Light-Triggered Drug Release Platform Based on

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Nanoscience and Nanotechnology Letters Vol. 8, 1–6, 2016

Light-Triggered Drug Release Platform Based on Superhydrophobicity of Mesoporous Silica Nanoparticles Wanyuan Gui1 , Junpin Lin1
∗ , Guojian Hao1 , Yongfeng Liang1 , Wenqian Wang2 , and Yongqiang Wen2
∗ 1

State Key Laboratory for Advanced Metals and Materials, University of Science and Technology Beijing, 100083 Beijing, China 2 Department of Chemistry and Biological Engineering, University of Science and Technology Beijing, 100083 Beijing, China A light-triggered drug delivery platform based on mesoporous silica nanoparticles (MSNs) was achieved by controlling the surface state of superhydrophobic/superhydrophilic of MSNs. The modified MSNs with an optimal ratio of octadecyltrichlorosilane (OTS) exhibited superhydrophobic character, which successfully inhibited the loaded cargo molecules-fluorescein release from MSNs. Under a condition of irradiation with a high pressure mercury lamp of 400 W for various time intervals, the decomposition of single molecule layer of OTS caused the MSNs surface changing from a “closed” state to an “open” state, owning to the converting of the surface state from superhydrophobic to superhydrophilic, followed by releasing of the fluorescein from pores of the MSNs. The light stimuli-responsive control delivery platform based on MSNs represents a new system, which is expected to have a promising application in nanomedicine, such as drug delivery for cancer chemotherapy.

Keywords:

1. INTRODUCTION Stimuli-responsive controlled delivery systems based on MSNs play an important role in durg delivery, due to MSNs with interesting features, such as high loading content, tunable pore sizes, thermal and photostability, and easy functionalization.1–5 The stimuli-responsive controlled delivery systems based on MSNs are expected to have a potential significant impact in many fields of nanomedicine including drug delivery, bioprobes, biosensing, bioimaging, biocatalysis and cancer treatment.6–17 In addition, it has plenty of advantages for nanomedicine such as controlled releasing time, location and dosage of the drug molecule.18
19 Although previous studies showed that delicate intelligent control delivery were effective, the free of cytotoxic drugs only in the lesion location is much more preferred in clinical application.20–24 Among the numerous response stimuli, light is recognized as one of the most effective triggers applied in drug delivery, because it enables remote activation of the release process to realize the controlled release of loading cargoes at a desired time and location.25 Recently, many smart switches have been designed to control the release of loaded cargoes.26–30 The ideal drugcontrolled delivery system should not only have good biocompatibility and tissue specificity, but should also ∗

Authors to whom correspondence should be addressed.

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release drug molecules at the desired location. Among these switches, most of them were designed to control the release of cargoes through constructing the blocking units on the surface of MSNs, including nanoparticles, organic compounds and polymer, etc.31–35 Although the MSNsbased drug controlled release systems have been proven greatly effective, most of these systems would still cause a series of side effects in cells. Additionally, hydrophobic coatings have been emerging as one hot topic in the field of fundamental surface science and practical coating applications.36–40 Inspired by those studies, we constructs a light-responsive release system by controlling the surface conversion of superhydrophobic/superhydrophilic of MSNs, which can achieve ‘zero level release’ until to the lesion location. Moreover, light as an external stimulus offers controllable drug release both spatially and temporally and thus exhibits great potentials for further biomedical application. Therefore, we report a novel strategy for controlled release system based on light-controllable superhydrophobicity of the MSNs surface. OTS, a photosensitive molecule, which can covalently bonds to the surface of MSNs to serve as a gatekeeper by transformation under UV-linght radiation.41 Under the phosphate buffer solution (PBS) conditions, the OTS is tightly wraped around the surface of MSNs, showing superhydrophobic properties. It helps to protect the surface from being wetted by 1941-4900/2016/8/001/006

doi:10.1166/nnl.2016.2158

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Light-Triggered Drug Release Platform Based on Superhydrophobicity of Mesoporous Silica Nanoparticles

PBS and to curb the release of encapsulated molecules. When it is exposured at UV-light for varied time intervals, OTS decomposes and exhibits superhydrophilic properties, resulting a wetting of the MSNs surface and then releasing the trapped molecules (Fig. 1). The conversion of superhydrophobic/superhydrophilic surface of MSNs represents a new strategy for an effective and efficient controlling release, which has potential applications in nanomedicine, nanodevices and biosensor, etc.

2. EXPERIMENTAL MATERIALS AND METHODS 2.1. Materials Octadecyltrichlorosilane (OTS, 95%) was purchased from Acros. Toluene was purchased from J&K Chemical Technology. Cetyl trimethyl ammonium bromide (CTAB, 96%), tetraethyl orthosilane (TEOS, 99%), fluorescein, and ethanol were purchased from Sigma-Aldrich. Phosphate buffered saline (PBS) were prepared with ultra-pure MilliQ water (resistance > 18 M · cm−1 . 2.2. Instruments SEM images was collected using a JEOL-6700FE instrument. TEM images was obtained using a TecnaiG2 F20 electron microscope. SAXS patterns were performed with a Rigaku D/max 2500 equipped with Cu K radiation. Fluorescence spectra were acquired by a Hitachi F-4500 FL Spectrophotometer in PBS. The specific surface areas was evaluated by BET model, and Pore size and pore volume were obtained by the BJH method at 77 K on

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a Micromeritics ASAP2020 automated sorption analyzer. The images of superhydrophobic/superhydrophilic of the mesoporous silica surface were analyzed by an OCA20 static contact Angle tester. 2.3. Synthesis of MSNs Monodisperse MSNs with small particulate size and large radial mesopores were successfully prepared according to a modified sol–gel method.3 Typically, 0.5 g of CTAB and 0.6 mL of NaOH (2 M) solution were dissolved in 12 mL ethanol and 48 mL of water. With vigorous stirring (600 r/min) for 60 min, 2.8 mL of TEOS was added to the solution under ambient conditions. After stirring for 8 h, the mixture was separated by centrifugation, washed with water and ethanol three times each, and dried in the an oven (60  C) overnight. To remove CTAB, the assynthesized silica nanoparticles were suspended in 100 mL of ethanol, 3 mL of HCl (37%) was added to the suspension. The suspension was refluxed for 24 h. The resulting white powder was filtered out, and washed with ethanol three times, and dried in an oven (60  C) overnight. In this way, MSNs with 89 nm diameter and 4.2 nm pore size were successfully prepared. 2.4. Synthesis of MSNs-OTS The as-prepared MSNs-OTS were first added with amount of OTS (20 L) in dry toluene (3 mL), and then the OTSmodified MSNs was obtained. In details, MSNs (100 mg) were added to 3 mL of dry toluene and stirred for 60 min at room temperature. Finally, the OTS-modified MSNs were separated from the supernatant by centrifugation

Fig. 1. The schematic illustration of the light-responsive delivery system by controlling the superhydrophocic/superhydrophilic surface conversion of MSNs.

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Light-Triggered Drug Release Platform Based on Superhydrophobicity of Mesoporous Silica Nanoparticles

Fig. 2. The characterizations of the mesoporous silica nanomaterials (MSNs): (a) SEM (b) TEM (c) N2 sorption isotherm of the MSNs (inset: pore size distribution), (d) SAXS.

(12000 rpm), and the slurry was washed extensively with dry toluene, collected via centrifugation several times, and dried in an oven (30  C) overnight. 2.5. Loading of Guest Molecules This system might hold promise for application in nanomedicine, nanodevices and biosensor, etc. Herein, the MSNs-OTS with fluorescein were incubated. To load fluorescein, MSNs-OTS (50 mg) were dispersed by sonication into 3 mL of dry toluene mixed solution containing fluorescein (2 mg) for 24 h. Then, samples were recovered by centrifugation, washed with water several times, and finally dried at 30  C under vacuum for 24 h to generate fluorescein-loaded samples. The loading content of MSNsOTS was approximately 0.969 g/mg, as calculated by Eq. (1) through recycling of the unloaded fluorescein. The loading contents of the different types of MSNs-OTS were calculated as follows.

light-responsive release platform had been designed by controlling the superhydrophobic/superhydrophilic surface conversion of mesoporous silica for controlled release of cargoes. Furthermore, dyes (fluorescein) were selected to evaluate the effect of the release, the release effect was extensive and the release rate reached 20.58%, as calculated by Eq. (2). percentage of releasing =

released fluorescein × 100% loaded fluorescein

(2)

percentage of loading =

total fluorescein − unloaded fluorescein × 100% (1) total fluorescein

2.6. Loading Efficiency Evaluation 5 mg of sample was placed in the bottom of a cuvette, and was kept submerged in 1 mL of PBS solution (0.1 M, pH 7.0) with irradiation by UV-light during the release process. The release of fluorescein molecules was monitored by detection at 520 nm using 490 nm light to excite the molecules. The above results showed that a Nanosci. Nanotechnol. Lett. 8, 1–6, 2016

Fig. 3. The FTIR spectra of MSNs: MSNs (blue curve); MSNsOTS exhibited new absorption peaks at 2913 cm−1 , 2849 cm−1 , and 1472 cm−1 . (fuchsia curve).

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Fig. 4. The mechanism of the superhydrophobic/superhydrophilic conversion process of the MSNs surface: (a) MSNs, before modification with OTS. (b) MSNs-OTS, before UV-light irradiation. (c) MSNs-OTS, after UV light irradiation for 60 min.

2.7. The Superhydrophobic/Superhydrophilic Conversion Experiment of MSN-OTS The silica film was made by spin coating silica gel on a glass and drying in an oven for 24 h at 30  C. Silanization was performed overnight by dipping these films in 20 L of OTS in 3 mL of toluene solution. Modified films were washed with toluene and were cured for 24 h at 30  C. The superhydrophobic/superhydrophilic performance of the MSNs-OTS was detected by the contact angle testing.

3. RESULTS AND DISCUSSION 3.1. Characterization of MSNs The surface morphology and structure of the MSNs were detected by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and N2 sorption isotherms. As shown in Figures 2(a and b), MSNs have well surface morphology and uniform particle size (89 nm). In addition, the N2 sorption analysis result was shown in Figure 2(c). MSNs were calculated to have a total surface area (BET) of 1306.89 m2 /g and an average pore diameter of 4.2 nm. In Figure 2(d), the MSNs were determined as MCM-41 type with the presence of a 2d-hexagonal mesostructure (4.2 nm lattice spacing of ca) confirmed by Small Angle X-ray powder diffraction (SAXS). 3.2. Design of the Light-Triggered Drug Delivery Platform A light-triggered drug delivery platform can control the release of cargo by controlling the surface state of superhydrophobic/superhydrophilic of MSNs. OTS was anchored on the external surface of MSNs by the formation of siloxane groups, which bond with the active hydroxyl of the silica surface. Therefore, the conversion of surface state between superhydrophobic and superhydrophilic was implemented to achieve the controlled release of cargoes at will. The superhydrophobic surface of the MSNs was modified with an optimal ratio of OTS, resulting in inhibition of releasing the model cargo molecule-fluorescein. When exposure to UV-light for varied time intervals, the decomposition of OTS single molecule layer led the surface state to convert from superhydrophobic to superhydrophilic, and the nanopores on the MSNs surface changed 4

from a “closed” state to an “open” state, and released the cargo molecule from the pores. Furthermore, the dye fluorescein was assigned to the model cargo molecule. Firstly, a quantitative of OTS was anchored on the external surface of the MSNs. Accordingly the amount of fluorescein was added to toluene for oscillating 24 h to load the cargo. After washing with water several times, the light-responsive controlled release system was formed. The Superhydrophobic-Modification external surface protected the pores from being infiltrated by water. With exposure to UV-light, the OTS transformed from superhydrophobic to superhydrophilic. The reactant concentration, reacting time and loading time determined the proportion of modification switch molecules and the amount of the loaded cargoes. 3.3. Characterization of the MSNs-OTS Based on the analysis above, OTS acted as a lightresponsive valve for the controlled release. Without UV-light irradiation, the MSNs-OTS prevented cargo molecules from leaving the pores. As shown in Figure 3, the FTIR showed that the OTS modified MSNs (MSNsOTS) exhibited new absorption peaks at 2913 cm−1 , 2849 cm−1 , and 1472 cm−1 (fuchsia curve). As mentioned above, the superhydrophobicmodification of MSNs can act as a light-responsive valve for the controlled release. As shown in Figure 4(a), the

Fig. 5. Fluorescent dye (fluorescein) concentration of fluorescein with the corresponding fluorescence intensity.

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Light-Triggered Drug Release Platform Based on Superhydrophobicity of Mesoporous Silica Nanoparticles

Fig. 6. The release profile of fluorescein molecules from samples in PBS solution (0.1 M, pH 7.0) as a function of time: (a) Without UV-light irradiation (the below black curve); With the increase of the irradiation time (the above black curve). (b) With UV-light irradiation for varied time intervals (the release rate curve).

initial surface of MSNs was hydrophilic, where the contact angle was 60.7. As shown in Figure 4(b), the MSNs-OTS surface was superhydrophobic with the contact angle of 157.7 before exposure to UV-light, which can prevent cargo molecules from leaving the pores. In addition, Figure 4(c) exhibited that the surface of MSNs-OTS was superhydrophilic after UV-light irradiation for 60 min, and its contact angle was 24.2, which opened a pathway for the rapid release of cargo molecules. This transformation could be induced in an irreversible manner. 3.4. Test of the Release of the Fluorescein-Loaded System The standard curves of fluorescein were established by fluorescence spectroscopy (Fig. 5). As showed in Figure 5, the fluorescence intensity of fluorescein signal occurred at 520 nm, indicating that fluorescent dye concentration of fluorescein was in accordance with fluorescence intensity. The release behavior of the fluorescein-loaded system was investigated. Before UV-light irradiation, the surface of MSNs-OTS was superhydrophobic, and the sealed cargo could not release from the pores of the MSNs. When the surface was irradiated with UV-light, the surface became superhydrophilic and displayed high wettability, and the amount of fluorescein molecule are capable to be modified by varying the time duration of UV-light irradiation. The guest molecules released dosage from the pores of MSNs was detected by the fluorescent intensity, which was monitored at 520 nm (Fig. 6). However, the Figure 6(a) (the below black curve) showed that, without UV light irradiation, the surface of the MSNs was superhydrophobic, and the sealed cargo could not release from the pores of the MSNs. During the process of the 60 min experiment, there was no obvious fluorescence signal at 520 nm was detected. Figure 6(a) displayed that the cargo molecules could release from the MSNs after exposure to UV-light for varied time intervals, and the released amount increased quickly with increasing the irradiation time. Figure 6(b) revealed that Nanosci. Nanotechnol. Lett. 8, 1–6, 2016

(fuchsia curve), the fluorescence signal had a dramatical increase near 520 nm, which indicated that the fluorescein molecules were massively released from the MSNs.

4. CONCLUSIONS In summary, a light-responsive release platform was established based on surface superhydrophobic-modification of MSNs, which could be used to effectively and efficiently delivery cargo by controlling the surface state of superhydrophobic/superhydrophilic of mesoporous silica. This novel nanocarrier satisfies the requirements of advanced nanomedicine, such as suitable nanoscale, excellent biocompatibility, and release of drug molecules at a desired time in a specific spatial location. The light-responsive controlled delivery system is an efficient and effective strategy for constructing a new generation of smart nanovehicles, and has a potential applications in nanomedicine, such as drug delivery for cancer chemotherapy. Acknowledgments: The authors would like to thank the NSFC (Nos. 51271016, 21171019, 21073203, 21127007, 21103009) and the State Key Laboratory for Advanced Metals and Materials, University of Science and Technology Beijing, under contract No. 2012Z-06.

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Received: 24 February 2016. Accepted: 16 April 2016.

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