Mesoporous silica functionalized with an AIE luminogen for drug delivery

Abstract

An aggregation-induced emission (AIE) luminogen, tetraphenylethene, has been successfully grafted onto mesoporous silica SBA-15 for the first time. The materials emit blue light upon UV irradiation, and are photostable for the ibuprofen (IBU) drug loading and release process, indicating their great potential for biomedical applications.

---

Recently, multifunctional materials have been applied to multimodal imaging and drug release in the field of biomedicine.¹ The mesoporous materials with large surface area, tunable pore size and good biocompatibility allow the efficient adsorption of biologically active species, especially drug molecules, onto the porous structures, as well as the controlled drug release.² The design and synthesis of fluorescent materials based on ordered mesoporous silica have great potential for imaging-guided therapy.³ So far, several types of fluorescent nanomaterials have been found to be useful as visualization tools in biomedical imaging,⁴ such as semiconductor quantum dots (QDs),⁵ metal nanoclusters,⁶ metal-doped nanomaterials⁷ and organic–inorganic hybrid materials,⁸etc. Among those materials, QDs (e.g., CdS) generally show low fluorescence quantum yield compared to the organic dyes and have high toxicity, which may limit their further applications.⁹ Many commonly used organic dyes (e.g., rhodamine, nile red) emit efficiently in the dilute solutions, but suffer from aggregation-caused quenching (ACQ) in the solid state and their emission may be weakened or they may even become nonemissive when they are incorporated into the solid materials.¹⁰ Since the first anti-ACQ namely aggregation-induced emission (AIE) material that shows high emissivity in the aggregated state was discovered by Tang and coworkers,¹¹ such materials have aroused great attention because of their intriguing fluorescence phenomenon.¹² More recently, AIE luminogens were utilized for the fabrication of silica nanoparticles and polymers with high fluorescence for intracellular imaging, holding great promise as a fluorescent probe in biolabeling.¹³ However, to the best of our knowledge, AIE dyes have not been introduced in mesoporous materials and tested as drug storage/release systems. In this work, we develop a simple method to synthesize AIE functionalized mesoporous SBA-15 through a reaction of the AIE luminogen, tetraphenylethene (BTPE), with the –NH₂groups modified in SBA-15. The BTPE chemically bonded to SBA-15 shows the characteristic AIE property, and is photostable in the drug storage and release process, indicating that such materials may be a new candidate for simultaneous drug carrying and cell imaging in potential bioapplications.

Both mesoporous SBA-15¹⁴ and 1,2-bis[4-(bromomethyl)phenyl]-1,2-diphenylethene¹⁵ were prepared according to the literature and selected for investigation. Scheme 1 shows the synthesis process of SBA-15 incorporated with BTPE. Firstly, –NH₂ modified SBA-15 (SN) was obtained via post-grafting with 3-aminopropyltriethoxysilane (APTS).¹⁶ The amount of APTS incorporated in SBA-15 was about 2.15 mmol g⁻¹ according to the thermogravimetric analysis (Fig. S1, ESI†). The SN was then functionalized with BTPE molecules. In a typical procedure, 250 mg of SN and 5 mg of 1,2-bis[4-(bromomethyl)phenyl]-1,2-diphenylethene were added into 20 ml of DMSO solution, and the mixture was stirred at 80 °C for 24 h, then the white solid was filtered off, washed with ethanol for several times and dried under vacuum. The product was transferred into the Soxhlet extractor, washed with acetone for 48 h to remove the organic molecules that did not participate in the reaction. After completely drying at 60 °C, the material functionalized with the AIE luminogen (BTPE), marked as SNF, was obtained.

Scheme 1 The synthetic route to prepare mesoporous SBA-15 functionalized with an AIE luminogen.

Fig. 1a shows the emission spectrum of SNF in the solution of DMSO and its image under UV irradiation. Strikingly, it emits blue light at 480 nm, showing a characteristic AIE feature. This indicates that the BTPE molecules have been successfully grafted onto SBA-15 by reacting with the –NH₂groups. As a comparison, the raw material of SN shows nearly no fluorescence signal (Fig. 1c). In order to prove that the BTPE molecules show luminescence only after they form chemical bonds with the solid materials rather than physical adsorption, we also mixed SBA-15 with BTPE (denoted SF) in DMSO solvent at 80 °C for 24 h. However, when SF was photoexcited nearly no fluorescence signal was recorded (Fig. 1d). Furthermore, it is noticed that when SN is initially mixed with BTPE in DMSO solvent, it shows no luminescence before the reaction (Fig. 1b), but emits strong luminescence after reaction at 80 °C for 24 h. The AIE phenomenon of SNF can be explained by that when the BTPE molecules bond with SN, the internal rotation of the molecules is largely restricted and thus block the nonradiative relaxation channel and populate the radioactive decay to the ground state, making the material emissive.

Fig. 1 Fluorescence spectra of samples in DMSO solvent. (a) SNF; (b) SN mixed with BTPE before reaction; (c) SN; (d) SF. Excitation wavelength: 380 nm. The photographs are taken under UV light illumination (365 nm).

The ordered pores and two-dimensional hexagonal mesostructure of SNF were confirmed by transmission electron microscopy (TEM) (Fig. S2, ESI†) and small-angle powder X-ray diffraction (XRD) (Fig. S3, ESI†). The N₂ adsorption–desorption (Fig. S4, ESI†) of SNF material shows type IV isotherms with H1 type hysteresis loops in the 0.5–0.7 P/P₀ range. The BET surface area and the pore volume are 263 m² g⁻¹ and 0.33 cm³ g⁻¹, respectively. The pore size distribution is around 5.76 nm, which is consistent with the result of TEM. The textural parameters of the materials are summarized in Table S1 (ESI†). It can be seen that the incorporation of a small amount of BTPE molecules (not more than the theoretical value of 0.039 mmol g⁻¹) has hardly any effect on the adsorption capacity of the material. The scanning electron microscopy (SEM) image (Fig. S5, ESI†) of SNF shows a rod-like morphology with a width of 300 nm and a length of 1 μm.

Ibuprofen (IBU) was used as the model drug for the drug loading and release in SNF material. It shows a drug immobilization of 59.8 wt% (Table S1, ESI†), determined by UV-vis at 263 nm, which is similar to that of SN. It can be seen that the incorporation of BTPE molecules does not affect the drug loading amount. The N₂ adsorption–desorption analyses of the SNF–IBU gave the surface area of 9 m² g⁻¹ (Fig. S4c, ESI†), which reflects that the mesoporous channels have been fully filled by IBU. FT-IR spectra of SNF, IBU and SNF–IBU were recorded to further prove the successful adsorption of IBU onto the material (Fig. S6, ESI†). The band at 1720 cm⁻¹ (Fig. S6b, ESI†) which is attributed to the COOH is still obvious in SNF—IBU, except for a slight decrease in the intensity compared with that of IBU, suggesting that the IBU molecules have been immobilized in the pores. Meanwhile, the band at 1560 cm⁻¹ can be attributed to the asymmetric stretching vibration of COO⁻ indicating the formation of COO⁻–NH₃⁺ bonds between IBU molecules and SNF.¹⁷ The bands at 2929 cm⁻¹ and 2851 cm⁻¹ (Fig. S6a, ESI†) are attributed to C–H asymmetric and symmetric stretching vibrations of APTS, respectively, and the peak at 688 cm⁻¹ can be assigned to the N–H bending vibrations of the aminopropyl groups anchored on the surface of SBA-15.

Fig. 2 shows the drug release process of the SNF by immersing 50 mg of the sample in the simulated body fluid (SBF)¹⁸ with slow stirring at 37 °C, as compared with SN. The ratio of SBF to adsorbed IBU was kept at 1 ml mg⁻¹. Both SNF and SN show almost the same release profiles. The initial burst release of about 80% in the first hour is ascribed to the IBU molecules that are adsorbed in the mesopores. As the time extended, the drug release achieved a balance around 87%, but was not complete because the amide bonding may prolong the drug release effect. Notably, after being loaded with IBU, the fluorescence intensity of SNF–IBU is further enhanced as compared with SNF (Fig. 3a). This is because the internal rotation of BTPE molecules might be further restricted inside the mesopore. On the other hand, after the release of IBU reached balance, the fluorescence intensity of SNF–IBU decreased (Fig. 3b), comparable with that of SNF without drug storage (Fig. 3c). Other drugs, such as metoprolol, were also used for the adsorption in SNF, all of which showed enhanced fluorescence. This character indicates that the AIE functionalized mesoporous materials may have the potential application as efficient bioprobes to be tracked by the luminescence.

Fig. 2 The release curves of IBU from (a) SNF and (b) SN in SBF.

Fig. 3 Fluorescence spectra of the materials in the solid state. (a) SNF–IBU; (b) SNF–IBU after drug release reaches balance; (c) SNF. Excitation wavelength: 380 nm. The photographs are taken under UV light illumination (365 nm).

In summary, we take advantage of the unique properties of the AIE luminogen and porous materials to develop the AIE-functionalized mesoporous materials for drug delivery for the first time. The obtained materials show blue light under photoexcitation. After being loaded with the IBU drug, the fluorescence intensity of the material is further enhanced and is photostable for the drug loading and release process. These materials will be useful in biomedical applications due to their simultaneous imaging and drug delivery.

This work is supported by the National Natural Science Foundation of China and the State Basic Research Project of China (Grants: 2011CB808703 and 2007CB936402).

Notes and references

1. M. Liong, S. Angelos, E. Choi, K. Patel, J. F. Stoddart and J. I. Zink, J. Mater. Chem., 2009, 19, 6251; S. L. Gai, P. P. Yang, C. X. Li, W. X. Wang, Y. L. Dai, N. Niu and J. Lin, Adv. Funct. Mater., 2010, 20, 1166; S. Jiang, M. K. Gnanasammandhan and Y. Zhang, J. R. Soc. Interface, 2010, 7, 3; P. P. Yang, Z. W. Quan, L. L. Lu, S. S. Huang and J. Lin, Biomaterials, 2008, 29, 692.
2. M. Vallet-Regí, A. Rámila, R. P. del Real and J. Pérez-Pariente, Chem. Mater., 2001, 13, 308; I. I. Slowing, B. G. Trewyn, S. Giri and V. S.-Y. Lin, Adv. Funct. Mater., 2007, 17, 1225; J. M. Rosenholm, C. Sahlgren and M. Lindén, Nanoscale, 2010, 2, 1870; W. R. Zhao, H. R. Chen, Y. S. Li, L. Li, M. D. Lang and J. L. Shi, Adv. Funct. Mater., 2008, 18, 2780; M. Vallet-Regí, Chem.–Eur. J., 2006, 12, 5934.
3. J. Kim, H. S. Kim, N. Lee, T. Kim, H. Kim, T. Yu, I. C. Song, W. K. Moon and T. Hyeon, Angew. Chem., Int. Ed., 2008, 47, 8438; J. E. Lee, N. Lee, H. Kim, J. Kim, S. H. Choi, J. H. Kim, T. Kim, I. C. Song, S. P. Park, W. K. Moon and T. Hyeon, J. Am. Chem. Soc., 2010, 132, 552; J. L. Vivero-Escoto, I. I. Slowing, B. G. Trewyn and V. S.-Y. Lin, Small, 2010, 6, 1952; J. Rosenholm, C. Sahlgren and M. Lindén, J. Mater. Chem., 2010, 20, 2707.
4. C. Feldmann, Nanoscale, 2011, 3, 1947.
5. M. Nakamura, S. Ozaki, M. Abe, T. Matsumoto and K. Ishimura, J. Mater. Chem., 2011, 21, 4689; J. Pan, D. Wan and J. L. Gong, Chem. Commun., 2011, 47, 3442.
6. X. L. Guével, B. Hötzer, G. Jung and M. Schneider, J. Mater. Chem., 2011, 21, 2974; I. Díez and R. H. A. Ras, Nanoscale, 2011, 3, 1963.
7. Z. H. Xu, Y. Gao, S. S. Huang, P. A. Ma, J. Lin and J. Y. Fang, Dalton Trans., 2011, 40, 4846.
8. Q. J. He, J. L. Shi, X. Z. Cui, J. J. Zhao, Y. Chen and J. Zhou, J. Mater. Chem., 2009, 19, 3395; X. J. Zhao, R. P. Bagwe and W. H. Tan, Adv. Mater., 2004, 16, 173.
9. K. Cottingham, Anal. Chem., 2005, 77, 354A; X. Q. Gao, J. He, L. Deng and H. N. Cao, Opt. Mater. (Amsterdam), 2009, 31, 1715.
10. S. W. Thomas III, G. D. Joly and T. M. Swager, Chem. Rev., 2007, 107, 1339.
11. J. D. Luo, Z. L. Xie, J. W. Y. Lam, L. Cheng, H. Y. Chen, C. F. Qiu, H. S. Kwok, X. W. Zhan, Y. Q. Liu, D. B. Zhu and B. Z. Tang, Chem. Commun., 2001, 1740.
12. Y. N. Hong, J. W. Y. Lam and B. Z. Tang, Chem. Commun., 2009, 4332; M. Wang, G. X. Zhang, D. Q. Zhang, D. B. Zhu and B. Z. Tang, J. Mater. Chem., 2010, 20, 1858; M. Wang, D. Q. Zhang, G. X. Zhang, Y. L. Tang, S. Wang and D. B. Zhu, Anal. Chem., 2008, 80, 6443; H. Tong, Y. N. Hong, Y. Q. Dong, M. Häussler, Z. Li, J. W. Y. Lam, Y. P. Dong, H. H. Y. Sung, I. D. Williams and B. Z. Tang, J. Phys. Chem. B, 2007, 111, 11817; Y. S. Zheng and Y. J. Hu, J. Org. Chem., 2009, 74, 5660.
13. M. Faisal, Y. N. Hong, J. Z. Liu, Y. Yu, J. W. Y. Lam, A. J. Qin, P. Lu and B. Z. Tang, Chem.–Eur. J., 2010, 16, 4266; D. Wang, J. Qian, S. L. He, J. S. Park, K. S. Lee, S. H. Han and Y. Mu, Biomaterials, 2011, 32, 5880; F. Mahtab, Y. Yu, J. W. Y. Lam, J. Z. Liu, B. Zhang, P. Lu, X. X. Zhang and B. Z. Tang, Adv. Funct. Mater., 2011, 21, 1733; F. Mahtab, J. W. Y. Lam, Y. Yu, J. Z. Liu, W. Z. Yuan, P. Lu and B. Z. Tang, Small, 2011, 7, 1448.
14. D. Y. Zhao, Q. S. Huo, J. L. Feng, B. F. Chmelka and G. D. Stucky, J. Am. Chem. Soc., 1998, 120, 6024.
15. A. J. Qin, L. Tang, J. W. Y. Lam, C. K. W. Jim, Y. Yu, H. Zhao, J. Z. Sun and B. Z. Tang, Adv. Funct. Mater., 2009, 19, 1891.
16. Z. H. Luan, J. A. Fournier, J. B. Wooten and D. E. Miser, Microporous Mesoporous Mater., 2005, 83, 150.
17. P. P. Yang, S. S. Huang, D. Y. Kong, J. Lin and H. G. Fu, Inorg. Chem., 2007, 46, 3203.
18. T. Kokubo and H. Takadama, Biomaterials, 2006, 27, 2907.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental details for the synthesis, TGA, TEM, SEM, XRD patterns, N₂ adsorption–desorption data and FTIR spectra. See DOI: 10.1039/c1cc14064g

---