Chem. Res. Chin. Univ., 2014, 30(4), 531—537 doi: 10.1007/s40242-014-4097-8

——————————— *Corresponding author. E-mail: zlr@jlu.edu.cn Received March 24, 2014; accept April 9, 2014. Supported by the National Natural Science Foundation of China(Nos. 21371067, 21171064). © Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH

co-Condensation Synthesis of Salicylaldimine Calcium Complex Containing Mesoporous Silica

Nanoparticles as Carriers for Drug Release

TANG Duihai, ZHANG Weiran, WANG Yifan, MIAO Jing, QIAO Zhen’an, HUO Qisheng and ZHANG Lirong*

State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun 130012, P. R. China

Abstract A series of functional mesoporous silica nanoparticles(MSNs) was synthesized by a one-step simple syn-thesis approach involving co-condensation of tetraethoxysilane(TEOS) and salicylaldimine ligand(Sal-Si) in the presence of cetyltrimethylammonium chloride(CTAC) under basic conditions. The target MSNs with different sizes (50, 100 and 200 nm, respectively) were obtained. Furthermore, the Ca2+ cations were also introduced into MSNs. The prepared nanoparticles were characterized by means of infrared(IR) spectra, thermogravimetric analysis(TGA), inductively coupled plasma(ICP), CHN elemental analysis, nitrogen adsorption-desorption, scanning electron micro-scope(SEM) and transmission electron microscope(TEM). Ibuprofen(IBU) which contains carboxyl groups was se-lected as a model drug. The results of drug loading and release reveal that the loading capacities and release behaviors of the model drug are highly dependent on the Ca2+ cations in MSNs. The release of IBU from the MSNs functiona-lized by Ca2+ cations is found to be effectively controlled when compared to the release from the MSNs without the functionalization of Ca2+ cations, which is due to the ionic interaction between carboxyl groups in IBU and Ca2+ ca-tions in MSNs. Keywords Mesoporous silica nanoparticle; co-Condensation method; Release of ibuprofen; Calcium ion

1 Introduction

The design of controlled drug-delivery systems(DDSs) is one of the most important studies[1―6]. Driven by the need of improving effectiveness of drug administration, there has been an increasing interest in developing the effective drug delivery systems, such as maximizing the therapeutic activity, minimi- zing the side effect and controlling the release rate[7―14].

Choosing a suitable carrier material is one of the critical factors of controlling the storage volume and release rate of a drug. A series of drug carriers has been synthesized, including carbon nanotubes[15―17], hollow silica nanoparticles[7,18,19], mesoporous silicas[20―24] and metal-organic frameworks[25]. Among these nanocarriers, mesoporous silica materials as controlled drug delivery matrixes were investigated because they have bio-compatibility, stable mesoporous structures, high surface areas and tunable pore sizes, as well as well-defined and easily modified surface properties[12,26,27]. The release of drugs from the mesoporous silica materials has been studied since decades ago[28], starting with the load of ibuprofen(IBU) into silica me-sopores. Later on, the results of systemic studies show that the release process is mainly dependent on the pore size and net surface charge of the material[20,29―34].

In the past decade, calcium silicate(CS) materials have

drawn growing attention because of their potential application in the bone tissue engineering field[14,22,35,36]. Jain et al.[37] and Li et al. [38] reported CS/polymer composite spheres for drug release. But the spheres reported were too large and the loading amounts of them were low. It has been reported that large spe-cific surface area and large pore volume are vital factors for achieving high loading amount. 3D and well-defined micro-structure with an interconnected pore network is important for building an ideal delivery system[39].

Nanoparticles have a predominant performance because of their small size and high surface area. Mesoporous silica nano-particles(MSNs)[40] are stable nanomaterials with well-defined and controllable morphology, porosity and size. MSNs would perform as a carrier in various fields such as adsorption, sepa-ration, drug delivery and nanodevices. The organic groups can be incorporated in the porous solids by grafting or co-condensation methods under surfactant control. If the uni-form coverage of surface with organic groups is desired in a single step synthesis, the direct method will be adopted, which also provides better control over the amount of organic groups incorporated in the structure. In 2005, Kawi’s group[20] synthe-sized mesoporous SBA-15 materials functionalized with amine groups via postsynthesis and one-pot synthesis and indicated that SBA-15 functionalized by one-pot synthesis was more

532   Chem. Res. Chin. Univ. Vol.30

favorable for the load and release of IBU than postsynthesis due to the balance of electrostatic interaction and hydrophilic interaction between IBU and the functionalized SBA-15 matrix[41]. The amine groups play an important role in the loading and release of IBU. In drug delivery system, nanopar-ticles are usually used as the carriers and the amine groups are essential to be introduced into this system. Thiel’s group[42] synthesized a series of MSNs via one-pot synthesis involving co-condensation of tetrathoxysilane(TEOS) and silanes pos-sessing amine groups. But these MSNs were slightly curved tubular-shaped particles with a mean length of approximately 1 μm. This morphology was not suitable for drug delivery system. So we avoided using the aminopropyl triethoxysilane (APTES) to synthesize MSNs.

Herein, we synthesized a series of nanoparticles by a one-step simple synthesis approach involving co-condensation of TEOS and salicylaldimine ligand(Sal-Si) in the presence of cetyltrimethylammonium chloride(CTAC) under basic condi-tions. The template extraction was performed by stirring the dried material in ethanol with Ca(NO3)2, which can also intro-duce the Ca2+ cations on the surface of the MSNs. The results show that the ionic interaction between carboxyl groups in IBU and Ca2+ cations plays an important role in loading capacities and release behaviors of the model drug. The MSNs functiona-lized by salicylaldimine calcium complex show better loading capacities and release behaviors than the MSNs functionalized by salicylaldimine. It is the Ca2+ cations on the surface of the MSNs that determine the loading capacities and release beha-viors of IBU. Moreover, the amount of the Ca2+ cations can also control the loading amount of the model drug, such as IBU.

2 Experimental

2.1 Materials

Salicylaldehyde, APTES(98%), TEOS(98%), CTAC, die-thanolamine(DEA), solvents and other inorganic chemicals were purchased from Beijing Chemical Works(Beijing, China) and used without further purification.

2.2 Synthesis of Salicylaldimine Ligand(Sal-Si)

Synthesis of the salicylaldimine ligand was performed using a reported method with slight modifications[43]. APTES(2.21 g, 10 mmol), dissolved in 40 mL of dry ethanol, was added to salicylaldehyde(1.22 g, 10 mmol). The resulting mixture was refluxed for 2 h, then the solvent was removed by rotary evaporator. The resulting viscose orange oil was dis-solved in 10 mL of dichloromethane and washed twice with 10 mL of portions of water. The organic layer was separated and then dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the solvent was removed and then the salicylaldimine ligand(Sal-Si) was obtained. Yield: 65%. 1H NMR(CDCl3), δ: 0.68(t, 3JH,H=8.4 Hz, 2H, Si-CH2), 1.23(t, 3JH,H=7.0 Hz, 9H, Si-OCH2CH3), 1.83(t, 3JH,H=7.0 Hz, 2H, NCH2), 3.60(m, 2H, NH2CH2), 3.81(q, 3JH,H=7.0 Hz, 6H, Si-OCH2), 6.87(m, 2H, Ar), 7.27(m, 2H, Ar), 8.34(s, 1H,

NCH).

2.3 Preparation of MSNs

MSNs were prepared as followed. 6.4 mL of water(0.36 mol), 1.8 g of ethanol(0.03 mol), 1.04 g of a 25%(mass fraction) CTAC solution(0.786 mmol) and 0.02 g of DEA(0.19 mmol) were mixed and stirred in a water bath at 40 °C for 30 min. Then 0.36 g of Sal-Si(1.11 mmol) was added to the mixture dropwise within 2 min under stirring. After 5 min, 0.36 g of TEOS(1.62 mmol) was added to the mixture dropwise within 2 min under stirring. A further 2 h of stirring was necessary. The mixture was then cooled to room temperature, and the as-prepared MSNs were collected by centrifugation and washed with absolute ethanol 3 times. The removal of the surfactant extraction was performed by stirring the dried material in 120 mL of ethanol with 0.5 g of Ca(NO3)2 under reflux for 48 h, which can also allow the complexation of ligand and calcium to happen. Finally, the product was dried under vacuum at room temperature overnight. In the process of preparation, the molar ratios of TEOS to Sal-Si(10:1, 20:1, 30:1, 40:1 and 50:1) were varied to obtain different MSNs, which were named as MSN-10/1, MSN-20/1, MSN-30/1, MSN-40/1 and MSN-50/1, respectively. The CTAC extraction was performed by stirring the dried material in ethanol with Ca(NO3)2 under reflux, and the obtained nanoparticles were named as Ca-MSN-10/1, Ca-MSN-20/1, Ca-MSN-30/1, Ca-MSN-40/1 and Ca-MSN- 50/1. Similarly, we varied the molar ratio of TEOS to Sal-Si (2:1, 1:1, 1:2 and 1:4) to obtain nanoparticles named as MSN-2/1, MSN-1/1, MSN-1/2 and MSN-1/4, respectively. The CTAC extraction was performed by stirring the MSN-2/1 in ethanol with Ca(NO3)2 under reflux, and the obtained MSNs named as Ca-MSN-2/1. When the molar ratio of TEOS to Sal-Si is fixed as 1:1, we varied the amount of the alcohol(0.9 and 1.8 g of ethanol, 0.9 g of propanol) to control the sizes of the MSNs. The CTAC extraction was performed by stirring the dried material in ethanol with Ca(NO3)2 under reflux, which can simultaneously introduce the Ca2+ cations to the surface of MSNs. We named these nanoparticles as Ca-MSN-50, Ca-MSN-100 and Ca-MSN-200, respectively. The CTAC extraction was also performed by stirring MSN-1/1-200 in ethanol with NH4Cl under reflux, and the obtained material is named as Sal-MSN-200.

2.4 Characterization

The particle morphologies and dimensions of the samples were determined by a JEOL JSM-6700F scanning electron microscopy(SEM) operating at an accelerating voltage of 5 kV and a JEOL JEM-3010 transmission electron microscopy(TEM) operating at 300 kV. Fourier transform infrared(FTIR) spectra were recorded on a JASCOFT/IR-420 spectrophotometer in a wavenumber range of 4000―400 cm–1 with a resolution of 4 cm–1 and the KBr pressed pellet technique. The thermogra-vimetric(TG) curves were recorded on a TA TGA Q500 thermal analyzer at a temperature-increase rate of 10 °C/min under the protection of nitrogen atmosphere. Elemental analysis was performed on a Perkin-Elmer 2400 Series II CHNS/O

No.4 TANG Duihai et al. 533

elemental analyzer. The inductively coupled plasma(ICP) ana-lyses were carried out on a Perkin-Elmer Optima 3300DV ICP instrument, with the samples dissolved in the aqueous solution of HF. The adsorption-desorption isotherms of nitrogen were measured at 77 K by a Micrometeritics TriStar 3000 system. The pore size distributions were calculated from the adsorption branches of N2 adsorption-desorption isotherms on the basis of the BJH model. The samples were outgassed at 373 K for 3 h before each measurement. 1H NMR spectra were measured on a Varian Mercury-300 spectrometer at room temperature using CDCl3 as the solution.

2.5 Loading and Release of Drug

IBU was dissolved in anhydrous ethanol(5 mg/mL), and 0.1 g of carrier material was added to 100 mL of the above solution. The mixture was shaken for 72 h at room temperature, collected by centrifugation, washed with water and then dried in an oven at 50 °C. The amount of drug loaded in the carrier was characterized quantitatively by a thermogravimetric ana-lyzer(TGA). All the samples were heated from 25 °C to 800 °C in air at a heating rate of 10 °C/min. In vitro drug release expe-riments were carried out by adding dried powder of carrier material loaded with drug to 10 mL of the phosphate buffer solution(PBS, pH=7.4, 0.1 mol/L). This mixture was added in the dialysis bag and the drug was released into 250 mL of PBS at 37 °C. The released concentration as a function of time was analyzed by UV-visible spectroscopy(Jasco V-550 spectropho-tometer) at 264 nm in PBS.

3 Results and Discussion We prepared a series of spherical shaped MSNs with

disordered mesopores by a one-step simple synthesis approach involving co-condensation of TEOS and Sal-Si in the presence of CTAC under basic conditions with the sizes of 50, 100 and 200 nm spherical shape, and disordered mesopores. Salicylal-dimine was selected as the ligand owing to its good coordina-tion capacities. Schiff base ligands are easily synthesized and can form complexes with almost all metal ions[44]. The results show that the drug loading and release behavior depends on the amounts of the Ca2+ cations.

3.1 Spectroscopic Measurements

The IR spectrum of Sal-MSN-200[Fig.1(A) curve a] shows the presence of C―H vibration bands in the region of 1550―1250 cm–1 which are absent in the case of MSNs, clear-ly indicating that Sal-Si has been introduced into the MSN matrix. The IR spectrum of Sal-MSN-200 also exhibits a band at 1637 cm–1, which can be attributed to the C=N stretching frequency of the imine group, indicating that C=N is pre-served in the synthesis of MSNs. FTIR spectra of Sal-MSN-200 and Ca-MSN-200 are shown in Fig.1(B). A band around 1625 cm–1 appears, which is assigned to the C=N stretching frequency of the complexation. According to Srini-vas’ work[45], this shift to a lower frequency is attributed to the complexation of metal ions with C=N. More specifically,

stretching vibration bands at 2953, 2885, 1242 and 742 cm–1 are assigned, respectively, to the aliphatic C―H stretching and the C―Si stretching vibrations can be observed for the both samples.

Fig.1 IR spectra(A) and comparison spectra at 1700―1500 cm-1(B) of Sal-MSN-200(a) and Ca-MSN-200(b)

Solid-state NMR spectroscopy was used to obtain spec-troscopic evidence for the presence of the desired organic func-tional groups in the particles as well as to confirm the chemical structure and relative concentrations. The presence of organic functional groups was further verified by solid-state 29Si MAS NMR spectroscopy. Peaks at δ –110, –100, –66 and –58 are assigned to the Q4[Si(OSi)4], Q3[Si(OH)(OSi)3], T3[SiR(OSi)3] and T2[Si(OH)R(OSi)2] sites, respectively(as shown in Fig.2).

Fig.2 29Si CP/MAS NMR spectrum of functionalized MSN sample Ca-MSN-200

3.2 Morphological Studies

SEM and TEM were used to study the morphology of as-prepared samples. The SEM and TEM images of the as-prepared samples synthesized by co-condensation method show that they are mesoporous silica nanoparticle material with a spherical shape. As shown in Fig.3, MSN-10/1, MSN-20/1, MSN-30/1, MSN-40/1 and MSN-50/1 are highly monodisperse

534   Chem. Res. Chin. Univ. Vol.30

and the average particle diameter of them is about 200 nm. It can be concluded from Fig.3 that the molar ratio of TEOS to Sal-Si in the range of 10:1―50:1 does not affect the morpho- logy of MSNs. But the effects of proportions of the Sal-Si are different. As shown in Fig.4, MSN-2/1 and MSN-1/1 are both monodisperse spherical nanoparticles with an average particle

diameter of about 200 nm. MSN-1/2 consists of adhered nano-particles and MSN-1/4 containing bulky materials does not consist of spherical nanoparticles. As shown in Fig.5, Ca-MSN-50, Ca-MSN-100 and Ca-MSN-200 are all highly monodisperse spherical MSNs.

Fig.3 SEM(A―E) and TEM(A′―E′) images of MSN-10/1, MSN-20/1, MSN-30/1, MSN-40/1 and MSN-50/1, respectively

Fig.4 SEM images of MSN-2/1(A), MSN-1/1(B), MSN-1/2(C) and MSN-1/4(D) and TEM images of MSN-2/1(E) and MSN-1/1(F)

Fig.5 SEM(A―C) and TEM(A′―C′) images of Ca-MSN-50, Ca-MSN-100 and Ca-MSN-200, respectively

No.4 TANG Duihai et al. 535

3.3 N2 Adsorption/Desorption Study

The N2 adsorption isotherms of MSNs shown in Fig.6 correspond to type IV adsorption isotherm, which is the cha-racteristic of mesoporous materials. The results are listed in Table 1. The BET surface areas of Ca-MSN-50, Ca-MSN-100 and Ca-MSN-200 are 519, 458 and 332 m2/g, respectively, and

Fig.6 N2 adsorption/desorption isotherms of Ca-MSN- 50(a), Ca-MSN-100(b) and Ca-MSN-200(c)

Table 1 Porous properties of Ca-MSN samples

Sample Average particle size/ nm

Pore size/nm

Surface area /(m2·g–1)

Pore volume /(cm3·g–1)

Ca-MSN-50 50 2.1 519 0.57 Ca-MSN-100 100 2.6 458 0.81 Ca-MSN-200 200 2.3 332 0.43

the Ca-MSN-50 material shows the highest surface area. The pore volumes of Ca-MSN-50, Ca-MSN-100 and Ca-MSN-200 are 0.57, 0.81 and 0.43 cm3/g, respectively, and the Ca-MSN- 100 material shows the highest pore volume.

3.4 Thermal Property

To calculate the amount of IBU loaded in the mesoporous materials, TG analyses were made and the results are displayed in Fig.7. The mass loss observed in the temperature range of 100―200 °C for all samples corresponds to the thermodesorp-tion of water from the porous structure. The TG curves of the nanoparticles also show a major mass loss in the temperature range of 200―600 °C, which corresponds to the loss of the metal complexes.

Fig.7 TG curves of the MSN materials (A) a. Ca-MSN-50, b. Ca-MSN-50-IBU; (B) a. Ca-MSN-100, b. Ca-MSN-100-IBU; (C) a. Ca-MSN-200, b. Ca-MSN-200-IBU; (D) a. Sal-MSN-200, b. Sal-MSN-200-IBU; (E) a. Ca-MSN-2/1, b. Ca-MSN-2/1-IBU; (F) a. Ca-MSN-10/1, b. Ca-MSN-10/1-IBU; (G) a. Ca-MSN-50/1, b. Ca-MSN-50/1-IBU.

From the above characterization, mesoporous materials obtained by one-pot synthesis are found to be more favorable for the loading and release of IBU due to the combination of electrostatic interaction and hydrophilic interaction between IBU and the organo-functionalized porous materials. In our

work, Ca2+ cations are introduced to the surface of MSNs. There are several reports on calcium doped mesoporous silica. Shi et al.[46] synthesized the mesoporous calcium doped silica spheres(CaMS) and silica spheres(MS) by a simple one-step method. The sphere morphology of MS was uniform and the

536   Chem. Res. Chin. Univ. Vol.30

mass fraction of CaO in CaMS was up to 8.18%. IBU drug storage capacities and release rate were investigated and there was no obvious difference of them between MS and CaMS.

3.5 Drug Loading

We chose IBU, which is a broad spectrum antibiotic from Streptomyces and a naturally hydrophobic drug molecule, as a model drug to study the release behavior. Furthermore, IBU contains carboxyl group. The molecular size of IBU is around 1.0 nm, which ensures that it can easily diffuse into the pores of materials synthesized in this work(2.1—2.6 nm).

All the MSN samples were soaked in the IBU solutions to entrap the drug molecules. Table 1 displays the loading capaci-ties of the model drug IBU in Ca-MSN-50, Ca-MSN-100 and Ca-MSN-200, respectively. The interaction between IBU and Ca-MSN is believed to originate from the combination of sur-face Ca2+ cations and hydrogen bonding[47]. Therefore, the IBU loading amount of Sal-MSN-200 is lower than that of Ca-MSN-200, because it does not contain Ca2+ cations. The results of TG curves of MSNs and their IBU loaded sys-tems(Fig.7) show that Ca-MSN-50, Ca-MSN-100 and Ca-MSN-200 exhibit much higher IBU loading capacities than Sal-MSN-200[9]. Among these materials, Ca-MSN-100 exhibits an extremely high drug loading capacity of 89%(i.e., 0.91 g of IBU is loaded per gram carrier), which is approximately three times that of MCM-41[21,28], owing to the high amount of Ca2+ and high pore volume. Ca-MSN-50 and Ca-MSN-200 show a drug loading capacity of 86% and 79%, respectively. To prove the effect of Ca2+ cations, Sal-MSN-200 was chosen as the contrast material, which shows nearly the same BET surface area as that of Ca-MSN-200, and contains no Ca2+ cations. Sal-MSN-200 exhibits a drug loading capacity of 33%, while Ca-MSN-200 exhibits a drug loading capacity of 79%, which is approximately two times that of Sal-MSN. The increase of the drug loading capacity may due to the existence of Ca2+ cations on the surface of Ca-MSN-200. We also studied the drug loading of Ca-MSN-2/1, Ca-MSN-10/1 and Ca-MSN-50/1. As shown in Fig.7(E)―(G), the order of loading amounts of these nanoparticles is Ca-MSN-2/1>Ca-MSN-10/1>Ca-MSN-50/1. The amounts of Ca2+ cations exhibit the same order, revealing that the amount of the Ca2+ cations determines the drug loading capacities.

3.6 Drug Release

The release profiles of Ca-MSN-50 and Ca-MSN-100 loaded with IBU in PBS(pH=7.4, 0.1 mol/L) release media are shown in Fig.8. All these nanoparticles have amorphous and disordered structures, and show the same release rate.

To further demonstrate the role of the Ca2+ cations, Sal-MSN-200 was synthesized as the carriers of IBU. It shows the same BET surface as that of Ca-MSN-200. As shown in Fig.9, Sal-MSN-200 shows higher IBU release rates than Ca-MSN-200 in the buffer solutions. So we can draw a conclu-sion that the Ca2+ cations on the surface of the MSNs play an important role in the drug delivery system. The amount of Ca2+ cations could control the loading amount and release rate of

Fig.8 IBU delivery from Ca-MSN-50(a) and

Ca-MSN-100(b) Fig.9 IBU delivery from Sal-MSN-200(a) and

Ca-MSN-200(b) IBU. More organic group and Ca2+ cations can be introduced by the co-condensation method. Although large specific surface area and pore volume are vital factors for high drug loading capacity, the intrinsic nature of carrier material is sometimes more crucial for the enhancement of drug loading capacities. Good linkages between IBU molecules and Ca-MSN-200 can be formed by the electrostatic bonding between Ca2+ cations and carboxyl groups under basic circumstances, and these lin-kages will be gradually broken under nearly neutral conditions. Coincidentally, Ca-MSN-200 exhibits a relatively strong basicity with Ca2+-enriched surfaces and the drug release medium, phosphate buffer solution, is nearly neural.

4 Conclusions In the present study, a series of mesoporous silica nano-

particles with different sizes(50, 100 and 200 nm) were synthe-sized by one-pot synthesis method. The nanoparticles obtained can be used as the carriers for drug delivery with high loading amount. The contrast test showed that high surface areas of MSNs and the existence of Ca2+ cations on the surface of MSNs lead to high loading amount, indicating that Ca2+ cations play an important role in the drug delivery system. The loading amount of IBU can be controlled by varying the amount of the Ca2+ cations.

References

[1] Ruiz-Hitzky E., Darder M., Aranda P., Ariga K., Adv. Mater., 2010, 22, 323

[2] De M., Ghosh P. S., Rotello V. M., Adv. Mater., 2008, 20, 4225 [3] Son S. J., Bai X., Lee S. B., Drug Discovery Today, 2007, 12, 650 [4] Vallet-Regi M., Colilla M., Gonzalez B., Chem. Soc. Rev., 2011, 40,

No.4 TANG Duihai et al. 537

596 [5] Arcos D., Lopez-Noriega A., Ruiz-Hernandez E., Terasaki O.,

Vallet-Regi M., 2009, 21, 1000 [6] de Cock L. J., de Koker S., de Geest B. G., Grooten J., Vervaet C.,

Remon J. P., Sukhorukov G. B., Antipina M. N., Angew. Chem. Int. Ed., 2010, 49, 6954

[7] Li Z. Z., Wen L. X., Shao L., Chen J. F. J., J. Controlled Release, 2004, 98, 245

[8] Rosler A., Vandermeulen G. W. M., Klok H. A., Adv. Drug Deliv. Rev., 2001, 53, 95

[9] Lin C. X., Qiao S. Z., Yu C. Z., Ismadji S., Lu G. Q., Microporous Mesoporous Mater., 2009, 117, 213

[10] Begu S., Pouessel A. A., Lerner D. A., Tourne-Peteilh C., Devoisselle J. M., J., Controlled Release, 2007, 118, 1

[11] Bernardos A., Aznar E., Coll C., Martinez-Manez R., Barat M. J., Dolores Marcos M., Sancenon F., Benito A., Soto J., J. Controlled Release, 2008, 131, 181

[12] Bikram M., Gobin A. M., Whitmire R. E., West J. L., J. Controlled Release, 2007, 123, 219

[13] Doadrio A. L., Sousa E. M. B., Doadrio J. C., Pariente J. P., Izquier-do-Barba I., Vallet-Regi M., J. Controlled Release, 2004, 97, 125

[14] Ginebra M. P., Traykova T., Planell J. A., J. Controlled Release, 2006, 113, 102

[15] Liu Z., Sun X., Nakayama-Ratchford N., Dai H., Acs Nano, 2007, 1, 50

[16] Hilder T. A., Hill J. M., Small, 2009, 5, 300 [17] Son S. J., Bai X., Nan A., Ghandehari H., Lee S. B., J. Controlled

Release, 2006, 114, 143 [18] Kapoor M. P., Vinu A., Fujii W., Kimura T., Yang Q. H., Kasama Y.,

Yanagi M., Juneja L. R., Microporous Mesoporous Mater., 2010, 128, 187

[19] Yan E. Y., Fu Y. L., Wang X., Ding Y., Qian H. Q., Wang C. H., Hu Y., Jiang X. Q., J. Mater. Chem., 2011, 21, 3147

[20] Song S. W., Hidajat K., Kawi S., Langmuir, 2005, 21, 9568 [21] Fang X. S., Zhai T. Y., Gautam U. K., Li L., Wu L. M., Bando Y.,

Golberg D., Progress in Materials Science, 2011, 56 , 175 [22] He Q. J., Shi J. L., J. Mater. Chem., 2011, 21, 5845 [23] Slowing I. I., Vivero-Escoto J. L., Wu C. W., Lin V. S. Y., Adv. Drug

Deliv. Rev., 2008, 60, 1278 [24] Zhang Y., Zhi Z., Jiang T., Zhang J., Wang Z., Wang S., J. Controlled

Release, 2010, 145, 257 [25] Horcajada P., Serre C., Maurin G., Ramsahye N. A., Balas F., Val-

let-Regi M., Sebban M., Taulelle F., Ferey G., J. Am. Chem. Soc., 2008, 130, 6774

[26] Xia W., Chang J., J. Controlled Release, 2006, 110, 522 [27] Tang Q., Xu Y., Wu D., Sun Y., Wang J., Xu J., Deng F., J. Controlled

Release, 2006, 114, 41 [28] Chen K. L., Zhao Y. H., Yuan X. Y., Chem. Res. Chinese Universities,

2014, 30(2), 339 [29] Coll C., Mondragon L., Martinez-Manez R., Sancenon F., Marcos M.

D., Soto J., Amoros P., Perez-Paya E., Angew. Chem. Int. Ed., 2011, 50, 2138

[30] Bernardos A., Mondragon L., Aznar E., Marcos M. D., Martinez-Manez R., Sancenon F., Soto J., Barat J. M., Perez-Paya E., Guillem C., Amoros P., Acs Nano, 2010, 4, 6353

[31] Climent E., Martinez-Manez R., Sancenon F., Marcos M. D., Soto J., Maquieira A., Amoros P., Angew. Chem. Int. Ed., 2010, 49, 7281

[32] Lopez-Noriega A., Arcos D., Vallet-Regi M., Chem. Eur. J., 2010, 16, 10879

[33] Nieto A., Colilla M., Balas F., Vallet-Regi M., Langmuir, 2010, 26, 5038

[34] Kaluderovic G. N., Perez-Quintanilla D., Sierra I., Prashar S., del Hierro I., Zizak Z., Juranic Z. D., Fajardo M., Gomez-Ruiz S., J. Mater. Chem., 2010, 20, 806

[35] Schmidt H. T., Gray B. L., Wingert P. A., Ostafin A. E., Chem. Mater., 2004, 16, 4942

[36] Manzano M., Vallet-Regi M., J. Mater. Chem., 2010, 20, 5593 [37] Jain S. K., Awasthi A. M., Jain N. K., Agrawal G. P., J. Controlled

Release, 2005, 107, 300 [38] Li H., Chang J., J. Controlled Release, 2005, 107, 463 [39] Biondi M., Ungaro F., Quaglia F., Netti P. A., Adv. Drug Deliv. Rev.,

2008, 60, 229 [40] Katz E., Willner I., Angew. Chem. Int. Ed., 2004, 43, 6042 [41] Wang S. B., Microporous Mesoporous Mater., 2009, 117, 1 [42] Shylesh S., Wagner A., Seifert A., Ernst S., Thiel W. R., Chem. Eur.

J., 2009, 15, 7052 [43] Ray S., Mapolie S. F., Darkwa J., J. Mol. Catal. A: Chem., 2007, 267,

143 [44] Gupta K. C., Sutar A. K., Coord. Chem. Rev., 2008, 252, 1420 [45] Bhadbhade M. M., Srinivas D., Inorg. Chem., 1993, 32, 5458 [46] Li X., Zhang L. X., Dong X. P., Liang J., Shi J. L., Microporous

Mesoporous Mater., 2007, 102, 151 [47] Ruiz-Hitzky E., Darder M., Aranda P., Ariga K., Adv. Mater., 2010,

22, 323