Amine-functionalized mesoporous silica KIT-6 as a controlled release drug delivery carrier

Amine-functionalized mesoporous silica KIT-6 as a controlled release drug delivery carrier

Microporous and Mesoporous Materials 229 (2016) 166e177 Contents lists available at ScienceDirect Microporous and Mesoporous Materials journal homep...

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Microporous and Mesoporous Materials 229 (2016) 166e177

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Amine-functionalized mesoporous silica KIT-6 as a controlled release drug delivery carrier Mohamad M. Ayad a, b, *, Nehal A. Salahuddin a, Ahmed Abu El-Nasr a, Nagy L. Torad a a b

Department of Chemistry, Faculty of Science, University of Tanta, Tanta, Egypt School of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria 21934, Egypt

a r t i c l e i n f o

a b s t r a c t

Article history: Received 13 March 2016 Received in revised form 17 April 2016 Accepted 21 April 2016 Available online 22 April 2016

Mesoporous silica KIT-6, has been prepared through the sol-gel method followed by a chemical modification using 3-aminopropyl triethoxysilane (APTS) to obtain KIT-6-NH2 as a drug delivery carrier. The mesostructure properties was fully characterized by transmission electron microscope (TEM), N2 sorption isotherm, Fourier transform infrared (FT-IR), low-angel X-ray diffraction (XRD) and small-angel x-ray scattering (SAXS). Loading of ketoprofen (KP) and 5-flurouracil (5-FU) drugs as models into KIT-6 and KIT-6-NH2 was studied using quartz crystal microbalance (QCM) and UVevisible spectroscopy. The loading uptake and release behaviors of KP and 5-FU were highly dependent on the textural properties of KIT-6 and KIT-6-NH2. The release of drugs was carefully studied in simulated gastric fluid (pH 2) and in simulated intestinal fluid (pH 7.4). First order, Higuchi, HixsoneCrowell and KorsmeyerePeppas release kinetic models were applied to the experimental data and the release was found to obey a first-order rate kinetic. © 2016 Elsevier Inc. All rights reserved.

Keywords: Mesoporous silica KIT-6 Sol-gel method Drug delivery Quartz crystal microbalance (QCM)

1. Introduction Mesoporous materials synthesized by the surfactant-templated method, resulting in highly ordered arrays of one-dimensional (1D), two-dimensional (2D) and three-dimensional (3D) channels. One of them, is mesoporous silica, has attracted much attention of scientists because of their outstanding features such as high surface area, high porosity, well-ordered structure, tunable pores, and non-cytotoxic properties [1,2]. Remarkable efforts have been devoted towards the development of mesoporous silica towards their practical applications as advanced catalysts, adsorbents, sensors, optical waveguides, electrochemical battery components/electrode materials and biomedical drug carriers [3e5]. Therefore, mesoporous silica materials with large pore diameters are considered good candidates as drug delivery system (DDS) for carrying high dosages of a variety of drugs in their mesopores by systematic tuning the pore sizes using different templates to improve the accommodation of large sized-drug molecules [6]. In addition, the presence of silanol groups can be

* Corresponding author. School of Basic and Applied Sciences, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City, Alexandria 21934, Egypt. E-mail address: [email protected] (M.M. Ayad). 1387-1811/© 2016 Elsevier Inc. All rights reserved.

further functionalized with different organic groups to modify the surface properties to induce favorable surface-drug interactions, which will in turn result in improved loading capacity for the drug molecules [7]. In 2001, mesoporous silica, MCM-41 was first reported as a DDS of ibuprofen drug [8]. In DDSs, the successful deliver of precise quantities of drugs to the targeted cells or tissues in a controlled release manner to enhance drug efficiency [9,10] have been considered as one of the most promising applications for human health care and represent a field for biomedical materials science [11e13]. Release of different kinds of drugs from mesostructured silica materials has been studied so far. For example, synthesis of mesoporous silica, SBA-15 inside a macroporous bioactive glassceramic scaffold of the type SiO2eCaOeK2O was reported by Cauda et al. [14] to combine the bioactivity of the latter with the release properties of the former, in view of local drug delivery of ibuprofen. They demonstrated that ibuprofen loading percentage onto SBA-15-scaffold (33%) was found to be almost five times higher than that of the scaffold alone. Vallet-Regí et al. [15] demonstrated the release of ibuprofen, erythromycin [16] and alendronate [17] from SBA-15 by using different strategies to modify the control of drug release. Tamanoi et al. [18] reported the release of camptothecin as anti-cancer drug from mesoporous silica nanoparticles fluorescent mesoporous silica nanoparticles

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(FMSNs) and confirmed the drug release inside of various cancercell lines. Very recently, Wojciech Chrzanowski et al. [19] reported the use of organically functionalized MCM-41 with CdS nanoparticle of surface area 941.0 m2 g1 and pore diameter 2.3 nm as a DDS for vancomycin drug. They demonstrated that the loading/release mechanism was found to depend on the electrostatic interaction between the drug molecules and the linker derivatized mesopores. In addition, loading of alendronate into MCM-41 and SBA-15 matrices modified with propylamine groups (PrNH2) was carefully studied and it was found to be 14% and 8%, respectively [20]. It was proved that the surface areas and mesopore sizes would have combined effects on the release kinetics. The release of alendronate drug from the MCM-41-modified PrNH2 groups of 3 nm in diameter was found to obey first order rate kinetics, whereas release from SBA-15-modified PrNH2 groups of 9 nm in diameter showed a linear or zero order rate kinetics. The loading/ release mechanism of alendronate drug was investigated to be an electrostatic attraction. Furthermore, SBA-15 and SBA-15/poly(Nisopropylacrylamide) functional hybrid was employed as a DDS for atenolol drug [21]. The remarkable surface area (326 m2 g1), pore volume 0.484 (cm3 g1), and pore diameter (3.76 nm) made the functional hybrid a good candidate for trapping atenolol drug into the porous structures of the silica network with a loading capacity of 60%. They concluded that the efficiency of atenolol DDS is influenced by volumetric contraction of poly(Nisopropylacrylamide). Moreover, carboxylic-modified mesoporous silica has been extensively studied as a DDS, as well. In this regard, trimethylsilyl-carboxyl bifunctionalized SBA-15 (TMS/COOH/SBA15) with high content of carboxyl groups up to 57.2% was synthesized by Yao Xu et al. [22]. The obtained TMS/COOH/SBA-15 exhibited a surface area of 359 m2 g1, pore diameter 4.2 nm, and total pore volume 0.436 cm3 g1 was studied as a carrier for controlled release of drug famotidine. By tuning the content of carboxyl groups, the loading capacity for famotidine was reached to about 50%. However, the post-treating drug-loaded COOH/SBA15 with hexamethyldisilazane, a controlled famotidine release of 80% of loading was achieved. Similar studies were demonstrated by Popova et al. [23]. They synthesized MCM-41 and SBA-15 functionalized with carboxylic groups for a higher degree of loading sulfadiazine drug reached to ~50e52 wt%. They explained that the drug release process was mainly depends on the carboxylic functionalization rather than the pore size. Thus, the pore diameters with the subsequent addition of organic function groups greatly enhance the loading and release of drug molecules and hence its kinetics. It is well known that KIT-6 has pores diameter relatively more than SBA-15. KIT-6 and functionalized KIT-6 have been studied extensively in many interesting applications such as, adsorption [24], sensor [25] and catalyst [26]. However, there is less attention has paid to the use of KIT-6 in DDS, thus our work originally provides a new application of mesoporous silica KIT-6. Herein, we present synthesis of KIT-6 and KIT-6-NH2 for controlled drug delivery application of analgesic drugs for the first time to the best of our knowledge. The loading capacity and release of KP and 5-FU as anionic drugs models were studied by QCM and UVevisible spectroscopy. Based on spectroscopic measurements and theoretical calculations, the amine functionalized KIT-6 is very crucial for drug loading/release properties due to the hydrogen bonding interaction with the carboxylic and carbonyl groups of the drug molecules. The release kinetics of KP and 5-FU drugs from functionalized KIT-6 were investigated by applying first order, Higuchi, HixsoneCrowell and KorsmeyerePeppas release kinetic models.


2. Experimental section 2.1. Chemicals Tetraethylorthosilicate (TEOS, 98%) (Sigma-Aldrich). Triblock poly(ethylene oxide)-b-poly(propyleneoxide)-b-poly(ethyleneoxide) copolymer Pluronic® P123 (Sigma-Aldrich), 3-aminopropyl triethoxysilane (APTS, MP biomedicals), butanol (HPLC grade, Fisher), propanol (99%) (ADWIC, Egypt), toluene (HPLC, Tedia), hydrochloric acid (35%) (ADWIC, Egypt), methylene chloride (ADWIC, Egypt), potassium dihydrogen phosphate (ADWIC, Egypt), sodium hydroxide (ADWIC, Egypt), potassium chloride (ADWIC, Egypt), sodium polystyrene sulfonate (PSS, Aldrich), polydiallyldimethylammonium chloride (PDDA, Aldrich), Ketoprofen (Alexandria for chemicals manufacturing, Egypt) and 5-flurouracil (Sigma-Aldrich). All raw chemicals were purchased and used without any further purification. 2.2. Preparation of KIT-6 and KIT-6-NH2 KIT-6 was synthesized based on sol-gel method according to the previous report [27]. Typically, hydrochloric acid (12 g, 35%) was added to 6.0 g of Pluronic® P123 dissolved in 220 mL distilled water. After the dissolution, the mixture was added in n-butanol (6.0 g) and stirred at 35  C for 1 h until a clear solution was obtained. Then 12.48 g TEOS was added dropwise with stirring into the homogenous clear solution and continue stirring at room temperature for 24 h. After that, the solution was refluxed at 100  C for 24 h. Finally, KIT-6 was successfully obtained. The sample was then filtered and washed with copious distilled water, and finally dried in air at room temperature and calcined at 550  C as shown in Scheme 1. The functionalization of KIT-6 with PrNH2 groups to obtain KIT6-NH2 was performed by post-grafting method [28]. In this preparation, 1.00 g of KIT-6 was added to 7 mL of APTS. The mixture was added to a 50 mL dry toluene and refluxed for 6 h as shown in Scheme 1. The mixture was extracted by methylene chloride for 24 h and the KIT-6-NH2 was then successfully obtained. The sample was dried in an oven under air atmosphere for 24 h. The formation mechanism of KIT-6-NH2 was proposed according to Scheme 1. 2.3. Preparation of KP and 5-FU solutions A stock solution of 0.82 mg L1 of KP was prepared by dissolving 0.055 g in a 100 mL of propanol, then complete the flask to 500 mL by phosphate buffer at pH 4. Following the same procedure, a stock solution of 0.96 mg L1 of 5-FU was prepared by dissolving 0.047 g in a 100 mL of propanol/water mixture then complete the flask to 500 mL by phosphate buffer at pH 4. Scheme 2 shows the molecular structure of KP and 5-FU. 2.4. Preparation of different buffer media (pH 7.4, 6.7, 2) Phosphate buffer solutions (pH 7.4, 6.7 and 2) was prepared by addition 50 mL of 0.2 M potassium dihydrogen phosphate (KH2PO4) to 39.5 mL of 0.1 M NaOH, 23.7 mL of 0.1 M NaOH and 1.5 mL of 0.1 M NaOH respectively, followed by the addition of deionized water till 200 mL. A buffer solution of pH 2 was prepared by the addition of 50 mL 0.2 M KCl to 13 mL of 0.2 M HCl and the total volume was completed to 200 mL by deionized water. 2.5. QCM measurements for drugs loading and experimental setup QCM technique was used to investigate the adsorption behavior of KIT-6-NH2 sample. The KIT-6-NH2 film was monitored by mounting a resonating quartz crystal in the cap of the


M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

OEt HO-(CH2CH2O)20-(CH2CHO)70-(CH2CH2O)20-H






P123 + HCl


(1) Reflux (24 hrs,100 oC)

TEOS Stirring (24 hrs)

+ Butanol (35 oC, 1 hr)

OH o

(2)Calcination (550 C)











Dry tolune


Reflux for 24 hrs N2 atm






Loading ketoprofen CH3

O Si





KIT-6-NH2 loaded ketoprofen Scheme 1. Schematic representation summarizes a one-step synthesis of mesoporous silica KIT-6, functionalization to generate KIT-6-NH2 and KP drug loaded- KIT-6-NH2 based on a favorable hydrogen bonding interaction.







Scheme 2. Molecular structure of KP and 5-FU drugs.

polypropylene bottle. The resonant frequency of the crystal (fo) was monitored by using the crystal as the frequency determining element of an electronic oscillator. A hole was made in the cap of the bottle, and a 5 MHz AT-cut quartz resonator, 2.5 cm in diameter, covered this hole and was sealed with silicone rubber. The crystal frequency was measured using a Fluke/Phillips PM 6654 frequency counter. Prior to the film deposition process, QCM electrodes were first cleaned with a mixture of ethanol and water. Then, the electrodes were dried in an oven at 60  C. The frequency was recorded as the initial frequency for the electrode (fo). The fo value was used for measuring the mass of the KIT-6-NH2 sample coated onto QCM electrodes according to the Sauerbrey equation (Eq. (1)) [29]. The mesoporous silica KIT-6-NH2 powder (1 mg) was dispersed in an aqueous solution of sodium polystyrene sulfonate PSS (0.3 mg mL1). The suspension solution was then sonicated for 30 min. To prepare the QCM electrode for drug loading, polyion

polydiallyldimethylammonium chloride (PDDA/PSS) layers were assembled as precursor layers onto the QCM electrodes. Subsequently, the KIT-6-NH2 solution was dropped onto the top surface of a QCM electrode by drop-coating at room temperature. After drying up for 2 h, the electrode surface was rinsed with pure water and then continuously dried overnight at 60  C. After that, the prepared QCM electrodes were then fixed and the measurements were conducted. The QCM-based adsorption method offers the capability of acquiring real-time monitoring of the sorption processes of active molecules in the nanogram range [30]. In this case, a small amount of KIT-6-NH2 deposited onto the gold electrodes of QCM (36 mg cm2), presented in the form of thin films, additionally result in a fast response due to the short diffusion times, thus allowing standard measurements to be completed in 50 min. When KIT-6-NH2 coating on the QCM electrodes was exposed to a 100 mL drug solution, the frequency was immediately decreased due to the fast uptake of drug molecules. The frequency was automatically recorded by a PC-supported measurement system. The time dependence of the frequency shift (DG) was plotted. All experiments were carried out in an air-conditioned room at 25  C. When a small amount of mass is adsorbed onto a quartz electrode surface, the frequency of the quartz is changed. By measurement of the frequency, the mass (per unit area) of the KIT-6NH2 sample (m0 , g cm2) coated onto the electrode can be calculated. Sauerbrey described the fractional decrease in the frequency of the oscillator upon deposition of a mass of material on its electrode surface [29]. The Sauerbrey equation is used to relate the frequency change (Df) to the mass loading of the sample (m0 ) according to the following equation:

M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

! 2f02 DG ¼  pffiffiffiffiffiffiffiffiffiffiffiffi m0

rQ mQ


where fo (Hz) is the fundamental resonance frequency of the quartz crystal, rQ is the quartz density (2.649 g cm3), and mQ is the shear modulus (2.947  1011 g cm1 s2). Df of the KIT-6-NH2 sample after drop-coating and drying-up was experimentally obtained as 1049 Hz. Thus, the sample amount coated onto the electrode was estimated to be 36 mg cm2. 2.6. Drug loading and release studies by UVevisible spectrophotometer To study the drugs loading, a 50 mL of KP solution (0.82 mg L1) was mixed with 0.06 g of KIT-6-NH2 or unmodified-KIT-6. The mixed solution was sonicated for 30 min and stirred at 700 rpm for 2 days at 60  C. Firstly, the KIT-6-NH2 or KIT-6 loaded KP were then centrifuged at 5000 rpm for 10 min and the supernatant drug was withdrawn by syringe into a quartz cuvette to measure the drug concentration using UVevisible spectrophotometer. The initial and final concentrations of KP solutions were determined by measuring the UVevisible spectrum. Similar loadings of 5-FU drug into KIT-6NH2 or unmodified-KIT-6 were made by using a solution of 5-FU drug of concentration 0.96 mg L1. The loading percentage was calculated according to the following equation [31]:

% Loading ¼

Weight of loaded drug  100 Weight KIT  6  NH2


where, weight of loaded drug ¼ initial weight of drug-weight of drug remaining after 48 h of loading. The in vitro release study of the drugs from unmodified-KIT-6 and KIT-6-NH2 was conducted by soaking of KIT-6-NH2 loaded drug in a 50 mL of buffer solutions with different pH media (pH 7.4, 6.7 and 2) with stirring (700 rpm) at 37  C. The absorbance spectrum was used for monitoring the release amount as a function of time and the release percentage was calculated according to the following equation:

% Release ¼

Weight of drug in solution  100 Weight of drug in KIT  6  NH2


2.7. Instruments The morphological structure of unmodified-KIT-6 and KIT-6NH2 was checked by the transmission electron microscope (TEM, S4800 X2.0 KV 8.1 mm X120K TE). N2 adsorption-desorption isotherms were obtained by using a Nova 3200e Quantachrome Autosorb automated gas sorption system at 77 K. Before the measurements were conducted, the samples were degassed in a vacuum at 100  C for 24 h. The surface areas were estimated by the multi-point Brunauer-Emmett-Teller (BET) method at a P/Po range of 0.05e0.3. The total pore volumes and mesopore sizes were calculated by the t-plot and Barrett-Joyner-Halenda (BJH) methods using the adsorption branches of the isotherms, respectively. The UVevisible absorption spectra were measured using UVevisible spectrophotometer (UVD-2960 Labomed, Inc). A centrifuge (Hettich, EBA 20) was used for separation processes. The IR spectra were recorded by using FT-IR Spectrometer (Bruker, Tensor 27 model). Thermogravimetric Analysis (TGA) was conducted in air by using Perkin Elmer STA from 25 to 800  C with a heating rate of 5  C$min1. Low-angle X-Ray powder diffraction (low-angle XRD) patterns were measured at room temperature using GNR, APD


2000 PRP step scan X-ray Diffractometer, with Cu as anode material and graphite monochromator, operated at a voltage of 30 mA, 40 kV. Small-angle X-ray scattering (SAXS) measurements were conducted on a NANOSTAR (Bruker Corporation, USA) equipped with a TURBO X-RAY SOURCE (TXS) rotating anode X-ray source by using monochromated CuKa radiation (l ¼ 0.1540 nm). 3. Results and discussion 3.1. Structural characterization and porosity assessment The synthesis approach for the mesoporous silica KIT-6 is depicted in Scheme 1. KIT-6 was synthesized through the sol-gel approach with a triblock copolymer Pluronic® P123, followed by a chemical modification using APTS to obtain KIT-6-NH2 (synthesis details are given in the Experimental Section). Post-synthesis functionalization of KIT-6 with amino group was performed according to a standard procedure in dry toluene under reflux and N2 atmosphere [28]. During the post-grafting functionalization process, organic functional groups (PrNH2) could be covalently attached via hydrogen bonding to the silanol groups (SieOH) on the external and inner pore surfaces (Scheme 1). The amine functionalization was confirmed by FTIR, N2 adsorption, and TG analysis. The SAXS and XRD patterns ensured that the ordered mesoporous framework of the materials was unaffected by the modification conditions. The mesostructures of the samples were carefully observed by TEM as shown in Fig. 1(a,b). Fig. 1(a) reveals the formation of a 3D interconnected cubic mesoporous KIT-6 with a pore diameter of around 12 nm. After successful functionalization to obtain KIT-6NH2, TEM observation (Fig. 1(b)) showed that the cubic structure is still preserved and the original mesostructure with wellarranged mesopores could even be retained, although the pore size was slightly shrinkage to almost 10 nm in diameter. Mesostructural ordering of the samples was carefully investigated by small-angel X-ray scattering (TI-SAXS) measurements. According to the SAXS patterns (Fig. 2A(a)), KIT-6 exhibited three identical the well-resolved diffraction peaks centered at 2q ¼ 1.3 , 1.7, and 2.2 which can be indexed as (211) and (220) and (332) planes of a 3D cubic mesostructured (Ia3d), respectively [32]. After functionalization, the SAXS pattern of KIT-6-NH2 (Fig. 2A(b)) showed two identical diffraction peaks located at 2q ¼ 1.3 , and 1.7, which can be indexed as (211), (220), respectively. In addition, the appearance of broadened and less-resolved peak (332) is a clear indication for pore walls functionalization with PrNH2. The same phenomenon was also observed in the low-angle X-ray diffraction patterns (low-angle XRD) for the KIT-6 and KIT-6-NH2 (Fig. 2B). From Fig. 2B(a), KIT-6 showed a well-resolved diffraction peak at 2q ¼ 0.9 , indexed as (211), indicating the formation of an excellent structural ordering with a symmetry of the body-centered cubic (bcc) space group Ia3d. Similar XRD patterns were reported for KIT6 materials [33]. After functionalization of KIT-6 with amino groups, as well as the interstitial sites created no uniform strain within KIT-6-NH2 which reflects the broadening of (211) diffraction pattern as shown in Fig. 2B(b). In other words, modification of external and inner surfaces of pore walls with Pr-NH2 groups is proved by the low intensity of the (211) diffraction peak, while the mesostructure remained unaltered after surface modification [34]. The functionalization of KIT-6 with amino groups and its loading with KP and 5-FU drugs were carefully investigated by FT-IR measurements (Fig. 3). FT-IR spectrum of the unmodified-KIT-6 (Fig. 3a) displayed a number of characteristic bands. The characteristic band located at 3435 cm1 is assigned to the stretching vibration of hydrogen bonded silanol group y( ≡SieOH) [35]. The band at about 1630 cm1 is attributed to the OeH bending vibration mode of


M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

Fig. 1. TEM micrograph of (a) KIT-6 and (b) KIT-6-NH2.

Fig. 2. (A) TI-SAXS measurements and (B) low-angle XRD patterns of (a) KIT-6, (b) KIT-6-NH2.

Fig. 3. FT-IR spectra of (a) KIT-6 (b) KIT-6-NH2, (c) KP, (d) KIT-6-NH2 loaded-KP, (e) 5FU and (f) KIT-6-NH2 loaded-5-FU.

physisorbed water molecules. Two characteristic bands observed at 1084 cm1 and 820 cm1 are assigned to the anti-symmetric and symmetric stretching vibration of SieOeSi groups, respectively [36]. Upon functionalization, the presence of eNH2 groups is observed at 3460 cm1 which overlapped with the OeH stretching vibration as shown in Fig. 3b [37]. However, the band located at 1560 cm1 is clearly indicates the presence of NeH (primary amine) bending vibration [37]. Furthermore, the low intense band located at around 2915 cm1 is assigned to the CeH stretching vibration of

the organosilane attached to KIT-6 framework confirming that the functionalization process was successfully realized. To explore the successful loading of KP and 5-FU drugs into the amine-functionalized KIT-6, FT-IR measurements were conducted, as well. Firstly, the FT-IR spectrum for KP drug was measured and was shown in Fig. 3c. The spectra are identified by seven characteristic bands appearing at 2942 cm1 (aromatic CeH stretching and carboxylic acid OeH stretching), 1695 cm1 (C]O stretching of acid), 1630 cm1 (C]O stretching of ketone), 1585 cm1 (carboxylic OeH out of plane deformation), 1417 cm1 (CHeCH3 deformation) and 866 cm1 (CeH out of plane deformation for substituted aromatic ring) [38]. After loading with KP drug (Fig. 3d), the sharp band observed at 1084 cm1 which is characteristic to the antisymmetric SieOeSi stretching vibration was shifted to 1047 cm1 and the intense peak at 1560 cm1, characteristic to NeH was shifted to 1552 cm1. In addition, the band appeared at 2942 cm1 in KP characteristic to carboxylic OeH was shifted to higher wavenumber 3921 cm1, while the band at 1695 cm1 characteristic to C]O was shifted to 1681 cm1 with less sharpness, confirming that the interaction occurred through carboxylic and carbonyl groups. In the same context, FT-IR spectrum of 5-FU before loading (Fig. 3e) showed characteristic bands at 3360 cm1 (NeH stretching free), 1728 cm1 (C]O stretching), 1652 cm1 (CeN stretching), 1394 cm1 (pyrimidine ring), and 1250 cm1 (CeO) [39]. After loading into the KIT-6-NH2, FT-IR spectra is conducted (Fig. 3f). The characteristic band observed at 1084 cm1 of SieOeSi antisymmetric stretching vibration of silanol groups was shifted to 1033 cm1. In addition, the characteristic bands of NeH, C]O and CeN stretching vibration of 5-FU observed at 3360 cm1, 1728 cm1 and 1652 cm1 were shifted to lower wavenumber at around

M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

3305 cm1, 1708 cm1 and 1648 cm1, respectively. The hydrogen bond interaction between eNH2 linked to KIT-6-NH2 and carbonyl group in 5-FU was clearly observed at 2835 cm1 which is assigned to the OeH stretching vibration. The degree of functionalization and drug loading content were examined by TGA (Fig. 4). All the samples showed an initial weight loss at about 150  C due to the physically adsorbed water molecules. In addition, there is no significant weight loss due to disintegration of KIT-6 which implied that the mesoporous silica KIT-6 is thermally stable. The thermal decomposition of the functionalized KIT-6 occurred in the interval of temperatures between 150 and 650  C. Compared to KIT-6, KIT-6-NH2 (Fig. 4) showed a weight loss of around 10% close to 650  C as a result of the decomposition of PrNH2 groups functionalized KIT-6. This is a significant evidence of the degree of functionalization in KIT-6. A broad exothermic effect attributed to the decomposition of organic moieties of KP- and 5FU-loaded KIT-6-NH2 was observed between 300 and 500  C. The total weight loss was dramatically increased to 14.1% and 12.9% for KP and 5-FU, respectively. To explore the mesoporosity, N2 adsorption-desorption isotherms of all samples were recorded at 77 K (Fig. 5). The BET surface areas, mesopore sizes and total pore volumes were analyzed and are summarized in Table 1. All the samples display type IV isotherms. In the range of P/Po > 0.25, the adsorbed volume in the adsorption isotherm gradually increased which is typically associated with the capillary condensation of nitrogen gas inside the mesopores. Also, the large hysteresis loops indicate that the KIT-6 and KIT-6-NH2 samples have a uniform pore texture with large channel-like mesopores (Fig. 5A (a) & (b)). In addition, the mesopores sizes are much consistent with those observed by TEM measurements. A part from the determination of porosity, N2 sorption isotherm has been used to confirm the successful loading of KP and 5-FU molecules within the mesopores. Furthermore, the loading of KP and 5-FU into the mesochannels of KIT-6-NH2 has a significant impact on the textural parameters such as specific surface area and total pore volume (Table 1). After loading, the specific surface area was drastically decreased from 940 m2 g1 to 390 m2 g1 and 255 m2 g1 for KIT-6-NH2 loaded-KP and KIT-6-NH2 loaded-5-FU, respectively (Fig. 5A & B). Along with the surface area, the pore diameter and total pore volume were thus decreased as seen in Table 1. These results show that the pore diameter indeed

Fig. 4. TGA curves of KIT-6 (black line), KIT-6-NH2 (red line), KIT-6-NH2 loaded-KP (blue line) and KIT-6-NH2 loaded-5-FU (green line). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)


decreased after functionalization and loading of KP and 5-FU drugs, which is much consistent with the decrease in unit-cell size observed from the XRD patterns. Thus, loading of drugs on the mesoporous framework was performed mainly in the inner surface of pores without affecting the mesostructure ordering of the mesopore channels. 3.2. Drugs loading and release studies 3.2.1. Loading of KP and 5-FU molecules into the KIT-6-NH2 Inspired by the high surface area and functionalization with PrNH2 groups, we investigated the successful loading capabilities of KIT-6-NH2 with KP and 5-FU drugs by using the QCM technique. High chemical and mechanical stabilities, and large surface area are also attractive for designing excellent DDS, as they provide copious space for drug molecules, as well as the presence of function group. Various mesoporous silica materials, have been considered as pioneering research for successful loading of drugs and have shown highly sensitive targeting of drug molecules [40]. For this purpose, thin layers of PSS/PDDA were assembled onto the QCM electrode, then the KIT-6-NH2 sample was deposited by the drop-coating process. The prepared QCM electrodes coated with the KIT-6-NH2 sample (36.0 mg cm2) were exposed to a 100 mL of 0.3 mg L1 of KP and 5-FU in buffer solution at pH 4 (Fig. 6). The crystal frequency change, DG, increases until it reaches the steady-state value. The increasing in DG is attributed to a mass increase into the mesoporous KIT-6-NH2 film coated QCM electrode, indicating the loading uptake of KP drug as shown in Fig. 6(a). The frequency difference, DG exhibited by KP is equal to 105 Hz, attained after 35 min. Similar experiment was carried out in case of 5-FU with the KIT-6-NH2 sample and DG is equal to 92 Hz, attained after 40 min. The maximum loading uptake of KP and 5-FU drugs by KIT-6-NH2 film coated QCM electrode was estimated to be 1.00 mg g1 and 0.88 mg g1, respectively. It can be seen that loading of KP is slightly higher than 5-FU, which may be attributed to the favorable hydrogen bonding interaction between carboxylic and carbonyl groups of the KP drug with the eNH2 groups functionalized KIT-6. To demonstrate how the amino-function group affects the corresponding release behavior, we used KIT-6-NH2 as host to encapsulate analgesic drugs KP and 5-FU and studied the release property of drugs by UVevis spectroscopic measurements. For comparison, unmodified-KIT-6 was used. The dry powders of KIT-6 and KIT-6-NH2 powder were suspended in KP or 5-FU solutions with stirred for 2 days. The degree of drug loading uptake was ascertained by FT-IR measurements, TGA analysis and N2 adsorption-desorption isotherm (see Figs. 3e5). The supernatant drug was withdrawn to measure the drug concentration using the UVevisible spectrophotometer. Fig. 7 shows the UVevis spectra recorded for KP and 5-FU drugs solutions before and after loading. As shown in Fig. 7(a), the concentration of supernatant solution of KP drugs decreased sharply with the time, indicating the successful loading uptake of KP molecules into the KIT-6-NH2 by diminishing of KP or 5-FU concentration in solution. Compared to KIT-6-NH2, loading uptake of KP drug into unmodified-KIT-6 was too small as shown in Fig. 7(b). Similar results obtained for 5-FU as shown in Fig. 7(c) & (d). Moreover, KIT-6-NH2 exhibited a gradual decrease in the supernatant concentration of 5-FU with a less noticeable loading capacity in comparison of KIT-6-NH2 loaded with KP (Fig. 7(c)). In contrast, loading uptake for 5-FU drug into the unmodified-KIT-6 was significantly smaller as shown in Fig. 7(d). Loading percentage of KP and 5-FU into KIT-6 and KIT-6-NH2 are shown in Fig. 8(a) & (b), respectively. It is clearly seen that the amount of KP and 5-FU loaded into the KIT-6-NH2 framework is significantly higher than the unmodified one. As clearly seen, KIT6-NH2 exhibiting a higher loading percentage for KP (60%) and for


M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

Fig. 5. Nitrogen adsorption-desorption isotherms (A) and BJH pore size distributions (B) of (a) KIT-6, (b) KIT-6-NH2, (c) KIT-6-NH2 loaded-KP and (d) KIT-6-NH2 loaded-5-FU.

Table 1 Porous properties of mesoporous silica KIT-6, KIT-6-NH2 and KIT-6-NH2 loaded KP and 5-FU drugs. Mesoporous silica samples

Surface area (m2 g1)a

Pore diameter (nm)b

Pore volume (cm3 g1)c

KIT-6 KIT-6-NH2 KP-loaded KIT-6-NH2 5-FU-loaded KIT-6-NH2

1085 940 390 255

12.3 10.8 9.5 7.7

0.942 0.813 0.531 0.486

a b c

The surface areas were calculated by the BET method. The mesopore sizes were calculated by the BJH method. The total pore volumes were calculated by the t-plot method.

saturation of mesopore sites that responsible for the fast diffusion of drug molecules. Thus, the uptake of KP drug in KIT-6-NH2 was 0.94 mg g1, greater than that of unmodified-KIT-6 (0.32 mg g1, estimated form Fig. 7(b)), due to the absence of function group which facilitate a hydrogen bonding interaction with the drug molecules. After 48 h in an aqueous KP solution, the KIT-6-NH2 showed a drug loading almost three times larger than unmodified KIT-6. With regard to 5-FU, KIT-6-NH2 exhibited higher loading uptake of 0.75 mg g1, in comparison of unmodified KIT-6 (0.44 mg g1, estimated form Fig. 7(d)). Moreover, the remarkable uptake of KP drug into the KIT-6-NH2 than 5-FU could be attributed to the higher acidic nature of KP. The results obtained from UVevis spectroscopy is consistent with the loading uptake data calculated form the QCM technique, indicating that the amount of KP loadedKIT-6-NH2 is higher than that of 5-FU drug.

Fig. 6. Mass-normalized time-dependence frequency shifts of QCM electrodes coated with KIT-6-NH2 film upon exposed to (a) KP and (b) 5-FU solution.

5-FU (50%). While, KIT-6 achieved low loading uptake of 15% and 11% for KP and 5-FU, respectively. The Effect of KP and 5-FU concentrations on their loading into KIT-6-NH2 was carefully studied, as well. In this case, 0.06 g of KIT6-NH2 was mixed with an initial concentration of KP (0.05 mg L1) and 5-FU (0.21 mg L1) for 48 h as shown in Fig. 9(a) & (b). Then, different concentrations were applied and the drugs were completely loaded within 24 h. The accumulating loading amount versus time is shown in Fig. 9(a) & (b), which is associated with the diffusion process related to the drug concentration. At lower concentration, KP and 5-FU drugs interact with the eNH2 in a favorable hydrogen bond and thus, the uptake was successfully realized in a short time. At higher concentration, the loading uptake of drugs into the framework structure occurred slowly because of the

3.2.2. pH-responsive drug release Since in vitro dissolution testing is an important study for drug development and quality control, it has been used to investigate the release rate of model drugs from KIT-6 and KIT-6-NH2 samples in different pH ranges (PH 2.0, 6.7 and 7.4) to evaluate the best formulations. The drug release behaviors of KP and 5-FU drugs were studied in phosphate buffer as a function of pH (PH 2.0, 6.7 and 7.4) at room temperature. The pH-triggered release of drugs was monitored by using UVevis spectroscopy at 260 nm and 265 nm for KP and 5-FU, respectively. It is known that the release property is related to the nature of interactions between the drug and its carrier. A graph of the release percentage versus time for KIT-6 and KIT-6-NH2 is plotted in Fig. 10. As seen from Fig. 10(a), at physiological pH (pH 2), the Hþ concentration is increased, therefore strengthened the hydrogen bond between carboxylic and carbonyl groups of KP and eNH2 group functionalized KIT-6-NH2, and hence a relatively small release of KP drug was observed. The release percent was gradually increased by decreasing the Hþ concentration (increasing pH from 6.7 to 7.4). Thus, the KP loaded-KIT-6-NH2 was readily protonated, and hence

M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

Fig. 7. UVevisible absorption spectra of: (a) & (c) loading of KP and 5-FU drugs into KIT-6-NH2 and (b) & (d) loading of KP and 5-FU into KIT-6, respectively.

Fig. 8. Loading percentage of (a) KP and (b) 5-FU by using KIT-6-NH2 and KIT-6, respectively.

Fig. 9. Concentration-time dependence on loading uptake of (a) KP and (b) 5-FU by KIT-6-NH2.



M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

Fig. 10. Release profiles of (a) KP and (b) 5-FU from KIT-6-NH2 in different pH ranges; PH 2 (red line), PH 6.7 (green line) and PH 7.4 (black line). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

weakened the hydrogen bonding interaction, then further dissociation of KP molecules occurred leading to an increase in release percent. Similar release behavior for 5-FU was obtained (Fig. 10(b)), however the release percent was relatively smaller (60%) than that in case of KP (75%). To simulate the all conditions through the gastrointestinal environment, the in vitro pH-response release behaviors of KP and 5-FU from KIT-6-NH2 in the release media of different pH values was carefully studied (Fig. 11). As clearly seen, in simulated gastric fluid (SGF, pH 2), about 27% of KP and 9% of 5-FU molecules was released from KIT-6-NH2 in the first 4 h. Within the next 4 h s, the release percent of KP and 5-FU was increased up to 45% and 18%, respectively. Finally, in simulated intestinal fluid (SIF, pH 7.4), a complete release of drug molecules was realized after 20 h for KP (75%) and 38 h for 5-FU (60%). In order to evaluate the mechanism which controls the release kinetic process, the first order, Higuchi, HixsoneCrowell and KorsmeyerePeppas models were carefully applied [41]:

First order :

logð100  WÞ ¼ log 100  K1 t

Higuchi kinetics :

W ¼ KH t 1=2

Hixson  Crowell kinetics :

(4) (5)

ð100  WÞ1=3 ¼ 1001=3  KHC (6)

Korsmeyer  Peppas equation :

Mt ¼ K tn M∞


where K1, KH and KHC are drug release rate constants of first order, Higuchi and HixsoneCrowell models, W is the percent released of drug at time t, Mt/M∞ is the fractional release of drug into the dissolution media, K is a constant that incorporate geometric and structural properties of tablet. Based on the KorsmeyerePeppas equation, n is the diffusion exponent that show the release of drug transport mechanism, values of n exponent equal to or less than 0.5 were characteristic of Fickian or quasi-Fickian diffusion, respectively, whereas values in the range of 0.5e1 is an indication of an anomalous mechanism for drug release. In order to study the mechanism of drug release kinetic process, the experimental data were fitted with different release kinetic models such as, first-order, Higuchi, HixsoneCrowell and KorsmeyerePeppas equations. For time intervals, excellent linear plots of release kinetics were obtained for KP and 5-FU released from KIT-6-NH2 as shown in Fig. 12(A) & (B). The parameters of all release kinetic models of KP and 5-FU were determined and tabulated in Tables 2 and 3, respectively. The release rate constants values were determined from the gradient of the kinetic plots. It was found that the release of KP and 5-FU from KIT-6-NH2 follows a first-order kinetic. Hence from Tables 2 and 3, it was further demonstrated that, KP loaded into KIT-6-NH2 proceeded more rapidly than 5-FU in different pH media (see Fig. 10). From KorsmeyerePeppas equation, good linear fits were obtained, allowing n to be calculated from the linear portion of the slope. The calculated values of n exponent for KP and 5-FU in different pH media, indicating that the release mechanism follows the non-Fickian mechanism (Tables 2 & 3) [41]. Based on these values, thus the understanding release mechanism might be proceeds as follows: (1) the initial release may be occurred due to

Fig. 11. In vitro pH-response release behaviors of (a) KP and (b) 5FU from KIT-6-NH2 in the release media of different pH values, used to simulate the conditions all through the gastrointestinal environment.

M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177


Fig. 12. Release kinetic models of (A) KP drug and (B) 5-FU drug from KIT-6-NH2: (a) First order, (b) Higuchi, (c) HixsoneCrowell and (d) KorsmeyerePeppas kinetics.

leaching of free drug molecules from the KIT-6-NH2 pore entrances, (2) thereafter, KP and 5-FU continues to dissolve slowly into the liquid phase as the solvent diffuses from the system out of mesochannels, and (3) followed by the dissociation of hydrogen bonded

KP and 5-FU with the eNH2 group of KIT-6-NH2. There is of no doubt that the loading capability of drug molecules is proportional to the surface area and pore diameter of the mesoporous silica samples. However, regarding the release kinetics and proportion,


M.M. Ayad et al. / Microporous and Mesoporous Materials 229 (2016) 166e177

Table 2 Release kinetic parameters of KP drug. Release medium

pH 7.4 pH 6.7 pH 2.0

First order




K1 (h1)


KH (%h1/2)


KHC (h1)


K (hn)



0.033 0.027 0.024

0.999 0.999 0.999

12.52 10.28 5.64

0.998 0.995 0.997

0.0397 0.0234 0.0144

0.994 0.992 0.997

0.1173 0.1083 0.1292

0.625 0.539 0.547

0.988 0.994 0.984

Table 3 Release kinetic parameters of 5-FU drug. Release medium

pH 7.4 pH 6.7 pH 2.0

First order




K1 (h1)


KH (%h1/2)


KHC (h1)


k (hn)



0.030 0.019 0.029

0.999 0.999 0.999

10.17 9.12 5.22

0.995 0.997 0.996

0.0296 0.0233 0.0145

0.996 0.994 0.990

0.1072 0.1012 0.1073

0.611 0.522 0.532

0.980 0.992 0.982

other factors should be highly considered. Thus, chemical functionalization is a crucial factor for improved drug loading and release rate.

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