAXS. Meanwhile, IBU was loaded into CMSs, and the physicochemical properties of CMSs before and after drug loading were systematically characterized by using IR, nitrogen adsorption, XRD and DSC. Particularly, ICD was introduced to characterize the chiral information of chiral templates, CMSs, IBU and IBU loaded CMSs [39,40]. Innovatively, the drug loading and release differentiation of IBU are thoroughly studied to explore the function of CMSs as chiral carries and further provide useful information to design CMSs for accomplishing drug release differentiation in the pharmaceutical industry [22,41–43].

2.3. Preparation of CMSs CMSs were prepared by using C14-L-Ala and C14-D-Ala as templates, APTES as CSDA, and TEOS as silica source. The synthesis process of CMSs was referred to Che's report, with some modifications [44]. Briefly, C14-L/D-Ala (0.297 g, 1 mmol) was sufficiently dissolved in a solution of 30 ml deionized water and 10 ml NaOH (0.1 mol/l, 1 mmol) with vigorous stirring at 600 rpm for 30 min. After cooling to room temperature, 2 ml HCl (0.1 mol/l, 0.2 mmol) was added to partially acidify the salt, and the homodisperse colloidal solution was obtained after agitating for 10 min. The sol-gel process was carried out by dropwise (one drop per second) adding the mixture of APTES (0.091 ml, 0.39 mmol) and TEOS (1.5 ml, 6.72 mmol) into the above solution under stirring at the speed of 500 rpm. The reaction was lasted for 5 min and was remained statically for 1 d at room temperature. After that, the reaction system was transferred into an oil bath at 80 °C for 1 d. Afterwards, the white product was collected by centrifugal separation, water washing and freeze drying. Finally, templates were removed by calcination at 650 °C for 6 h to get the resulting production. 2.4. IBU-loading procedure

2. Materials and methods 30 mg IBU was accurately weighted and dissolved in 2 ml hexane to prepare the high concentration of drug solution (15 mg/ml). Afterwards, 30 mg CMS was added to the above solution with vigorously stirring for 24 h to prepare drug-loaded samples with the drug/ carrier ratio of 1:2 (w/w). Finally, samples were separated by centrifuged to eliminate solvent, washed with hexane to wipe off the drugs adsorbed on the surface, and completely dried under vacuum. The drug loading capacity was measured by both HPLC and TGA. For HPLC method, 5 mg drug-loaded samples was precisely weighed and thoroughly dissolved in 10 ml methanol at volumetric flask under ultrasound to extract IBU from samples. Then the above solution was filtered through 0.22 μm polytetrafluoroethylene (PTFE) membrane filter, and 20 μl filtrate was injected into the liquid chromatograph with a UV detector set at 263 nm. The mobile phase was consisted of sodium acetate buffer (pH 2.5) and acetonitrile (50:50, v/v), and was filtered through 0.22 μm membrane filter and degassed by sonication before analysis. The flow rate was 1.0 ml/min. Besides, C18 column (Kromasil) was used for separation preceded by a JanuSep C18 pre-column (Benxi, China). The quantitative analysis of IBU was according to the standard

2.1. Materials 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT) were obtained from GL Biochem Ltd. (Shanghai, China). Dimethylformamide (DMF) and 4(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCM) were purchased from Shanghai Jinjinle Industrial Co., Ltd. Alanine methyl ester hydrochloride (H-L/D-Ala-Ome·HCl), Tetraethoxysilane (TEOS), 3-aminopropyltriethoxysilane (APTES) and Myristic acid were purchased from Aladdin (Shanghai, China). Double distilled water was obtained by ion exchange and used in all experiments. 2.2. Synthesis of chiral anionic surfactants L-Alanine methyl ester hydrochloride (0.153 g, 1 mmol) was dissolved in 10 ml DMF under stirring at room temperature, and then 2 ml trimethylamine (Et3N) was dropwise added to prepare L-alanine methyl

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process can be classified as biomimetic synthesis, because it involved some key features of biomimetic synthesis, such as alanine-derivative templates, efficient cascade reactions and mild synthesis conditions [11,48]. Finally, the products were calcined at 650 °C for 6 h to completely remove the alanine derivative templates and organic functional amino groups (step G).

curves, and the drug loading capacity (Cd, %) was calculated using the following equation:

Cd (%) =

W2 × 100 W1

(W1: Weight of CMS with loaded IBU; W2: Weight of IBU loaded in CMS).

3.2. Helix morphology and mesoscopic phase investigation of CMSs 2.5. Characterization Mesoscopic structures of the prepared CMSs were studied using a TEM instrument (JSM-6510A, JEOL, Japan). Before testing, the calcined CMSs samples were deeply crushed using a mortar and pestle, dispersed in ethanol under ultrasound and deposited on carbon-coated copper grids with porous carbon films. The nitrogen adsorption-desorption isotherm of samples was tested using a surface area and pore size analyzer (V-Sorb 2800P, Gold APP, China) to get the information of the specific surface area (SBET), pore size distributions (WBJH) and total pore volume (Vt). The specific surface area was calculated according to the Brunauer-Emmett-Teller (BET) method, and the pore size distribution was obtained from the corresponding adsorption branch over the relative pressure range from 0.05 to 0.2 by using Barrett-JoynerHalenda (BJH) approach. Besides, the total pore volume (Vt) was evaluated from N2 adsorption at the relative pressure of 0.99. The XRD patterns of samples were collected from an x-ray diffractometer (DX2700, Haoyuan, China) equipped with a Ni-filtered CuKa line as the source of radiation at 30 mA and 30 kV. Data were obtained from 5° to 45° (diffraction angle 2θ). The physical state of the pure IBU and the IBU-loaded CMSs were examined by DTA-TG instrument (DTG-60, Shimadzu, Japan) to gain the DSC curves and TGA graphs. The chirality features were studied using CD apparatus (MOS-500, Bio-Logic, France). The SAXS patterns were recorded by using SAXSpace (Anton Paar, Austria) operated at 40 KV and 50 MA.

Fig. 2 showed the typical TEM images with different enlargements and the Fourier transformation diffractograms of synthesized CMSs. TEM studies revealed that the prepared materials L-CMS and D-CMS had a twisted hexagonal rod-like morphology with the outer diameter of 100 and 80 nm, the length of 500 and 800 nm, and the helical pitch of 167 nm and 160 nm, respectively (Fig. 2(a1) and (b1)). As reported by previous studies of TEM simulated image, CMSs also possessed helix channels running inside, paralleling to the long axis of the rods and winding around the central axis of the rods [31]. As indicated in Fig. 3, the SAXS patterns of calcined L-CMS and DCMS showed three well-resolved peaks at very small scattering angles with d spacing of 18.6 nm and 19.1 nm, 4.6 nm and 4.8 nm, 2.6 nm and 2.6 nm (values estimated from Bragg's law), respectively, which could be indexed as the (10), (11) and (20) reflections on the basis of the typical two-dimensional hexagonal p6mm structure. Interestingly, we noted that there were two kinds of fringes indicated by arrows in Fig. 2(a) and 2(b), which were consistent with the interplanar spacing (10) and (11), respectively. The corresponding Fourier diffractograms (the insets a2, b2) confirmed the presence of intense central unscattered spot around very weak diffraction spots, as expected from an ordered mesoporous material constituted by walls of amorphous silica. All these indices indicated that the synthesized CMSs had well-defined twisted rod-like morphologies with a highly ordered hexagonal mesoscopic phase.

2.6. In vitro release

3.3. Characteristics before and after drug loading

According to the USP II paddle method, the drug-release experiment in vitro was carried out by using a ZRD 6-B dissolution tester (Shanghai Huanghai Medicament Test Instrument Factory, China) at the stirrer speed of 50 rpm at 37 °C. Pure IBU and IBU loaded CMSs were respectively exposed to 100 ml enzyme-free SGF and SIF. At predesigned time intervals, 5 ml release medium was extracted and replenished by the same volume of medium immediately. The withdrawn medium samples were passed through 0.22 μm microporous membrane and analyzed using HPLC method.

3.3.1. Chirality of templates, CMSs and IBU loaded CMSs With the purpose of exploring the influence of alanine-derivative chiral anionic surfactants on the prepared CMSs, CD as the most authoritative testing method was carried out to characterize and elucidate the chiral nature of the synthetized materials. Fig. 4(a) showed that, the templates of C14-L-Ala and C14-D-Ala successfully copied the chirality of L- and D-alanine, respectively, without the inversion of chirality. Furthermore, because of the lack of chromophores in silica materials, ICD was introduced to confirm the chirality of CMSs and IBU loaded CMSs. This technique was based on the CD measurement of the asymmetry induced by the chiral molecule in chiral environment [41,42]. In this study, phenol was selected as an appropriate chiral probe, and Fig. 4(b) showed the CD spectra obtained in the ICD experiments of IBU, L/DCMSs and IBU loaded L/D-CMSs. It can be easily inferred that a reversal of chirality was occurred in the synthesis of chiral materials L-CMS and D-CMS by using chiral surfactants C14-L-Ala and C14-D-Ala as templates. Due to the reversal of chirality, CMSs prepared by C14-L-CMS and C14-DCMS were denoted as D-CMS and L-CMS, respectively. More importantly, after drug loading, the drug-loading systems shared the chiral characteristic of carriers but not the simple overlap of CMSs and IBU, which was beneficial for their application in vivo.

3. Results and discussion 3.1. Formation mechanism of CMSs CMSs were synthesized through the sol-gel method by using APTES as CSDA, alanine-derivative surfactants as templates and TEOS as silica sources. Fig. 1 showed the schematic diagram of cooperative self-assembly formation mechanism of D-CMS, and the synthesis of L-CMS by using C14-D-Ala as template was similar to D-CMS. After addition of NaOH solution, the carboxyl group of surfactant templates transferred from protonation to non-protonation (step C). Then the surfactants were formed into helical rod-like micelles by self-assembly before the APTES/TEOS solutions were added (step D). It should be noted that the charge density of the micelles was strongly governed by pH, which caused differences in ionization degree and led to different surfactant arrangements [10,45,46]. Meanwhile, TEOS polymerized with the alkoxysilane sites of APTES to form silica framework. Particularly, the cooperative interactions, including surfactants with APTES and APTES with TEOS, actively catalyzed the helical packing of surfactants and the condensation of silica precursors (step E) [39,47]. In general, this

3.3.2. IR studies Fig. 5 showed the IR spectra of IBU before and after drug loading. In the spectra of L-CMS, the typical characteristic band at 3440 cm−1 was assigned to the stretching vibration of silanol groups, and the bands at 1173, 1097, 789 and 469 cm−1 were attributed to asymmetric stretching vibration of Si-O-Si, symmetric stretching vibration of Si-O-Si and bending vibration of Si-O-Si, respectively [48,49]. Moreover, crude drug IBU showed a strong carbonyl band at 1720 cm−1, which assigned 3

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Fig. 1. Schematic illustration of cooperative self-assembly formation mechanism of D-CMS (A–C). The synthesis process of chiral anionic surfactants; (D)(E) Cooperative self-assembly process of chiral anionic surfactants and APTES; (F) Silica source deposition procedure; (G) The removal of surfactant templates and organic functional groups by calcination; (H) The process of drug loading.

Fig. 2. Representative TEM images and Fourier diffractograms of a) L-CMS and b) D-CMS, among them, a1, b1 and a3, b3 are the amplifying images of a and b with different enlargements, showing both morphology features as a whole and fringes (indicated by arrows), respectively; a2, b2 are the images with reflection spots, showing the pores hexagonally arranged.

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Fig. 3. SAXS patterns of a) L-CMS and b) D-CMS after calcination, and the inset table is the relevant fitting parameters.

Fig. 5. IR spectra of IBU, L/D-CMSs and IBU loaded L/D-CMSs.

Fig. 6. N2 adsorption-desorption isotherms of CMSs before and after drug loading, the inset figure shows the pore size distribution of CMSs.

3.3.3. Nitrogen adsorption/desorption measurement As shown in Fig. 6, the nitrogen adsorption/desorption isotherms of the prepared CMSs samples were typical type IV isotherms with a clear hysteresis loop, demonstrating the existence of uniform mesoporous [52]. The calculated texture parameters were listed in Table 1. Generally speaking, CMSs possessed high SBET and Vt, indicating their potential application as drug delivery system to bond or store an adequate amounts of cargo [53]. Notably, the textural properties including SBET, Vt and WBJH were reduced apparently after drug loading, which provided sufficient evidence that IBU was successfully incorporated into the mesopores of CMSs. Moreover, despite the reduction in the adsorbed amount of nitrogen, the shape of the hysteresis loop remained unchanged. This meant that the pore shape was not remarkably changed by drug loading.

Fig. 4. (a) CD spectra corresponding to chiral anionic surfactants (b) Solid-state ICD spectra (ellipticity in mdeg) corresponding to IBU, L/D-CMSs and IBU loaded L/D-CMSs.

3.3.4. Drug crystalline state in CMSs Whether the crystalline drug was present or absent, it can be

to the stretching vibration of carboxyl group presented in IBU. For IBU loaded L-CMS and D-CMS, most of the characteristic bands of IBU disappeared, implying that IBU was successfully incorporated into carriers [50]. After IBU incorporated into carriers, it can be seen that the wavenumber of silanol groups and Si-O-Si bands showed redshifted from 3440 to 3425 cm−1, and from 1097 to 1096 cm−1, respectively. Meanwhile, due to the hydrogen bonds formed between the silanol groups of CMSs and the carboxyl groups of IBU, there was a slight redshift and a band broadening of the band at 1630 cm−1 [51]. The spectra of IBU loaded D-CMS was also consistent with the above principles.

Table 1 Specific surface area, pore volume, pore diameter and drug loading capacity of L-CMS and D-CMS. Sample

SBET 2

L-CMS D-CMS

IBU/L-CMS IBU/D-CMS

5

Vt 3

WBJH

Cd

Cd

(m /g)

(cm /g)

(nm)

(%, TGA)

(%, HPLC)

390 382 85 99

0.86 0.63 0.22 0.22

2.8 3.1 2.3 2.5

– – 22.8 24.4

– – 20.6 22.8

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Fig. 9. TGA curves of IBU, IBU loaded L/D-CMSs. Fig. 7. DSC thermograms of IBU, CMSs (shown one DSC thermograms as representative of L/D-CMSs) and IBU loaded CMSs (shown one DSC thermograms as representative of IBU loaded L/D-CMSs).

600 °C, which were caused by the endothermic evaporation of IBU [21,55,59]. As shown in Table 1, the drug loading capacity of IBU/LCMS and IBU/D-CMS obtained from HPLC were 20.6% and 22.8%, respectively while TGA method showed that the weight loss of IBU/L-CMS and IBU/D-CMS were 22.8% and 24.4%, respectively. It was worth noticing that the drug loading amount of IBU loaded D-CMS was higher than that of IBU loaded L-CMS. The results showed that the drug loading capacity was positively correlated with the pore size and the total pore volume of carriers, as indicated by previous reports [60–63].

confirmed by DSC and XRD analyses. The DSC thermogram (Fig. 7) of IBU showed an intense and characteristic endothermic peak at 77 °C, which was in agreement with the melting point depression of IBU [54–56]. However, after being incorporated into carriers, the thermogram of IBU loaded CMSs (Fig. 7, carrier and IBU loaded carrier) became almost a smooth line without any bulk phase transitions or glass transition, demonstrated that the mesoporous channels of CMSs prevented the crystallization of IBU due to the space confinement [57]. Moreover, the same results could be obtained from the XRD study. As displayed in Fig. 8, the XRD pattern of pure IBU showed highly crystalline state as indicated by numerous diffraction peaks. Nevertheless, the broad bands in the range of 5° to 45° 2θ (Fig. 8, carrier and IBU loaded carrier) revealed the amorphous nature of both CMSs and IBU loaded CMSs, which further indicated the conversion of drug crystalline state caused by the mesoporous helix channels and limited nano-space of CMSs. In general, the DSC and XRD results both suggested the amorphous nature of synthesized CMSs and IBU loaded CMSs, which could be beneficial for enhancing the bioavailability of poorly soluble drugs [58].

3.4. In vitro release of racemic IBU from CMSs Racemic IBU was selected as a model drug to investigate the different release behavior of L-CMS and D-CMS. It was well-known that, IBU was mainly absorbed in the stomach and the proximal small intestine where the pKa value was about 4.4. To further study the influence of pH on the dissolution behavior of IBU and IBU loaded L/D-CMS, in vitro drug release experiments were performed in SGF medium (pH 1) and SIF medium (pH 6.8), respectively. According to the cumulative release profiles shown in Fig. 10, IBU released remarkably faster in SIF than in SGF, the release percentage of IBU, IBU loaded L-CMS and IBU loaded D-CMS were 31%, 42%, 61% in SGF medium and 98%, 86%, 66% in SIF medium, respectively. The different release behavior might be attributed to the fact that most of IBU was ionized in the stationary phase at SIF (pH > pKa), while IBU molecules were more stable without ionization at SGF (pH < pKa), because of the abundance protons under the acidic environment [64]. The faster release of IBU was resulted from its higher solubility in SIF medium [49]. It should be mentioned that, in SIF medium (Fig. 10A), the release of IBU from carriers was obviously slower than pure IBU, and the carrier LCMS with smaller pore size (2.8 nm) showed faster release rates than that of D-CMS with larger pore size (3.1 nm), which was exactly the opposite of the previous studies [65,66]. We speculated that, in this case the pore geometry played a major role on the drug release behavior of chiral mesoporous silica. CMSs with different chirality (L/D) would provide different steric hindrances in the loading and dissolution process of chiral drug ibuprofen, and resulted in drug-loading and drugrelease differentiation [43]. In SGF medium, compared to pure IBU, both the release rate and release amount of IBU loaded CMSs were significantly improved, this can be explained by the transformation of crystal drug after being incorporated into carriers [49,67,68]. Particularly, in SGF, the release of IBU from two carriers with different chirality showed drug release differentiation, which was caused by the pore geometry of these two materials with different local chiral characteristics. Based on these results, it can be easily concluded that the synthesized CMSs with different chirality (D/L) could be applied as carriers to

3.3.5. Drug loading capacity Herein TGA and HPLC analysis were used to precisely quantify the drug loading amount of samples. TGA measurement of pure IBU and IBU loaded CMSs (Fig. 9) depicted the weight loss between 143 °C and

Fig. 8. XRD patterns of IBU, CMSs (shown one XRD pattern as representative of L/D-CMSs) and IBU loaded CMSs (shown one XRD pattern as representative of IBU loaded L/D-CMSs). 6

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Fig. 10. In vitro release profiles of A: a) IBU, b) IBU loaded L-CMS, c) IBU loaded D-CMS in simulated intestinal fluid (SIF) (the inset figure is the enlargement of the rectangle area labeled in Fig. A); B: a) IBU, b) IBU loaded LCMS, c) IBU loaded D-CMS in simulated gastric fluid (SGF).

accomplish drug release differentiation and improved the dissolution of IBU in SGF medium.

4. Conclusion In summary, twisted rod-like CMSs were synthesized by using L-and derivatives as templates. As confirmed by ICD analysis, the helix channels of CMSs exhibited local chiral characteristics, which was successfully transferred from alanine-derivative templates with a reversal of chirality. Besides, racemic IBU was selected as model drug to study the drug release differentiation of CMSs with different local chiral characteristics. After drug loading, IBU was effectively converted into amorphous state, and the drug-loading samples shared the chiral characteristic of carriers. Particularly, CMSs with different chirality (D/ L) could be applied as carriers to accomplish drug release differentiation and improved the dissolution of IBU in SGF medium. Herein, the drug release differentiation of IBU could be attributed to the different pore geometry of CMSs with different chirality. We believe that chiral mesoporous silica is promising to be impelled in practical application of drug delivery, and studying the correlations between chiral structures (D/L) and release behavior of CMSs will provide useful information on the biological application of silica-based drug carriers. D-alanine

Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 81773672) and the China Postdoctoral Science Foundation (No. 2018M641755). 7

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