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Long-lasting phosphorescence functionalization of mesoporous silica nanospheres by CaTiO3:Pr3+ for drug delivery
Microporous and Mesoporous Materials 176 (2013) 48–54
Contents lists available at SciVerse ScienceDirect
Microporous and Mesoporous Materials journal homepage: www.elsevier.com/locate/micromeso
Long-lasting phosphorescence functionalization of mesoporous silica nanospheres by CaTiO3:Pr3+ for drug delivery Zhan-Jun Li, Yi-Juan Zhang, Hong-Wu Zhang ⇑, Hai-Xia Fu Institute of Urban Environment, Chinese Academy of Sciences, Jimei Road 1799, Xiamen City 361021, China
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Article history: Received 12 September 2012 Received in revised form 15 February 2013 Accepted 18 February 2013 Available online 5 April 2013 Keywords: Long-lasting phosphorescence Mesoporous Drug delivery Imaging in vivo CaTiO3:Pr3+
a b s t r a c t Long-lasting phosphorescence functionalization of the ordered mesoporous silica nanospheres (MSNs) was realized by depositing a CaTiO3:Pr3+ phosphor layer on its surface via the Pechini sol–gel process, resulting in the formation of the MSNs@CaTiO3:Pr3+ composite material. This material, which combines the mesoporous structure of MSNs and the red long-lasting phosphorescence property of CaTiO3:Pr3+, can be used as a novel functional drug delivery system. The results indicate that a CaTiO3:Pr3+ layer can be synthesized when the annealing temperature reaches 600 °C and impurity phases start to appear when the annealing temperature reaches 800 °C or higher. The specific surface area of MSNs@CaTiO3:Pr3+ decreases along with the increase of annealing temperature. The MSNs@CaTiO3:Pr3+ sample synthesized at 700 °C has appropriate phosphorescence intensity and enough specific surface area (306 m2/g) to load drug molecules. The as-synthesized MSNs@CaTiO3:Pr3+ composite material can be tracked in vivo by optical imaging in 12 min after peritoneal injection. The quercetin-loaded MSNs@CaTiO3:Pr3+ system still shows the red phosphorescence of Pr3+ (614 nm) after UV irradiation and possesses sustained drug release property. In addition, the phosphorescence intensity of Pr3+ increases with an increase in the cumulative released amount of quercetin in the system, making the extent of drug release easily identifiable, trackable, and monitorable by the change of phosphorescence. Our research supplies a new way to fabricate in vivo visible drug delivery system. Ó 2013 Elsevier Inc. All rights reserved.
1. Introduction In the past several decades, controlled drug delivery systems have attracted more and more attention in the fields of modern medicine and pharmaceuticals because of their high drug delivery efficiency and reduced toxicity in comparison with conventionally administrated drugs in dosage forms [1–3]. Generally, controlled drug delivery systems can not only deliver the drugs to the targeted focus but also maintain the optimum concentration of drugs in precise sites of organs, which can both improve therapeutic efficiency and reduce side effect [4–6]. Recently, ordered mesoporous silica nanoparticles (MSNs) have gained considerable attention as drug carriers because of their stable mesoporous structure, tunable pore size, high specific surface area, nontoxic nature, well-defined surface properties and good biocompatibility. So far, a large number of drug storage/release systems based on MSNs have been reported [7–11]. It is worth noting that mesoporous materials functionalized with photoluminescence have demonstrated feasible applications in the fields of drug delivery and disease diagnosis and therapy
⇑ Corresponding author. Tel./fax: +86 592 619 0773. E-mail address: [email protected] (H.-W. Zhang). 1387-1811/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.micromeso.2013.02.050
[1,7,9–16]. This is because these controlled drug delivery systems not only have high pore volume for storage and delivery of drugs but also possess photoluminescence properties which can be tracked to evaluate the efficiency of the drug release. Photoluminescence functionalized mesoporous silica may be employed for qualitative and quantitative detection of disease position and drug release efficiency. Therefore, the design of mesoporous materials functionalized with photoluminescence properties and drug storage capabilities plays a key role in achieving this application [1]. Various luminescent materials, e.g., YVO4:Eu [1], Gd2O3:Er [13], NaYF4:Yb, Er [15], have been fabricated into mesoporous silica (such as MCM-41 and SBA-15) and tested as drug storage/release systems. The mesoporous silica-based luminescent materials show stable porous structures, large pore volumes, large specific surface areas, which are suitable for loading a high quantity of drug molecules and possess high sustained-release properties. However, one problem may hinder the application of the reported luminescence functionalized mesoporous drug delivery system in which an excitation light source must be used to generate the emission. Moreover, the excitation light is usually shortwave UV light, which is very hard to penetrate deep biological issue. And, due to constant illumination during signal acquisition, shortwave excitation will encounter serious autofluorescence from tissue organic components, which often results in poor signal-to-noise ratio.
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Furthermore, long time UV illumination will hurt the biological tissue. To overcome these difficulties, persistent phosphorescent nanoparticles have been developed for in vivo imaging to avoid most of inherent problems encountered in classical optical systems [17]. In previous reported results, the persistent phosphorescence allows detection in rather deep organs and real-time biodistribution monitoring for more than 1 h after injection [18]. However, the reported persistent phosphorescent nanoparticles have no capability to carry drugs or biological functional molecules. Herein, in order to utilize the advantages of both mesoporous materials and persistent phosphor, we propose a novel design to fabricate drug storage/release systems by incorporating persistent phosphor, CaTiO3:Pr3+, onto the surface of MSNs via Pechini sol–gel process. CaTiO3:Pr3+ was chosen as persistent phosphor because of its long-wave phosphorescence spectra at 614 nm (lower autofluorescence and higher tissue penetration ability than shortwave light), relatively low synthesis temperature (450 °C), and good biocompatibility [19–21]. In our experiment, the phosphorescencefunctionalized MSNs materials were used in imaging in vivo to show their trace and also used as drug-carriers to study the release properties in the release media of simulated body fluid based on its high pore volume, phosphorescence and nontoxic properties. The obtained results showed that the emission intensity of Pr3+ increases with the increasing cumulative released amount of the drug (quercetin) in the system, which suggested that the extent of drug release can be easily identified, tracked, and monitored by the change of phosphorescence.
2. Experimental
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2.3. In vivo imaging of MSNs@CaTiO3:Pr3+ The as-synthesized MSNs@CaTiO3:Pr3+ nanospheres were milled using a pestle and mortar and dispersed in normal saline assisted by ultrasound. 200 lL of MSNs@CaTiO3:Pr3+ colloid in normal saline (about 5 mg/mL) was injected into the abdomen of a mouse after irradiated by a UV lamp (330 nm) for 10 min. The afterglow signals were acquired for 60 s at every 1 min interval during 12 min by a small animal imaging in vivo system with a CCD camera (Caliper LifeSciences, IVIS Lumina II, America). 2.4. Controlled drug release of quercetin loaded MSNs@CaTiO3:Pr3+ The drug storage/release profile for MSNs@CaTiO3:Pr3+ system was prepared according to the previous report [24]. Quercetin was selected as the model drug. Typically, 0.5 g of the MSNs@CaTiO3:Pr3+ was added to 50 mL of ethanol solution of quercetin with a concentration of 2.5 mg/mL at room temperature and soaked for 24 h with stirring in a sealed vial. The quercetin loaded MSNs@CaTiO3:Pr3+ sample was separated by centrifugation, and then dried at 60 °C for 12 h. The in vitro delivery of quercetin was performed by immersion of 0.3 g of the sample in the release media of simulated body fluid (SBF) containing 20 v% of ethanol with stirring, and the temperature was kept at 37 °C. The ionic composition of the as-prepared SBF solution was similar to that of human body plasma with a molar composition of 142.0:5.0:2.5:1.5:147.8:4.2:1.0:0.5 for Naþ =Kþ =Ca2þ =Mg2þ =Cl 2 2 =HCO =HPO =SO (pH 7.4). The ratio of release media to ad3 4 4 sorbed quercetin was kept at 2.5 mL/mg. The amount of quercetin adsorbed onto MSNs@CaTiO3:Pr3+ was monitored by elemental analysis.
2.1. Synthesis of MSNs The starting materials for the synthesis of MSNs included tetraethylorthosilicate (TEOS), diethanolamine, cetyltrimethylammonium bromide (CTAB) and anhydrous ethanol. All reagents were analytical reagents and used as-received. MSNs were prepared by controlled hydrolysis of TEOS using CTAB as surfactant according to Qiao’s method with modifications [22]. Typically, 0.2 g of CTAB, 25 mL of water, 10 mL of ethanol, 50 lL of diethanolamine were mixed together and stirred in water bath of 80 °C for 30 min. Then 2 mL of TEOS was added into the solution rapidly. The solution turned white gradually. Finally, the solution was cooled to room temperature after a further 2 h stirring. MSNs were centrifuged after 20 mL acetone was added to the as-synthesized mixture. The precipitate was calcined at 550 °C for 2 h to remove CTAB templates.
2.2. Functionalization of MSNs by CaTiO3:Pr3+ MSNs@CaTiO3:Pr3+ core–shell particles were prepared by a previous reported sol–gel process with modifications [19,23]. Suitable amount of water–ethanol (1:7, v/v) solution containing citric acid as the chelating agent for the metal ions was prepared. Then stoichiometric weights of Ca(NO3)2 and Pr(NO3)3 were dissolved in the solution. After the solution turned transparent, stoichiometric amount of titanium tetrabutoxide was added with a final concentration of 0.2 g/mL. The solution was stirred for about 4 h to form transparent sol. Then the as-synthesized MSNs was added into the sol, stirred for 1 h, separated by centrifugation and dried at 105 °C immediately and then annealed to 500 °C. The above process was repeated 3 times to increase the thickness of CaTiO3:Pr3+ shell. After that, these samples were annealed to certain temperatures for 2 h in air atmosphere to obtain the final core–shell structured MSNs@CaTiO3:Pr3+ phosphors.
2.5. Characterization The X-ray diffractions (XRD) patterns were performed on polycrystal X-ray diffractometer equipped with Cu Ka radiation (k = 1.5418 Å) (PANalytical, X’pert PRO, Holland). The morphology of the samples was inspected using field emission scanning electron microscopy (FE-SEM, HITACHI, S-4800, Japan) and Transmission electron microscopy (TEM, Hitachi, H-7000 FA, Japan). The photoluminescence spectra and time decay curves were measured using a fluorescence spectrometer (Hitachi, F4600, Japan). N2 adsorption/desorption isotherms were obtained on a full-automatic physical and chemical adsorption apparatus (Micromeritics, ASAP2020C, America). Pore size distribution was calculated from the adsorption branch of N2 adsorption/desorption isotherm and the Brunauer–Emmett–Teller (BET) method. The BET specific surface areas were calculated using the data between 0.05 and 0.35 just before the capillary condensation. The total pore volumes were obtained by the t-plot method. Total organic carbon analyzer was used to determine the exact loading level of quercetin on the MSNs@CaTiO3:Pr3+ on a CNS elemental analyzer (Elementar Portfolio, Vario MAX, Germany). The absorbance of the released quercetin solution was detected on a UV–vis spectrometer (Thermo, Evolution 300, USA). 3. Results and discussion 3.1. Characterization of the as-prepared MSNs Fig. 1 shows the characterization data of the as-prepared MSNs. The low angle XRD pattern shows only one diffraction peak at 2h = 2.42°, which indicates a disordered crystal structure. At the same time, from the wide-angle XRD pattern (the inset of Fig. 1(A)), it can be observed that there is also only one broad band
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Fig. 1. XRD pattern (A), N2 adsorption/desorption isotherms (B) and FE-SEM photograph (C) of the as-synthesized MSNs.
Fig. 2. XRD patterns of MSNs@CaTiO3:Pr3+ phosphors.
located at 2h = 23°, which can be assigned to the characteristic diffraction peak of amorphous SiO2 (JCPDS card, No. 00-049-1712). As shown in the N2 adsorption/desorption isotherms (Fig. 1(B)), the MSNs sample shows typical type IV isotherm with H1-hystersis, indicating a typical mesoporous material with hexagonal cylindrical channels. The BET specific surface area of MSNs is calculated to be 1258 m2/g. The FE-SEM image (Fig. 1(C)) shows that the MSNs sample consists of uniform spherical particles with an average particle size of about 400 nm with very narrow size distribution. Both the ultrahigh specific surface area and monodisperse morphology are in accordance with the requirements of controlled drug delivery systems. 3.2. Characterization of the as-synthesized MSNs@CaTiO3:Pr3+ phosphor Fig. 2 shows the XRD patterns of the MSNs@CaTiO3:Pr3+ hybrid phosphor synthesized at various temperatures. It can be observed
that no CaTiO3 phase can be formed at 500 °C. CaTiO3 phase can be formed when the temperature increases to 600 °C and 700 °C. All the diffraction peaks can be attributed to the CaTiO3 phase (JCPDS card, No. 00-022-0153). The doping of 0.1% Pr3+ has no obvious effect on the diffraction peaks of CaTiO3. Additionally, no additional peaks for other phases can be detected, indicating that no reaction occurred between the MSNs core and CaTiO3 shell. The intensity of the diffraction peaks of CaTiO3 increase as the annealing temperature increases. In order to generate CaTiO3 phase with high degree of crystallinity, higher annealing temperature will be preferred. However, weak peaks of impurities start to appear at 31.435° when the annealing temperature increases to 800 °C. When the annealing temperature further increases from 800 °C to 900 °C and then to 1000 °C, more and more impurity peaks appear at 43.930°, 51.177°, 57.748°, 63.872°, 29.978°, 29.567°, 29.74°, 29.837°, 29.916°, 34.301°, 33.1°, 29.025°, 31.435°, 43.311°, 47.099°, 51.448°. These impurities may be attributed to the silicates, e.g., CaSiO3, CaSi2O5, Ca3(SiO4)O, formed from the reactions between calcium ions and mesoporous silica. In order to synthesize MSNs@CaTiO3:Pr3+ with both high degree of crystallinity and phase purity, the optimum annealing temperature will fall in the range from 700 °C to 800 °C. Fig. 3 exhibits the photoluminescence spectra of the as-synthesized MSNs@CaTiO3:Pr3+ phosphors. The as-synthesized MSNs@CaTiO3:Pr3+ (800 °C) has an apparent excitation peak at 325 nm, which can be attributed to the band edge absorption of the CaTiO3 host due to O(2p)–Ti(3d) transition.[19] The weak excitation peak at 397 nm can be attributed to 4f–5d transitions of Pr3+ [25]. Under the excitation of 325 nm, the phosphors show red sharp emission at 614 nm, which can be attributed to the intra4f 1D2–3H4 transitions of Pr3+ [26]. The maximum emission intensity of the phosphors appears at 800 °C. The photoluminescence intensity of MSNs@CaTiO3:Pr3+ samples firstly increases from 500 °C to 800 °C, and then decreases from 800 °C to 1000 °C. The increase is due to the better crystalline of CaTiO3:Pr3+ at higher temperature and the decrease can be attributed to the formation of impurity silicate phases.
Z.-J. Li et al. / Microporous and Mesoporous Materials 176 (2013) 48–54
Fig. 3. Photoluminescence spectra of MSNs@CaTiO3:Pr3+ phosphors.
In order to fabricate novel phosphorescent functionalized mesoporous drug carrier, the mesopores of the MSNs have to be retained after the annealing process. But the stability of the active, amorphous silica of MSNs is uncertain and doubted at high temperature. The N2 adsorption/desorption analysis indicates that the adsorption ability of MSNs@CaTiO3:Pr3+ phosphors decreases apparently when the annealing temperature increases from 600 °C to 800 °C (Fig. 4(A)). The BET specific surface area of the phosphors decreases nearly 40% from 600 °C (493 m2/g) to 700 °C (306 m2/g). When the annealing temperature increases further to 800 °C, only 5.6% specific surface area (27.4 m2/g) can be retained
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(Fig. 4(B)). Since the phosphor prepared at 700 °C still has relatively high specific surface area, we chose the MSNs@CaTiO3:Pr3+ phosphor synthesized at 700 °C to be used as phosphorescent drug carrier. The morphologies of MSNs@CaTiO3:Pr3+ phosphor synthesized at 700 °C were characterized by FE-SEM and TEM. It can be observed that the as-synthesized MSNs@CaTiO3:Pr3+ still keeps the similar morphological properties of the MSNs (Fig. 5(A)). However, the MSNs@CaTiO3:Pr3+ nanospheres become coarse with some irregular smaller nanoparticles adhering to their surfaces and have a slightly larger particle size which may be caused by the coating of CaTiO3:Pr3+ through a sol–gel approach. The morphological and structural features of the sample were further examined by TEM, as shown in Fig. 5(B). The TEM image obviously indicates that monodisperse nanospheres with narrow size distribution are obtained, which are well consistent with the corresponding SEM images. Additionally, from the TEM image of the MSNs@CaTiO3:Pr3+ particles, the core–shell structure can be clearly distinguished due to the different electron penetrability between the cores and shells. Furthermore, the MSNs@CaTiO3:Pr3+ spheres are well-dispersed and nonagglomerated, indicating that the nanospheres are water-dispersible and good for further surface functional modifications by various biomolecules, such as antibody, DNA, polyethylene, etc. 3.3. Application of MSNs@CaTiO3:Pr3+ in imaging in vivo CaTiO3:Pr3+ is a chemically and thermally stable red phosphor which has widely application as a promising red phosphor for low voltage field emission displays or for photoluminescent devices. It should be noted that CaTiO3:Pr3+ is also a promising red
Fig. 4. N2 adsorption/desorption isotherms (A) and specific surface areas (B) of MSNs@CaTiO3:Pr3+ phosphors.
Fig. 5. FE-SEM and TEM photographs of MSNs@CaTiO3:Pr3+.
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Fig. 6. Phosphorescence spectra (A) and decay curve (B) of MSNs@CaTiO3:Pr3+, the inset is the phosphorescence image of MSNs@CaTiO3:Pr3+ dispersed in water photographed by a SLR camera immediately after turning off the UV lamp.
long persistent phosphor [19]. The red emission can last for 20 min after cessation of the excitation light. The phosphorescence spectra of MSNs@CaTiO3:Pr3+ are shown in Fig. 6(A), which are similar with its luminescence spectra. The phosphorescence can be excited by UV light with wavelength less than 350 nm, and can be effectively excited by a commercial 254 nm UV lamp. The phosphorescence emission peaks at 614 nm and the emission spectrum is very sharp with a very narrow peak width at half height of about 28 nm, which is good for screening background signal. Fig. 6(B) illustrates the phosphorescence decay curve of MSNs@CaTiO3:Pr3+ after irradiation with 330 nm UV light for 10 min. After the cessation of the 254 nm excitation light, MSNs@CaTiO3:Pr shows a rapid decay (<20 s) and subsequently long lasting phosphorescence which may be employed to track the MSNs@CaTiO3:Pr3+ in vivo without simultaneous usage of UV excitation light. The inset of Fig. 6(B) is the intense phosphorescence picture of the MSNs@CaTiO3:Pr3+ phosphor dispersed in water photographed after the cessation of 330 nm UV lamp for 20 s by a Nikon D7000 SLR camera in a dark room (exposure time, 1 min). Since the as-prepared MSNs@CaTiO3:Pr3+ has long persistent phosphorescence property. It has the potential to be detected in real time in vivo for long time without the need of an UV excitation light source. Fig. 7 shows the in vivo imaging of MSNs@CaTiO3:Pr3+ phosphor after peritoneal injection in a living mouse. The MSNs@CaTiO3:Pr3+ can be clearly in 12 min after injection. There is a relatively strong background signal at the first 4 min
observation. This may be attributed to the light scattering of the tissue. When time went on, the phosphorescence signal decreased and less light could penetrate the animal tissue, the light scattering area also decreased. It is worth noting that long persistent phosphor has already found their applications in bioimaging and have shown unique in vivo trackable properties in mice [17,18,27]. However, the reported long persistent nanophosphors have no mesopores and cannot be used as efficient drug carriers. Although the lasting phosphorescence time is only several minutes in this MSNs@CaTiO3:Pr3+ system, our research supplies a route to fabricate nanophosphors possessing both drug-carrying capability and in vivo visible persistent phosphorescence property. If some kinds of more powerful long-lasting phosphorescence materials are fabricated together with mesoporous silica, better results will be expected. 3.4. Application of MSNs@CaTiO3:Pr3+ in controlled drug release The mesopores of the MSNs@CaTiO3:Pr3+ can be used as efficient vehicles to carry drug molecules. The relative loading degree of quercetin loaded MSNs@CaTiO3:Pr3+ is 4.171 wt.% determined by elemental analysis (C loading is 2.486%). The cumulative drug release profile of MSNs@CaTiO3:Pr3+ system is shown in Fig. 8. As shown in the figure, the release profile can clearly prove that the system exhibits sustained-release property. It can be observed that this delivery system shows a feature of two stages of release. In the
Fig. 7. In vivo imaging of MSNs@CaTiO3:Pr3+ photographed for 1 min exposure at every minute in 12 min after peritoneal injection in a living mouse.
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increasing the cumulative released amount of quercetin. And the relationship between normalized phosphorescence intensity (Y) and cumulative released amount of quercetin (X) can be well fitted with the following function.
Y ¼ expð0:00782 0:358=ðX þ 0:0988ÞÞ
Fig. 8. Cumulative quercetin release from MSNs@CaTiO3:Pr3+.
first stage from the start to 30 h, the amount released from MSNs@CaTiO3:Pr3+ delivery system reaches about 3.58%. In the second stage from 30 h to 130 h, the release rate became slower. Only a more 1.72 wt.% of the quercetin in MSNs@CaTiO3:Pr3+ was released even after another 100 h. This very slow drug release property may be attributed to the poor solubility of quercetin in water. The drug release result indicates that the as-synthesized MSNs@CaTiO3:Pr3+ nanospheres have potential applications in the development of controlled or delayed drug delivery system. Based on the concept of time-resolved luminescence assay, the detection of phosphorescence allows to effectively eliminate the short-lived background noise from the biological samples and scattering from nearby optics, and thus results in better signal-to-noise ratio than fluorescence or luminescence [28,29]. However, until to now, the lifetimes of the reported time-resolved luminescence bioassay systems are usually in microsecond or millisecond scale, and expensive time-resolved fluorescence spectrometer have to be used. The long-lasting phosphorescence of CaTiO3:Pr3+ can last for several minutes [30,31]. Therefore, the detection of time-resolved phosphorescence spectra of MSNs@CaTiO3:Pr3+ can be achieved in a common fluorescence spectrometer in our assay (Fig. 6). The phosphorescent emission intensity of quercetin loaded MSNs@CaTiO3:Pr3+ nanospheres has been investigated as a function of cumulative released amount of quercetin, as shown in Fig. 9. It can be seen that the phosphorescent intensity increases along with
Fig. 9. Phosphorescence emission intensity of MSNs@CaTiO3:Pr3+ as a function of cumulative release amount of quercetin.
It is well-known that the emission of lanthanide ions may be quenched to some extent in the environments which contain high phonon frequency. The organic groups of quercetin may quench the emission of Pr3+ to a great extent in the quercetin loaded MSNs@CaTiO3:Pr3+ system. In addition, the strong absorption of quercetin in the UV spectrum will hinder the efficient excitation of CaTiO3:Pr3+. With the release of quercetin, its quenching effect on the emission of Pr3+ and UV absorbance will be weakened, resulting in an increase of phosphorescence emission intensity. This correlation between the emission intensity and drug release extent can be potentially used as a probe to monitor the drug-release process and efficiently in the course of the disease therapy. 4. Conclusions In summary, we have fabricated a novel drug-storage/release system functionalized with long-lasting phosphorescent properties by deposition of a CaTiO3:Pr3+ layer onto the particle surface of MSNs. This system can be tracked in vivo by optical imaging and possesses sustained-release properties of the drug in an in vitro assay. The phosphorescence intensity increases along with the increase of the cumulative released amount of quercetin. The combination of both mesoporous nanoparticles and long-lasting phosphorescence properties in MSNs@CaTiO3:Pr3+ system makes it possible to identify, track, and monitor the drug delivery and disease therapy process. Acknowledgments This work was supported by the ‘‘One Hundred Talents’’ Program of CAS (Grant No. 09i4281c10), the Main Direction Program of Knowledge Innovation of Chinese Academy of Sciences KZCXZYW-453 ‘‘Development and Demonstration of Digital Urban Environmental Network’’ and Xiamen Funds for Distinguished Young Scientists. References [1] P. Yang, S. Huang, D. Kong, J. Lin, H. Fu, Inorg. Chem. 46 (2007) 3203–3211. [2] A. Patil, A.A. Lafarga, M. Chebrot, D.A. Lamprou, A. Urquhart, D. Douroumis, J. Biomed. Nanotechnol. 8 (2012) 550–557. [3] M. Wang, J. Zhang, Z. Yuan, W. Yang, Q. Wu, H. Gu, J. Biomed. Nanotechnol. 8 (2012) 624–632. [4] M. Alnaief, S. Antonyuk, C.M. Hentzschel, C.S. Leopold, S. Heinrich, I. Smirnova, Microporous Mesoporous Mater. 160 (2012) 167–173. [5] J. Gu, S. Su, M. Zhu, Y. Li, W. Zhao, Y. Duan, J. Shi, Microporous Mesoporous Mater. 161 (2012) 160–167. [6] F. Sevimli, A. Yilmaz, Microporous Mesoporous Mater. 158 (2012) 281–291. [7] I.I. Slowing, J.L. Vivero-Escoto, C.W. Wu, V.S.Y. Lin, Adv. Drug Delivery Rev. 60 (2008) 1278–1288. [8] P. Yang, Z. Quan, L. Lu, S. Huang, J. Lin, Biomaterials 29 (2008) 692–702. [9] Z. Hou, C. Li, Adv. Funct. Mater. 22 (2012) 2713–2722. [10] X. Kang, Z. Cheng, D. Yang, Adv. Funct. Mater. 22 (2012) 1470–1481. [11] P. Yang, S. Gai, J. Lin, Chem. Soc. Rev. 41 (2012) 3679–3698. [12] S. Gai, P. Yang, C. Li, W. Wang, Y. Dai, N. Niu, J. Lin, Adv. Funct. Mater. 20 (2010) 1166–1172. [13] Z. Xu, Y. Gao, S. Huang, P.a. Ma, J. Lin, J. Fang, Dalton Trans. 40 (2011) 4846– 4854. [14] Z. Xu, C. Li, P.a. Ma, Z. Hou, D. Yang, X. Kang, J. Lin, Nanoscale 3 (2011) 661– 667. [15] Y. Dai, P.a. Ma, Z. Cheng, X. Kang, X. Zhang, Z. Hou, C. Li, D. Yang, X. Zhai, J. Lin, ACS Nano 6 (2012) 3327–3338. [16] Y. Dai, C. Zhang, Z. Cheng, Biomaterials 33 (2012) 2583–2592. [17] T. Maldiney, A. Lecointre, B. Viana, A. Bessiere, M. Bessodes, D. Gourier, C. Richard, D. Scherman, J. Am. Chem. Soc. 133 (2011) (1815) 11810–11815.
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Microporous and Mesoporous Materials journal homepage: www.elsevier.com/locate/micromeso
Long-lasting phosphorescence functionalization of mesoporous silica nanospheres by CaTiO3:Pr3+ for drug delivery Zhan-Jun Li, Yi-Juan Zhang, Hong-Wu Zhang ⇑, Hai-Xia Fu Institute of Urban Environment, Chinese Academy of Sciences, Jimei Road 1799, Xiamen City 361021, China
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Article history: Received 12 September 2012 Received in revised form 15 February 2013 Accepted 18 February 2013 Available online 5 April 2013 Keywords: Long-lasting phosphorescence Mesoporous Drug delivery Imaging in vivo CaTiO3:Pr3+
a b s t r a c t Long-lasting phosphorescence functionalization of the ordered mesoporous silica nanospheres (MSNs) was realized by depositing a CaTiO3:Pr3+ phosphor layer on its surface via the Pechini sol–gel process, resulting in the formation of the MSNs@CaTiO3:Pr3+ composite material. This material, which combines the mesoporous structure of MSNs and the red long-lasting phosphorescence property of CaTiO3:Pr3+, can be used as a novel functional drug delivery system. The results indicate that a CaTiO3:Pr3+ layer can be synthesized when the annealing temperature reaches 600 °C and impurity phases start to appear when the annealing temperature reaches 800 °C or higher. The specific surface area of MSNs@CaTiO3:Pr3+ decreases along with the increase of annealing temperature. The MSNs@CaTiO3:Pr3+ sample synthesized at 700 °C has appropriate phosphorescence intensity and enough specific surface area (306 m2/g) to load drug molecules. The as-synthesized MSNs@CaTiO3:Pr3+ composite material can be tracked in vivo by optical imaging in 12 min after peritoneal injection. The quercetin-loaded MSNs@CaTiO3:Pr3+ system still shows the red phosphorescence of Pr3+ (614 nm) after UV irradiation and possesses sustained drug release property. In addition, the phosphorescence intensity of Pr3+ increases with an increase in the cumulative released amount of quercetin in the system, making the extent of drug release easily identifiable, trackable, and monitorable by the change of phosphorescence. Our research supplies a new way to fabricate in vivo visible drug delivery system. Ó 2013 Elsevier Inc. All rights reserved.
1. Introduction In the past several decades, controlled drug delivery systems have attracted more and more attention in the fields of modern medicine and pharmaceuticals because of their high drug delivery efficiency and reduced toxicity in comparison with conventionally administrated drugs in dosage forms [1–3]. Generally, controlled drug delivery systems can not only deliver the drugs to the targeted focus but also maintain the optimum concentration of drugs in precise sites of organs, which can both improve therapeutic efficiency and reduce side effect [4–6]. Recently, ordered mesoporous silica nanoparticles (MSNs) have gained considerable attention as drug carriers because of their stable mesoporous structure, tunable pore size, high specific surface area, nontoxic nature, well-defined surface properties and good biocompatibility. So far, a large number of drug storage/release systems based on MSNs have been reported [7–11]. It is worth noting that mesoporous materials functionalized with photoluminescence have demonstrated feasible applications in the fields of drug delivery and disease diagnosis and therapy
⇑ Corresponding author. Tel./fax: +86 592 619 0773. E-mail address: [email protected] (H.-W. Zhang). 1387-1811/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.micromeso.2013.02.050
[1,7,9–16]. This is because these controlled drug delivery systems not only have high pore volume for storage and delivery of drugs but also possess photoluminescence properties which can be tracked to evaluate the efficiency of the drug release. Photoluminescence functionalized mesoporous silica may be employed for qualitative and quantitative detection of disease position and drug release efficiency. Therefore, the design of mesoporous materials functionalized with photoluminescence properties and drug storage capabilities plays a key role in achieving this application [1]. Various luminescent materials, e.g., YVO4:Eu [1], Gd2O3:Er [13], NaYF4:Yb, Er [15], have been fabricated into mesoporous silica (such as MCM-41 and SBA-15) and tested as drug storage/release systems. The mesoporous silica-based luminescent materials show stable porous structures, large pore volumes, large specific surface areas, which are suitable for loading a high quantity of drug molecules and possess high sustained-release properties. However, one problem may hinder the application of the reported luminescence functionalized mesoporous drug delivery system in which an excitation light source must be used to generate the emission. Moreover, the excitation light is usually shortwave UV light, which is very hard to penetrate deep biological issue. And, due to constant illumination during signal acquisition, shortwave excitation will encounter serious autofluorescence from tissue organic components, which often results in poor signal-to-noise ratio.
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Furthermore, long time UV illumination will hurt the biological tissue. To overcome these difficulties, persistent phosphorescent nanoparticles have been developed for in vivo imaging to avoid most of inherent problems encountered in classical optical systems [17]. In previous reported results, the persistent phosphorescence allows detection in rather deep organs and real-time biodistribution monitoring for more than 1 h after injection [18]. However, the reported persistent phosphorescent nanoparticles have no capability to carry drugs or biological functional molecules. Herein, in order to utilize the advantages of both mesoporous materials and persistent phosphor, we propose a novel design to fabricate drug storage/release systems by incorporating persistent phosphor, CaTiO3:Pr3+, onto the surface of MSNs via Pechini sol–gel process. CaTiO3:Pr3+ was chosen as persistent phosphor because of its long-wave phosphorescence spectra at 614 nm (lower autofluorescence and higher tissue penetration ability than shortwave light), relatively low synthesis temperature (450 °C), and good biocompatibility [19–21]. In our experiment, the phosphorescencefunctionalized MSNs materials were used in imaging in vivo to show their trace and also used as drug-carriers to study the release properties in the release media of simulated body fluid based on its high pore volume, phosphorescence and nontoxic properties. The obtained results showed that the emission intensity of Pr3+ increases with the increasing cumulative released amount of the drug (quercetin) in the system, which suggested that the extent of drug release can be easily identified, tracked, and monitored by the change of phosphorescence.
2. Experimental
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2.3. In vivo imaging of MSNs@CaTiO3:Pr3+ The as-synthesized MSNs@CaTiO3:Pr3+ nanospheres were milled using a pestle and mortar and dispersed in normal saline assisted by ultrasound. 200 lL of MSNs@CaTiO3:Pr3+ colloid in normal saline (about 5 mg/mL) was injected into the abdomen of a mouse after irradiated by a UV lamp (330 nm) for 10 min. The afterglow signals were acquired for 60 s at every 1 min interval during 12 min by a small animal imaging in vivo system with a CCD camera (Caliper LifeSciences, IVIS Lumina II, America). 2.4. Controlled drug release of quercetin loaded MSNs@CaTiO3:Pr3+ The drug storage/release profile for MSNs@CaTiO3:Pr3+ system was prepared according to the previous report [24]. Quercetin was selected as the model drug. Typically, 0.5 g of the MSNs@CaTiO3:Pr3+ was added to 50 mL of ethanol solution of quercetin with a concentration of 2.5 mg/mL at room temperature and soaked for 24 h with stirring in a sealed vial. The quercetin loaded MSNs@CaTiO3:Pr3+ sample was separated by centrifugation, and then dried at 60 °C for 12 h. The in vitro delivery of quercetin was performed by immersion of 0.3 g of the sample in the release media of simulated body fluid (SBF) containing 20 v% of ethanol with stirring, and the temperature was kept at 37 °C. The ionic composition of the as-prepared SBF solution was similar to that of human body plasma with a molar composition of 142.0:5.0:2.5:1.5:147.8:4.2:1.0:0.5 for Naþ =Kþ =Ca2þ =Mg2þ =Cl 2 2 =HCO =HPO =SO (pH 7.4). The ratio of release media to ad3 4 4 sorbed quercetin was kept at 2.5 mL/mg. The amount of quercetin adsorbed onto MSNs@CaTiO3:Pr3+ was monitored by elemental analysis.
2.1. Synthesis of MSNs The starting materials for the synthesis of MSNs included tetraethylorthosilicate (TEOS), diethanolamine, cetyltrimethylammonium bromide (CTAB) and anhydrous ethanol. All reagents were analytical reagents and used as-received. MSNs were prepared by controlled hydrolysis of TEOS using CTAB as surfactant according to Qiao’s method with modifications [22]. Typically, 0.2 g of CTAB, 25 mL of water, 10 mL of ethanol, 50 lL of diethanolamine were mixed together and stirred in water bath of 80 °C for 30 min. Then 2 mL of TEOS was added into the solution rapidly. The solution turned white gradually. Finally, the solution was cooled to room temperature after a further 2 h stirring. MSNs were centrifuged after 20 mL acetone was added to the as-synthesized mixture. The precipitate was calcined at 550 °C for 2 h to remove CTAB templates.
2.2. Functionalization of MSNs by CaTiO3:Pr3+ MSNs@CaTiO3:Pr3+ core–shell particles were prepared by a previous reported sol–gel process with modifications [19,23]. Suitable amount of water–ethanol (1:7, v/v) solution containing citric acid as the chelating agent for the metal ions was prepared. Then stoichiometric weights of Ca(NO3)2 and Pr(NO3)3 were dissolved in the solution. After the solution turned transparent, stoichiometric amount of titanium tetrabutoxide was added with a final concentration of 0.2 g/mL. The solution was stirred for about 4 h to form transparent sol. Then the as-synthesized MSNs was added into the sol, stirred for 1 h, separated by centrifugation and dried at 105 °C immediately and then annealed to 500 °C. The above process was repeated 3 times to increase the thickness of CaTiO3:Pr3+ shell. After that, these samples were annealed to certain temperatures for 2 h in air atmosphere to obtain the final core–shell structured MSNs@CaTiO3:Pr3+ phosphors.
2.5. Characterization The X-ray diffractions (XRD) patterns were performed on polycrystal X-ray diffractometer equipped with Cu Ka radiation (k = 1.5418 Å) (PANalytical, X’pert PRO, Holland). The morphology of the samples was inspected using field emission scanning electron microscopy (FE-SEM, HITACHI, S-4800, Japan) and Transmission electron microscopy (TEM, Hitachi, H-7000 FA, Japan). The photoluminescence spectra and time decay curves were measured using a fluorescence spectrometer (Hitachi, F4600, Japan). N2 adsorption/desorption isotherms were obtained on a full-automatic physical and chemical adsorption apparatus (Micromeritics, ASAP2020C, America). Pore size distribution was calculated from the adsorption branch of N2 adsorption/desorption isotherm and the Brunauer–Emmett–Teller (BET) method. The BET specific surface areas were calculated using the data between 0.05 and 0.35 just before the capillary condensation. The total pore volumes were obtained by the t-plot method. Total organic carbon analyzer was used to determine the exact loading level of quercetin on the MSNs@CaTiO3:Pr3+ on a CNS elemental analyzer (Elementar Portfolio, Vario MAX, Germany). The absorbance of the released quercetin solution was detected on a UV–vis spectrometer (Thermo, Evolution 300, USA). 3. Results and discussion 3.1. Characterization of the as-prepared MSNs Fig. 1 shows the characterization data of the as-prepared MSNs. The low angle XRD pattern shows only one diffraction peak at 2h = 2.42°, which indicates a disordered crystal structure. At the same time, from the wide-angle XRD pattern (the inset of Fig. 1(A)), it can be observed that there is also only one broad band
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Fig. 1. XRD pattern (A), N2 adsorption/desorption isotherms (B) and FE-SEM photograph (C) of the as-synthesized MSNs.
Fig. 2. XRD patterns of MSNs@CaTiO3:Pr3+ phosphors.
located at 2h = 23°, which can be assigned to the characteristic diffraction peak of amorphous SiO2 (JCPDS card, No. 00-049-1712). As shown in the N2 adsorption/desorption isotherms (Fig. 1(B)), the MSNs sample shows typical type IV isotherm with H1-hystersis, indicating a typical mesoporous material with hexagonal cylindrical channels. The BET specific surface area of MSNs is calculated to be 1258 m2/g. The FE-SEM image (Fig. 1(C)) shows that the MSNs sample consists of uniform spherical particles with an average particle size of about 400 nm with very narrow size distribution. Both the ultrahigh specific surface area and monodisperse morphology are in accordance with the requirements of controlled drug delivery systems. 3.2. Characterization of the as-synthesized MSNs@CaTiO3:Pr3+ phosphor Fig. 2 shows the XRD patterns of the MSNs@CaTiO3:Pr3+ hybrid phosphor synthesized at various temperatures. It can be observed
that no CaTiO3 phase can be formed at 500 °C. CaTiO3 phase can be formed when the temperature increases to 600 °C and 700 °C. All the diffraction peaks can be attributed to the CaTiO3 phase (JCPDS card, No. 00-022-0153). The doping of 0.1% Pr3+ has no obvious effect on the diffraction peaks of CaTiO3. Additionally, no additional peaks for other phases can be detected, indicating that no reaction occurred between the MSNs core and CaTiO3 shell. The intensity of the diffraction peaks of CaTiO3 increase as the annealing temperature increases. In order to generate CaTiO3 phase with high degree of crystallinity, higher annealing temperature will be preferred. However, weak peaks of impurities start to appear at 31.435° when the annealing temperature increases to 800 °C. When the annealing temperature further increases from 800 °C to 900 °C and then to 1000 °C, more and more impurity peaks appear at 43.930°, 51.177°, 57.748°, 63.872°, 29.978°, 29.567°, 29.74°, 29.837°, 29.916°, 34.301°, 33.1°, 29.025°, 31.435°, 43.311°, 47.099°, 51.448°. These impurities may be attributed to the silicates, e.g., CaSiO3, CaSi2O5, Ca3(SiO4)O, formed from the reactions between calcium ions and mesoporous silica. In order to synthesize MSNs@CaTiO3:Pr3+ with both high degree of crystallinity and phase purity, the optimum annealing temperature will fall in the range from 700 °C to 800 °C. Fig. 3 exhibits the photoluminescence spectra of the as-synthesized MSNs@CaTiO3:Pr3+ phosphors. The as-synthesized MSNs@CaTiO3:Pr3+ (800 °C) has an apparent excitation peak at 325 nm, which can be attributed to the band edge absorption of the CaTiO3 host due to O(2p)–Ti(3d) transition.[19] The weak excitation peak at 397 nm can be attributed to 4f–5d transitions of Pr3+ [25]. Under the excitation of 325 nm, the phosphors show red sharp emission at 614 nm, which can be attributed to the intra4f 1D2–3H4 transitions of Pr3+ [26]. The maximum emission intensity of the phosphors appears at 800 °C. The photoluminescence intensity of MSNs@CaTiO3:Pr3+ samples firstly increases from 500 °C to 800 °C, and then decreases from 800 °C to 1000 °C. The increase is due to the better crystalline of CaTiO3:Pr3+ at higher temperature and the decrease can be attributed to the formation of impurity silicate phases.
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Fig. 3. Photoluminescence spectra of MSNs@CaTiO3:Pr3+ phosphors.
In order to fabricate novel phosphorescent functionalized mesoporous drug carrier, the mesopores of the MSNs have to be retained after the annealing process. But the stability of the active, amorphous silica of MSNs is uncertain and doubted at high temperature. The N2 adsorption/desorption analysis indicates that the adsorption ability of MSNs@CaTiO3:Pr3+ phosphors decreases apparently when the annealing temperature increases from 600 °C to 800 °C (Fig. 4(A)). The BET specific surface area of the phosphors decreases nearly 40% from 600 °C (493 m2/g) to 700 °C (306 m2/g). When the annealing temperature increases further to 800 °C, only 5.6% specific surface area (27.4 m2/g) can be retained
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(Fig. 4(B)). Since the phosphor prepared at 700 °C still has relatively high specific surface area, we chose the MSNs@CaTiO3:Pr3+ phosphor synthesized at 700 °C to be used as phosphorescent drug carrier. The morphologies of MSNs@CaTiO3:Pr3+ phosphor synthesized at 700 °C were characterized by FE-SEM and TEM. It can be observed that the as-synthesized MSNs@CaTiO3:Pr3+ still keeps the similar morphological properties of the MSNs (Fig. 5(A)). However, the MSNs@CaTiO3:Pr3+ nanospheres become coarse with some irregular smaller nanoparticles adhering to their surfaces and have a slightly larger particle size which may be caused by the coating of CaTiO3:Pr3+ through a sol–gel approach. The morphological and structural features of the sample were further examined by TEM, as shown in Fig. 5(B). The TEM image obviously indicates that monodisperse nanospheres with narrow size distribution are obtained, which are well consistent with the corresponding SEM images. Additionally, from the TEM image of the MSNs@CaTiO3:Pr3+ particles, the core–shell structure can be clearly distinguished due to the different electron penetrability between the cores and shells. Furthermore, the MSNs@CaTiO3:Pr3+ spheres are well-dispersed and nonagglomerated, indicating that the nanospheres are water-dispersible and good for further surface functional modifications by various biomolecules, such as antibody, DNA, polyethylene, etc. 3.3. Application of MSNs@CaTiO3:Pr3+ in imaging in vivo CaTiO3:Pr3+ is a chemically and thermally stable red phosphor which has widely application as a promising red phosphor for low voltage field emission displays or for photoluminescent devices. It should be noted that CaTiO3:Pr3+ is also a promising red
Fig. 4. N2 adsorption/desorption isotherms (A) and specific surface areas (B) of MSNs@CaTiO3:Pr3+ phosphors.
Fig. 5. FE-SEM and TEM photographs of MSNs@CaTiO3:Pr3+.
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Fig. 6. Phosphorescence spectra (A) and decay curve (B) of MSNs@CaTiO3:Pr3+, the inset is the phosphorescence image of MSNs@CaTiO3:Pr3+ dispersed in water photographed by a SLR camera immediately after turning off the UV lamp.
long persistent phosphor [19]. The red emission can last for 20 min after cessation of the excitation light. The phosphorescence spectra of MSNs@CaTiO3:Pr3+ are shown in Fig. 6(A), which are similar with its luminescence spectra. The phosphorescence can be excited by UV light with wavelength less than 350 nm, and can be effectively excited by a commercial 254 nm UV lamp. The phosphorescence emission peaks at 614 nm and the emission spectrum is very sharp with a very narrow peak width at half height of about 28 nm, which is good for screening background signal. Fig. 6(B) illustrates the phosphorescence decay curve of MSNs@CaTiO3:Pr3+ after irradiation with 330 nm UV light for 10 min. After the cessation of the 254 nm excitation light, MSNs@CaTiO3:Pr shows a rapid decay (<20 s) and subsequently long lasting phosphorescence which may be employed to track the MSNs@CaTiO3:Pr3+ in vivo without simultaneous usage of UV excitation light. The inset of Fig. 6(B) is the intense phosphorescence picture of the MSNs@CaTiO3:Pr3+ phosphor dispersed in water photographed after the cessation of 330 nm UV lamp for 20 s by a Nikon D7000 SLR camera in a dark room (exposure time, 1 min). Since the as-prepared MSNs@CaTiO3:Pr3+ has long persistent phosphorescence property. It has the potential to be detected in real time in vivo for long time without the need of an UV excitation light source. Fig. 7 shows the in vivo imaging of MSNs@CaTiO3:Pr3+ phosphor after peritoneal injection in a living mouse. The MSNs@CaTiO3:Pr3+ can be clearly in 12 min after injection. There is a relatively strong background signal at the first 4 min
observation. This may be attributed to the light scattering of the tissue. When time went on, the phosphorescence signal decreased and less light could penetrate the animal tissue, the light scattering area also decreased. It is worth noting that long persistent phosphor has already found their applications in bioimaging and have shown unique in vivo trackable properties in mice [17,18,27]. However, the reported long persistent nanophosphors have no mesopores and cannot be used as efficient drug carriers. Although the lasting phosphorescence time is only several minutes in this MSNs@CaTiO3:Pr3+ system, our research supplies a route to fabricate nanophosphors possessing both drug-carrying capability and in vivo visible persistent phosphorescence property. If some kinds of more powerful long-lasting phosphorescence materials are fabricated together with mesoporous silica, better results will be expected. 3.4. Application of MSNs@CaTiO3:Pr3+ in controlled drug release The mesopores of the MSNs@CaTiO3:Pr3+ can be used as efficient vehicles to carry drug molecules. The relative loading degree of quercetin loaded MSNs@CaTiO3:Pr3+ is 4.171 wt.% determined by elemental analysis (C loading is 2.486%). The cumulative drug release profile of MSNs@CaTiO3:Pr3+ system is shown in Fig. 8. As shown in the figure, the release profile can clearly prove that the system exhibits sustained-release property. It can be observed that this delivery system shows a feature of two stages of release. In the
Fig. 7. In vivo imaging of MSNs@CaTiO3:Pr3+ photographed for 1 min exposure at every minute in 12 min after peritoneal injection in a living mouse.
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increasing the cumulative released amount of quercetin. And the relationship between normalized phosphorescence intensity (Y) and cumulative released amount of quercetin (X) can be well fitted with the following function.
Y ¼ expð0:00782 0:358=ðX þ 0:0988ÞÞ
Fig. 8. Cumulative quercetin release from MSNs@CaTiO3:Pr3+.
first stage from the start to 30 h, the amount released from MSNs@CaTiO3:Pr3+ delivery system reaches about 3.58%. In the second stage from 30 h to 130 h, the release rate became slower. Only a more 1.72 wt.% of the quercetin in MSNs@CaTiO3:Pr3+ was released even after another 100 h. This very slow drug release property may be attributed to the poor solubility of quercetin in water. The drug release result indicates that the as-synthesized MSNs@CaTiO3:Pr3+ nanospheres have potential applications in the development of controlled or delayed drug delivery system. Based on the concept of time-resolved luminescence assay, the detection of phosphorescence allows to effectively eliminate the short-lived background noise from the biological samples and scattering from nearby optics, and thus results in better signal-to-noise ratio than fluorescence or luminescence [28,29]. However, until to now, the lifetimes of the reported time-resolved luminescence bioassay systems are usually in microsecond or millisecond scale, and expensive time-resolved fluorescence spectrometer have to be used. The long-lasting phosphorescence of CaTiO3:Pr3+ can last for several minutes [30,31]. Therefore, the detection of time-resolved phosphorescence spectra of MSNs@CaTiO3:Pr3+ can be achieved in a common fluorescence spectrometer in our assay (Fig. 6). The phosphorescent emission intensity of quercetin loaded MSNs@CaTiO3:Pr3+ nanospheres has been investigated as a function of cumulative released amount of quercetin, as shown in Fig. 9. It can be seen that the phosphorescent intensity increases along with
Fig. 9. Phosphorescence emission intensity of MSNs@CaTiO3:Pr3+ as a function of cumulative release amount of quercetin.
It is well-known that the emission of lanthanide ions may be quenched to some extent in the environments which contain high phonon frequency. The organic groups of quercetin may quench the emission of Pr3+ to a great extent in the quercetin loaded MSNs@CaTiO3:Pr3+ system. In addition, the strong absorption of quercetin in the UV spectrum will hinder the efficient excitation of CaTiO3:Pr3+. With the release of quercetin, its quenching effect on the emission of Pr3+ and UV absorbance will be weakened, resulting in an increase of phosphorescence emission intensity. This correlation between the emission intensity and drug release extent can be potentially used as a probe to monitor the drug-release process and efficiently in the course of the disease therapy. 4. Conclusions In summary, we have fabricated a novel drug-storage/release system functionalized with long-lasting phosphorescent properties by deposition of a CaTiO3:Pr3+ layer onto the particle surface of MSNs. This system can be tracked in vivo by optical imaging and possesses sustained-release properties of the drug in an in vitro assay. The phosphorescence intensity increases along with the increase of the cumulative released amount of quercetin. The combination of both mesoporous nanoparticles and long-lasting phosphorescence properties in MSNs@CaTiO3:Pr3+ system makes it possible to identify, track, and monitor the drug delivery and disease therapy process. Acknowledgments This work was supported by the ‘‘One Hundred Talents’’ Program of CAS (Grant No. 09i4281c10), the Main Direction Program of Knowledge Innovation of Chinese Academy of Sciences KZCXZYW-453 ‘‘Development and Demonstration of Digital Urban Environmental Network’’ and Xiamen Funds for Distinguished Young Scientists. References [1] P. Yang, S. Huang, D. Kong, J. Lin, H. Fu, Inorg. Chem. 46 (2007) 3203–3211. [2] A. Patil, A.A. Lafarga, M. Chebrot, D.A. Lamprou, A. Urquhart, D. Douroumis, J. Biomed. Nanotechnol. 8 (2012) 550–557. [3] M. Wang, J. Zhang, Z. Yuan, W. Yang, Q. Wu, H. Gu, J. Biomed. Nanotechnol. 8 (2012) 624–632. [4] M. Alnaief, S. Antonyuk, C.M. Hentzschel, C.S. Leopold, S. Heinrich, I. Smirnova, Microporous Mesoporous Mater. 160 (2012) 167–173. [5] J. Gu, S. Su, M. Zhu, Y. Li, W. Zhao, Y. Duan, J. Shi, Microporous Mesoporous Mater. 161 (2012) 160–167. [6] F. Sevimli, A. Yilmaz, Microporous Mesoporous Mater. 158 (2012) 281–291. [7] I.I. Slowing, J.L. Vivero-Escoto, C.W. Wu, V.S.Y. Lin, Adv. Drug Delivery Rev. 60 (2008) 1278–1288. [8] P. Yang, Z. Quan, L. Lu, S. Huang, J. Lin, Biomaterials 29 (2008) 692–702. [9] Z. Hou, C. Li, Adv. Funct. Mater. 22 (2012) 2713–2722. [10] X. Kang, Z. Cheng, D. Yang, Adv. Funct. Mater. 22 (2012) 1470–1481. [11] P. Yang, S. Gai, J. Lin, Chem. Soc. Rev. 41 (2012) 3679–3698. [12] S. Gai, P. Yang, C. Li, W. Wang, Y. Dai, N. Niu, J. Lin, Adv. Funct. Mater. 20 (2010) 1166–1172. [13] Z. Xu, Y. Gao, S. Huang, P.a. Ma, J. Lin, J. Fang, Dalton Trans. 40 (2011) 4846– 4854. [14] Z. Xu, C. Li, P.a. Ma, Z. Hou, D. Yang, X. Kang, J. Lin, Nanoscale 3 (2011) 661– 667. [15] Y. Dai, P.a. Ma, Z. Cheng, X. Kang, X. Zhang, Z. Hou, C. Li, D. Yang, X. Zhai, J. Lin, ACS Nano 6 (2012) 3327–3338. [16] Y. Dai, C. Zhang, Z. Cheng, Biomaterials 33 (2012) 2583–2592. [17] T. Maldiney, A. Lecointre, B. Viana, A. Bessiere, M. Bessodes, D. Gourier, C. Richard, D. Scherman, J. Am. Chem. Soc. 133 (2011) (1815) 11810–11815.
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