A Light-Responsive Reversible Molecule-Gated System Using

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A Light-Responsive Reversible Molecule-Gated System Using Thymine-Modified Mesoporous Silica Nanoparticles Dinggeng He, Xiaoxiao He,* Kemin Wang,* Jie Cao, and Yingxiang Zhao State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Changsha 410082, People's Republic of China S Supporting Information *

ABSTRACT: In this paper, a reversible light-responsive molecule-gated system based on mesoporous silica nanoparticles (MSN) functionalized with thymine derivatives is designed and demonstrated. The closing/opening protocol and release of the entrapped guest molecules is related by a photodimerization−cleavage cycle of thymine upon different irradiation. In the system, thymine derivatives with hydrophilicity and biocompatibility were grafted on the pore outlets of MSN. The irradiation with 365 nm wavelength UV light to thymine-functionalized MSN led to the formation of cyclobutane dimer in the pore outlet, subsequently resulting in blockage of pores and strongly inhibiting the diffusion of guest molecules from pores. With 240 nm wavelength UV light irradiation, the photocleavage of cyclobutane dimer opened the pore and allowed the release of the entrapped guest molecules. As a proof-of-the-concept, Ru(bipy)32+ was selected as the guest molecule. Then the light-responsive loading and release of Ru(bipy)32+ were investigated. The results indicated that the system had an excellent loading amount (53 μmol g−1 MSN) and controlled release behavior (82% release after irradiation for 24 h), and the light-responsive loading and release procedure exhibited a good reversibility. Besides, the light-responsive system loaded with Ru(bipy)32+ molecule could also be used as a lightswitchable oxygen sensor.

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INTRODUCTION The design of delivery systems with “molecular gates” able to selectively release entrapped guests in response to environmental stimuli has played an important role in drug and gene delivery recently. To date, traditional delivery systems usually rely on simple diffusion-controlled processes or degradation of the nanocarrier,1 such as microcapsules,2 micelles,3 vesicles,4 or liposomes.5 As an alternative to these materials, mesoporous silica nanoparticles (MSN) show a large load capacity, high thermal stability, biocompatibility, tunable pore size and volume, and great diversity in surface functionalization.6 In particular, the unique architecture of MSN, containing parallel pores with two unique openings, makes it possible to design systems able to achieve zero release, which can be fully opened on command by using external physical or chemical stimuli to control cargo release. Up to now, MSN-based controlled release systems, which use a range of stimuli, including light,7 pH,8 temperature,9 competitive binding,10 enzymes,11 and redox activation12 for opening the nanopores, have been reported. Among these stimuliresponsive systems, the photoresponsive controlled-release systems are of more interest because of the noninvasive and high spatiotemporal resolution character of light. Recent reported light-operated MSN systems are capped by nanovalves,13 nanoparticles,14 block-copolymer,15 etc. However, some examples of photoresponsive gated systems still have some drawbacks, such as lack of reversibility, which hinder the application. To improve the reversibility, some functional molecules with the photodimerization-cleavage ability were noted. For example, © 2012 American Chemical Society

Tomlinson et al. first held the photodimers, formed by polycyclic aromatic hydrocarbons and photodissociated to the original monomers, in rigid transparent polymer matrices.16 This design has made such a system able to write and erase diffraction gratings repeatedly. Fujiwara et al. attached coumarin derivatives onto the pore outlets of MCM-41 solids and developed a reversible light-responsive molecule-gated release system.17 A similar gate-like ensemble was recently functionalized with a lightdriven “molecular stirrer” using the reversible isomerization of azobenzene groups.13 In addition to good reversibility, however, it is equally important to improve the hydrophilicity and biocompatibility of light-operated MSN systems for their application in biomedicine. It is well-known that thymine base is hydrophilic and biocompatible. In addition, thymine bases photodimerize upon irradiation above 270 nm and revert back to monomeric thymine again upon irradiation below 270 nm.18 Herein, we grafted thymine derivatives on the surface of MSN and designed a light-responsive molecule-gated release system. In this system, the irradiation of thymine-functionalized MSN (TA-MSN) with 365 nm wavelength UV light leads to the formation of cyclobutane, due to the dimerization of thymine monomer. Cyclobutane formation subsequently results in blockage of pores and strongly inhibits the diffusion of guest Received: December 1, 2011 Revised: January 31, 2012 Published: February 6, 2012 4003

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Ru(bipy)32+ Loading. The purified TA-MSN (10.0 mg) was soaked and stirred in a solution of Ru(bipy)32+ (10 mM) in PBS solution (2.00 mL, 100.0 mM, pH 7.4) in the dark for 24 h. Then, the mixture was stirred with irradiation at 365 nm wavelength UV light for another 24 h, followed by centrifugation and extensive washing with PBS to remove physisorbed, uncapped Ru(bipy)32+ from the exterior surface of the material. The resulting precipitate (denoted as M1) was isolated and dried under high vacuum. The loading of Ru(bipy)32+ (0.14 mmol g−1) was calculated by subtracting the amount of Ru(bipy)32+ remaining in the phosphate buffer and combined washings from the amount of Ru(bipy)32+ initially added to the reaction. The load stability of M1 was monitored by fluorescence emission spectroscopy (ex. at 454 nm, em. at 594 nm). Ru(bipy)32+ Release Studies. M1 (5.00 mg) was dispersed in PBS buffer (5.00 mL, 100.0 mM, pH 7.4) with irradiation of 240 nm UV light. Aliquots (0.20 mL) were taken periodically from the suspension at room temperature, followed by centrifugation (14000 rpm, 20 min). The release of Ru(bipy)32+ from the pore voids to the buffer solution was determined by fluorescence emission spectroscopy (ex. at 454 nm, em. at 594 nm). Cytotoxicity Assay. The cytotoxicity caused by irradiation of 240 nm light was investigated by MTT assay. For the MTT assay, HeLa cells and CEM cells were respectively seeded into 96-well plates and grown overnight. The cells were then incubated with irradiation at 240 nm for different times (1, 3, 5, 7 h). Afterward, cells were incubated in media containing 0.5 mg mL−1 of MTT for 3 h. The precipitated formazan violet crystals were dissolved in 150 μL of dimethyl sulfoxide (DMSO) at 37 °C. The absorbance was measured at 490 nm by a multidetection microplate reader. Light-Switched Sensor for Oxygen. M1 (5.00 mg), dispersed in PBS solution (5.00 mL, 100.0 mM, pH 7.4), was exposed at 240 nm wavelength UV light for different times (0, 1, 2, 4, and 8 h). Various percentage mixtures of nitrogen and oxygen were respectively poured into the above solution for 10 min, monitoring their fluorescence by fluorescence emission spectroscopy (ex. at 454 nm, em. at 594 nm).

molecules from pores. With 240 nm UV light irradiation, the photocleavage of the cyclobutane dimer can open the pore and allow the escape of the entrapped guest molecules. To demonstrate the system, Ru(bipy)32+ was selected as a guest molecule. The loading and release of Ru(bipy)32+ were then investigated.

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EXPERIMENTAL SECTION

Materials. N-Cetyltrimethylammonium bromide (CTAB, ⩾99%), thymine-1-acetic acid (TA, 98%), 1-[3-(dimethylamino)propyl]-3ethylcarbodiimide hydrochloride (EDC), and [3-(2-aminoethyl)aminopropyl]trimethoxysilane (APTES, 99%) were purchased from Alfa Aesar. N-Hydroxysuccinimide (NHS, 98%) was purchased from Dingguo reagent company (Beijing, China). [Ru(bipy)3]Cl2 (bipy = 2,2′-bipyridine) dye (Ru(bipy)32+) and 3-[4,5-dimethylthialzol-2-yl]2,5-diphenyltetrazolium bromide (MTT) were purchased from SigmaAldrich. Sodium hydroxide (NaOH), ammonium hydroxide solution (25%), and tetraethylorthosilicate (TEOS, 28%) were purchased from Xilong reagent company (Guangdong, China). All buffers were prepared with ultrapure Milli-Q water (resistance >18 MΩ cm−1). Characterization. Transmission electron microscopy (TEM) images were obtained on a JEOL 3010 microscope and an accelerating voltage of 100 kV. The MSN materials ζ potential was measured at 25 °C using a Nano ZS90 laser particle analyzer (Malvern Instruments, UK). UV−vis spectra were collected with use of a DU-800. Smallangle powder X-ray diffraction patterns of the MSN materials were obtained in a Scintag XDS-2000 powder diffractometer, using Cu Kα irradiation (λ = 0.154 nm). N2 adsorption−desorption isotherms were obtained at −196 °C on a Micromeritics ASAP 2010 sorptometer by static adsorption procedures. Samples were degassed at 100 °C and 10−3 Torr for a minimum of 12 h prior to analysis. Brunauer− Emmett−Teller (BET) surface areas were calculated from the linear part of the BET plot according to IUPAC recommendations. Pore size distribution was estimated from the adsorption branch of the isotherm by the BJH method. All fluorescence spectra were recorded on a Hitachi F-4500 FL spectrophotometer in PBS buffer. A UV lamp (0.2 W/cm−2) was used as the UV light source (China). Synthesis of the 3-Aminopropyl-Modified MSN (AP-MSN). N-Cetyltrimethylammonium bromide (CTAB, 0.50 g, 1.37 mmol) was dissolved in 240 mL of nanopure water. Then, a sodium hydroxide aqueous solution (2.00 M, 1.75 mL) was introduced to the CTAB solution and the temperature of the mixture was adjusted to 353 K. Subsequently, tetraethoxysilane (TEOS, 2.50 mL, 11.2 mmol) was added dropwise to the surfactant solution under vigorous stirring. The mixture was then allowed to react for 2 h to give rise to a white precipitate. Finally, this solid crude product was filtered, washed with nanopure water and methanol, and dried under high vacuum to yield the as-synthesized MSN. To remove the surfactant template (CTAB), 0.70 g of the as-synthesized MSN was refluxed for 6 h in a methanolic solution of 0.70 mL of HCl (37.2%) in 70 mL of methanol. The resulting material was filtered and extensively washed with nanopure water and methanol. The surfactant-free MSN material was then placed under high vacuum with heating at 333 K to remove the remaining solvent from the mesopores. To modify the amine group on the surface of MSN, MSN (0.50 g) was refluxed for 20 h in 40.0 mL of anhydrous toluene with 0.50 mL (2.85 mmol) of [3-(2-aminoethyl)aminopropyl]trimethoxysilane (APTES) to yield AP-MSN material. The resulting particles were then separated by centrifugation, washed with nanopure water and methanol, and dried under high vacuum at 333 K. Synthesis of the Thymine-Functionalized MSN (TA-MSN). TA-MSN was synthesized via the EDC/NHS cross-linking method. Briefly, 0.05 g (0.27 mmol) of thymine-1-acetic acid (TA) was reacted with 0.04 g (0.35 mmol) of EDC and 0.08 g (0.7 mmol) of NHS in MES buffer (2.00 mL, pH 5), with stirring at room temperature for 30 min before being added to the purified AP-MSN (40 mg). The mixture was stirred at room temperature for 24 h, followed by centrifugation and washing with nanopure water. The remaining surface thymine groups were quantified at 0.8 mmol g−1 by UV−vis spectra. The obtained particles, denoted as TA-MSN, were dried under high vacuum.

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RESULTS AND DISCUSSION For the design of the stated molecule-gated system, two components were chosen, namely a suitable support and the lightresponsive “gate-like” ensemble. In this study, we selected MCM41-type mesoporous silica material as a suitable inorganic matrix because of its high homogeneous porosity, good biocompatibility, and ease of functionalization on its surface. For the gating mechanism, it was our aim to develop a reversible system that could load and release guest molecules triggered by light in aqueous solution. Thus, our attention was focused on the reversible transformation between thymine monomers and thymine dimers by light. This proposed molecule-gated ensemble is depicted in Figure 1. In this work, the thymine derivatives are first anchored on the surface of the mesoporous silica material in order to create a molecule-gated ensemble. To study the functional closing/ opening protocol of the gate-like system, the dye Ru(bipy)32+ was selected as guest molecules and loaded on the inner mesopores of the thymine functionalized MSN due to the simplicity of monitoring its release in the aqueous phase. The pore outlets of the dye-loaded MSN are then blocked by the irradiation of UV light at 365 nm to form cyclobutane dimer through the dimerization of thymine monomer (denoted as M1). The cyclobutane dimer could be cleaved with the irradiation of a shorter wavelength of UV light around 240 nm to regenerate the thymine monomer. Hence, the blocked pores of the dye-loaded MSN can be opened and the entrapped dye molecules released. Following this procedure, MSN was first synthesized as previously reported.14 Then the amine groups were introduced onto the surface of the MSN to form AP-MSN by using APTES 4004

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Figure 3. Powder X-ray diffraction patterns of MSN (a), TA-MSN (b), M1 (c), and M2 (M1 after dye released) (d). MSN, TA-MSN, and M2 exhibit the typical diffraction patterns of MCM-41-type mesoporous silica with hexagonal symmetry. The changes in the M1 diffraction pattern might be caused by pore filling and dimerization of thymine effects. Figure 1. Representation of the light-responsive reversible moleculegated system. The light-responsive release mechanism of the system is based on the photodimerization and photocleavage of thymine modified on MSN. The release of the entrapped guest (Ru(bipy)32+) is selectively accomplished in light.

strong, sharp adsorption step at intermediate relative partial pressure values around 0.3, a specific surface area of 935.2 m2 g−1, an average pore diameter of 3.1 nm, and a narrow pore distribution (Figure 4a). From XRD and porosimetry, a value for the

treatment. The AP-MSN was reacted with thymine-1-acetic acid via the EDC/NHS cross-linking method to furnish TA-MSN, which was loaded with Ru(bipy)32+ molecules in order to prepare M1. The surface modification of mesoporous silica was confirmed by UV−vis spectra and ζ-potential. Figure S1 gave the UV−vis spectra of MSN before and after functionalization. The TA-MSN displayed apparent enhancement of absorption band around 272 nm corresponding to the absorption band of free thymine. However, both pure MSN and AP-MSN showed no absorption band around 272 nm. The different ζ-potential, −26.1, 30.3, and −14.9 mV for MSN, AP-MSN, and TA-MSN, respectively, also suggested that the successive modification of amino groups and thymine was successful. The quantities of thymine on the MSN were determined by UV−vis spectroscopy to be approximately 1.5 mmol g−1 MSN. The morphology and pore structure of MSN before and after modification were characterized by transmission electron microscopy (TEM), powder X-ray diffraction (XRD), and N2 adsorption−desorption measurements. The TEM images in Figure 2 demonstrated a typical hexagonally arranged porosity

Figure 4. Nitrogen adsorption−desorption isotherms for (a) MSN, (b) TA-MSN, (c) M1, and (d) M2. Insets: BJH pore size distribution of each material.

wall thickness of 0.82 nm can be calculated as the difference between a0 (3.88 nm) and pore size (3.06 nm) (Table 1). After the MSN were functionalized with thymine, no obvious changes in the Brunauer−Emmett−Teller (BET) area and pore sizes were observed according to Figure 4b and Table 2. The effect of UV light irradiation on dimerization of the thymine attached on the surface of MSN was examined by UV−vis spectra. The change in UV−vis spectra of TA-MSN during 365 nm UV light irradiation was shown in Figure 5a. The absorption band around 272 nm decreased with irradiation time, indicating the photodimerization was successful. To prove that this change was reversible, the UV−vis spectra of dimerized samples under 240 nm UV light irradiation were further examined. The thymine absorption band at 272 nm regenerated within 24 h owing to the photocleavage of the dimerized thymine, as shown in Figure 5b. These results clearly confirmed that the irradiation with 365 nm wavelength UV light leads to the formation of a cyclobutane ring by the dimerization

Figure 2. Representative TEM images of MSN (a) and TA-MSN (b).

for the prepared MSN and TA-MSN. The X-ray diffraction (XRD) of MSN in the 1.3° < 2θ < 10° range showed a low-angle reflection typical of a hexagonal array that can be indexed as (100) Bragg peaks with an a0 cell parameter of 38.8 Å (d100 spacing of 33.6 Å) (Figure 3). The N2 adsorption−desorption isotherms of MSN showed a typical type IV curve with a single, 4005

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Table 1. Powder X-ray Diffraction Patternsa sample

d100 (Å)

a0 (Å)

dpore wall (Å)

MSN TA-MSN M1 M2

33.6 34.2 41.8 35.5

38.8 39.5 48.3 40.1

8.2 10.9

by using luminescence spectroscopy. It was demonstrated that the M1 displayed strong fluorescence emission at 594 nm (Figure S2), indicating the loading was successful. The loading of Ru(bipy)32+ was determined by UV−vis spectroscopy to be approximately 53 μmol g−1 MSN. In contrast, Ru(bipy)32+ was not efficiently loaded into the pores in the absence of UV light with 365 nm wavelength (2.3 μmol g−1 MSN). Meanwhile, the N2 adsorption−desorption isotherm of M1 was typical of mesoporous systems with filled mesopores, and a significant decrease in the N2 volume adsorbed was observed (Figure 4c). In fact, this solid presented relatively flat curves when compared to the MSN, indicating that there was significant pore blocking. The changes in pore volume and diameter were also investigated by nitrogen sorption experiments (Table 2). The decline in surface area and pore volume by ∼90% in the sample M1 is attributed to the pore blocking effect induced by the dye molecules in the pores of the MSN. Then the light-triggered release of guest molecules was investigated. Figure 6a showed

13.6

a

The d100 numbers represent the d-spacing corresponding to the main (100) XRD peak. The unit-cell size (a0) is calculated from the d100 data by using the formula a0 = 2d100/31/2.10b The pore wall thickness dpore wall = a0 − WBJH10b (WBJH is from Table 2).

Table 2. BET and BJH Parameters sample MSN TAMSN M1 M2

BET surface area SBET(m2/g)

BET pore volume Vp(cm3/g)

BJH pore diameter WBJH (Å)

935.2 819.6

0.715 0.696

30.6 28.6

82.7 763.8

0.083 0.679

22.3 26.5

Figure 6. (a) Release behavior of the M1 in the dark and with UV light irradiation around 240 nm in PBS buffer. Luminescence spectroscopy was used to monitor Ru(bipy)32+ release into the solution. (b) Fluorescence intensity showing the cyclic activation of the moleculegated system.

Figure 5. (a) The changes in UV−vis spectra of TA-MSN during irradiation of UV light (365 nm). (b) The changes in UV−vis spectra of the sample obtained by Ru(bipy)32+-unloaded M1 during irradiation of UV light (240 nm). The concentration of MSN suspension is 2.0 g L−1.

the release behavior of this system. In the dark, the emission intensity of Ru(bipy)32+ in supernatant was essentially constant, indicating good capping efficiency. Whereas M1 was irradiated with UV light at 240 nm (≈0.2 W/cm2), the emission intensities of Ru(bipy)32+ in supernatant gradually increased, confirming that the irradiation triggered the opening of the molecular gate and allowed the entrapped Ru(bipy)32+ to be released. After 5 h of irradiation, the emission intensity remained constant, indicating that no more dye was released. 82% of the Ru(bipy)32+ stored was released from mesopores of MSN to supernatant after continuous irradiation for 24 h. Figure S3 showed the change of fluorescence intensity of supernatant after the treatment in the dark and irradiation with UV light at 240 nm for 5 h, respectively. In addition, we measured the luminescence properties of Ru(bipy)32+ in the presence of photoirradiation (Figure S4). However, we could not find any

of thymine monomer, and also indicated that photoreactions (dimerization and cleavage) of the thymine fixed on the surface of MSN were reversible. To investigate the light-triggered controlled release, the reaction was performed by the irradiation of UV light at 365 nm wavelength for 24 h to block the pores. Ru(bipy)32+ was selected as guest molecules and loaded into the pores before the irradiation with 365 nm wavelength UV light. Then, the excess dye was removed by centrifugation and repeated washing with PBS buffer (5.00 mL, 100.0 mM, pH 7.4). The resulting particles were denoted as M1. The successful loading and light-triggered release of guest molecules were monitored 4006

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influences in Ru(bipy)32+ with photoirradiation, because we used a low-power UV lamp. The on−off switching could be repeated by adjustment of irradiation between 365 and 240 nm. Figure 6b showed that the M1 after dye was released (denoted as M2) could be used to load the dye again. The reloaded efficiency almost had no change. Moreover, the result showed that the cyclic activation of this molecule-gated system was excellent. For investigating the feasible applications, the cytotoxicity caused by irradiation of 240 nm light (≈0.2 W/cm2) was demonstrated. As shown in Figure S5, the cytotoxicity of the light against HeLa cells and CEM cells increased with the increase of irradiation time. After irradiation with 240 nm light for 7 h, the cell viabilities were 81% (HeLa cells) and 86% (CEM cells), indicating no obvious cytotoxic effect. Because the fluorescence of Ru(bipy)32+ can be quenched in the presence of oxygen. This proof of concept provides an idea to design a photoswitchable oxygen sensor. To test this, the fluorescence emission spectra of M1 under various irradiation times and different oxygen partial pressures were examined (Figure 7). In the dark, the fluorescence intensities of M1

detection and hypoxia imaging. Based on the stated cyclic activation of the molecule-gated system above, this photoswitchable oxygen sensor could be regenerable.

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CONCLUSION We have designed and synthesized a reversible molecule-gated system based on the photodimerization-cleavage cycle of thymine modified on mesoporous silica nanoparticles. A thymine derivative was attached directly to the outlet of the mesopores by the highly efficient EDC/NHS reaction and served as a blockage to entrap guest molecules within the mesopores. Dye loading was accomplished by soaking TA-MSN in a solution of Ru(bipy)32+ and blocking the pores through thymine dimer under irradiation with 365 nm wavelength UV light. Cargo release was triggered by 240 nm wavelength UV light to cleave the cyclobutane (thymine dimer). The system showed high loading efficiency and good release behavior. The results indicated that the molecule-gated system had excellent cyclic activation. In addition, a photoswitchable oxygen sensor with Ru(bipy)32+ as guest molecules was successfully designed. Therefore, this proof of concept might provide a general route for the use of other functional small molecules as blockages for controlled delivery nanodevices.

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ASSOCIATED CONTENT

S Supporting Information *

Fluorescence emission spectroscopic data, photographs of M1 in blue light after its irradiation with UV light at 240 nm for 5 h, and luminescence properties of free Ru(bipy)32+ after its exposure to UV light. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; [email protected]. Figure 7. The photoswitchable oxygen sensors exhibited significant quenching in the presence of oxygen. The changes in fluorescence intensity of M1 were ultraviolet irradiation time-dependent and oxygen concentration-dependent. The relative fluorescence intensities of M1 were monitored under different oxygen partial pressures after irradiation for 0 (black circles), 1 (open circles), 2 (black triangles), 4 (open triangles), and 8 h (black quadrangle) by ultraviolet light. I0 is the emission intensity in the deoxygenated buffer obtained by flushing with nitrogen. I is the emission intensity of oxygen-containing solutions equilibrated with different oxygen partial pressures.

Notes

remained relatively constant, indicating that the MSN could protect and prevent the enwraped Ru(bipy)32+ dye from being quenched by oxygen in solution. Whereas the fluorescence intensity of M1 in 594 nm after irradiation with 240 nm UV light for a certain time decreased apparently at the same condition. Moreover, the changes of fluorescence intensities of M1 were ultraviolet irradiation time-dependent and oxygen concentration-dependent. When the exposure time was extended, the fluorescence intensity of M1 was decreased more and more severly because of the increased amount of Ru(bipy)32+ dye releasing from M1 to PBS buffer. Besides, the fluorescence intensities of the system were also decreased with increasing oxygen partial pressure. The tendency of decrease in fluorescence intensity of M1 was similar to that of free Ru(bipy)32+ dye under different oxygen partial pressures. These results indicated that M1 could be used as a photoswitchable oxygen sensor and might have potential in intracellular oxygen

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by the Key Project of Natural Science Foundation of China (90606003, 21175039, 21190044), International Science & Technology Cooperation Program of China (2010DFB30300), and project supported by Hunan Provincial Natural Science Foundation of China (10JJ7002). ABBREVIATIONS MSN, mesoporous silica nanoparticles; TA-MSN, thyminefunctionalized MSN; M1, TA-MSN after pore filling and dimerization of thymine; M2, M1 after cargo release and photocleavage of cyclobutane dimer

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REFERENCES

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dx.doi.org/10.1021/la2047504 | Langmuir 2012, 28, 4003−4008