Microporous and Mesoporous Materials 199 (2014) 40–49

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Microporous and Mesoporous Materials

journal homepage: www.elsevier.com/locate/micromeso

Versatile drug releaser derived from the Ti-substituted mesoporous

silica SBA-15
Mi Mi Wan a, Xiao Dan Sun a, Shuai Liu a,b, Jing Ma a,b, Jian Hua Zhu a,⇑
a
Key Laboratory of Mesoscopic Chemistry of MOE, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
b
Kuang Yaming Honored School, Nanjing University, Nanjing 210093, China

a r t i c l e i n f o a b s t r a c t

Article history: Multiple modification of SBA-15 in its electrostatic and geometric properties was simultaneously
Received 15 May 2014 performed by titanium substitution in the framework of mesoporous silica, in order to fabricate versatile
Received in revised form 1 August 2014 drug releaser based on the Ti-SBA-15 with subtle ‘‘critical state’’. The SBA-15 with proper Ti-content, no
Accepted 2 August 2014
more than 4.2 lmol g 1 without formation of TiO2, was synthesized via special hydrothermal conditions
Available online 12 August 2014
with assistance of fluorine ion, and the resulting composite had the appropriately distorted mesoporous
structure provided the Si/Ti of initial gel no less than 50, plus the lowered surface negative charge
Keywords:
(Zeta-potential). The controlled Ti-substitution enabled SBA-15 to be more active in adsorbing negative
Versatile drug releaser
Ti substituted SBA-15
charged drug like heparin, especially in dilute solution. Also, sustained heparin release was achieved on
Critical state of mesoporous vessel the Ti-SBA-15 with a little initial burst. Ti-substitution also improved the loading and release of small
Zeta-potential drug such as ibuprofen on SBA-15, compensating the lack of fine geometric confinement in mesoporous
Burst effect silica. Moreover, liquid adsorption of probes with different negative charge and molecular size, including
heparin, ibuprofen and volatile nitrosamines N-nitrosopyrrolidine was investigated to explore the
influence of Ti-substitution on the electrostatic attraction and structural distortion of SBA-15, offering
a tool to characterize the mesoporous materials and providing a valuable clue for design of new drug
releaser.
Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction different sizes. Consequently, in situ or post-synthesis modification

Mesoporous silica is the promising candidate for drug release
because of its ordered pore structure, high pore volume, high sur-
face area and the silanol-containing surface [1]. And it is also non-
toxic and able to be taken up by cells [1–4]. However, mesoporous
silica still faces some challenges for sustained release. The first one
is the unsteady release rate with a burst effect in the initial release
period [1], especially on the SBA-15 vessel to delivery diazepam,
heparin, and nifedipine [4–7]. One reason for this phenomenon is
the host–guest mismatching, that is, the pore size of vessel was
too wide to grasp the loaded drug hence a fast release emerged
in initial period. Thus, how to conquer the mismatching and
compensate the lack of fine geometric confinement is the second
challenge facing mesoporous silica. It is very difficult, if not impos-
sible, to directly prepare a versatile porous vessel with the suitable
and changeable channels to grasp and release various drug with
⇑ Corresponding author. Tel.: +86 25 83595848; fax: +86 25 83317761.
E-mail address: jhzhu@netra.nju.edu.cn (J.H. Zhu).
of mesoporous silica is necessary to control its textural parameters
and surface state [1].
Organic modification was tried to attract drug and optimized
the release process in mesoporous materials [1,8], but it was hard
to adjust the amount of organic groups in the carrier, which often
declined the release of drug due to the too strong interaction from
the modified vessel [5]. Recently, adsorption and release of drug in
ordered mesoporous materials is reported to be related to the
adequate modulation of their surface electrochemistry [9], and it
is feasible to adjust the host–guest interactions with electrochem-
ical assistance through proper surface modification with metal
cation incorporators. For practice, Aluminum was introduced into
the framework of SBA-15 to enhance adsorption of heparin by ade-
quately tailoring the Zeta potential of vessel [6]. However, the
burst release was not well controlled because the more adsorbed
drugs gushed in the initial period of release, which spurs the search
of other modifier for mesoporous drug vessel. Compared with alu-
minum, titanium is a more promising candidate for medical appli-
cations due to its excellent biocompatibility and bioactivity, and
titanium alloy has been widely utilized as an implant material in

http://dx.doi.org/10.1016/j.micromeso.2014.08.005
1387-1811/Ó 2014 Elsevier Inc. All rights reserved.
 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49
Scheme 1. Structures and sizes of the probe molecules.
orthopedic and dental applications [10–12a]. Besides, cytotoxicity
of Ti-functionalized mesoporous materials has been studied in
detail, and their cytotoxic nature can be greatly reduced [12]. Con-
sequently, Ti-containing materials have been widely used as drug
deliver [13a,b] apart from catalyst [13c]. Especially, Ti has a smaller
electronegativity than that of Al hence substitution of silicon with
titanium in the framework of mesoporous silica may adjust the
surface negative charge (Zeta potential) of vessel more moderately.
Towards this purpose, however, all of the Ti modifiers should be
substituted in the framework of SBA-15 rather than formation of
anatase TiO2. On the other hand, the even release of drug also
requires the modified mesoporous vessel to have special geometric
structure because the common wide, flat and straight channels are
helpless to suppress the burst release of drug. Instead, the vessel
should have the sinuate and indented channel with the rough sur-
face to hinder the diffusion and thus delay the release of adsorbed
drug, similar to that observed in plugged Al-SBA-15 [6]. Nonethe-
less, such anfractuous state of mesoporous vessel is really close
to the ‘‘critical state’’ of ordered mesoporous materials, which dif-
fers from the Ti-SBA-15 reported in literature with a high struc-
tural quality [13c,14], therefore it should be carefully to master
the hydrothermal synthesis parameters such as raw materials,
aging temperature and additives in order to obtain the special
Ti-substituted SBA-15 sample with subtle structure. Here,
Ti-containing SBA-15 is synthesized by one-pot method, and
NH4HF2 is used as catalyst to accelerate hydrolysis of silicon source
because of the large difference in the hydrolysis rate between tita-
nium alkoxides and silicon precursors [13].
Heparin and ibuprofen are selected to assess how the modified
electrostatic interaction and channel tortuosity of Ti-SBA-15
affect the adsorption and release of unequal-sized drugs. Heparin
is a water soluble drug with relatively large molecular size of
1.5 nm  10 nm (Scheme 1), and it has been widely applied in
the prophylaxis and treatment of deep vein thrombosis and pul-
monary embolism in many forms, including soluble heparin and
the heparin immobilized into supports through adsorption, cova-
lent chemical or photochemical attachment [15,16]. Ibuprofen is
the water-insoluble molecule with a size of 0.6 nm  1.3 nm, a
safe anti-inflammatory and analgesic drug for the relief of symp-
toms of inflammation, acute pain and fever [17]. N-nitrosopyrrol-
idine (NPYR) is also chosen as the third probe for its relatively
weak negative charge and small size of 0.4 nm  0.5 nm. Nitrosa-
mines can induce the cancer or tumor in laboratorial animals
even with a trace amount [18] and their adsorption by zeolite
has been extensively investigated [19]. Adsorption of NPYR in
Ti-SBA-15 composite will explore its new function of trapping
toxic substance apart from delivering both water-soluble and
water-insoluble drugs.
41
2. Experimental section
2.1. Materials and reagents
Pluronic P123 (EO20PO70EO20, Mw = 5800) was obtained from
Sigma, and titanium isopropoxide was the product of ACROS.
Ibuprofen (J&K chemical, China) was of analytical grade. Tetraeth-
oxysilane (TEOS), hydrochloric acid (HCl, 37%), sodium chloride
(NaCl) were purchased from Nanjing Chemical Reagent (China).
All reagents were used as received without further purification.
Heparin (sodium salt, 160 IU mg 1) with an estimated Mw of
6000 was bought from market [20]. Phosphate buffer solution
(PBS, pH = 7.1) was prepared by dissolving Na2HPO4
12H2O and
NaH2PO4
2H2O in deionized water [5,6]. N-nitrosopyrrolidine
(NPYR) was provided by Sigma and dissolved in dichloromethane
(A.R.) at the ratio of 1:19 (V/V).
2.2. Methods
2.2.1. Characterization of the materials
The X-ray diffraction (XRD) patterns of samples were recorded
on an ARL XTRA diffractometer with Cu Ka radiation in the 2h
range from 0.5° to 8°. Nitrogen adsorption and desorption
isotherms were measured at 77 K by using a Micromeritics ASAP
3020 volumetric adsorption analyzer, and about 100 mg of
samples were evacuated at 573 K for 4 h in the degas port of the
analyzer prior to test. However, the sample adosrbed heparin
was evacuated at 373 K for 5 h before measurement. The
Brunauer–Emmett–Teller (BET) specific surface area was calcu-
lated using adsorption data in the relative pressure range from
0.04 to 0.2, and the total pore volume of sample was determined
from the amount adsorbed at a relative pressure of about 0.99,
while the pore size distribution curve was calculated from the
analysis of the adsorption branch of the isotherm using the Barrett
Joyner Halenda (BJH) algorithm. The primary mesoporous volume,
Vp of sample was calculated by the t-plot method. TEM analysis
was carried out on a JEM-1011 electron microscope operating at
200 kV. Thermo-Gravimetric and Differential Scanning Calorimet-
ric (TG–DSC) analysis was performed on a NETZSCH STA449C
apparatus in air from 293 K to 1073 K with a heating rate of
10 K min 1. The titanium content of composite was determined
by use of an ARL9800XP XRF analyzer. UV–vis spectra of sam-
ples were collected on a UV-3600 scanning spectrophotometer
equipped with an integrating sphere from 190 to 800 nm. The FTIR
spectrum of sample was recorded in the range of 400–4000 cm 1
on a NEXUS870 spectrometer, and the sample was mixed with
KBr at a ratio of 3:97 (w/w) and then pressed as a thin disk for
measurement. Zeta potential was measured by Zetasizer Nano-Z
42 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49
instrument [6], and the sample was made up in deionized water
and shaken for 12 h prior to test. X-ray photoelectron (XPS) spectra
were recorded with a PHI 5000 VersaProbe system equipped with a
hemispherical electron analyzer, and C1s (284.6 eV) was taken as a
reference to calculate the binding energy (Eb).
2.2.2. Synthesis of samples
To obtain SBA-15 samples containing titanium [13], 3 g of
Pluronic P123, 22.5 g of water, 0.0262 g of NH4HF2 and 90 g of
HCl aqueous solution (2 mol L 1) were stirred for 3 h at room tem-
perature to give the solution of template. And 4.6 g of TEOS and
certain amount of titanium isopropoxide (with the Si/Ti molar ratio
of 200, 100, 50, 33) were stirred for 3 h to obtain the solution of
Si–Ti precursors. Then the Si/Ti precursors were added to the Plu-
ronic P123 solution dropwise, and the mixture was stirred for 20 h
at 313 K, followed by hydrothermal treatment in an autoclave at
373 K for 24 h. The solid was recovered by filtration, washed with
distilled water, and air-dried to give the as-synthesized sample
denoted as TS-n-as, where n corresponds to the initial Si/Ti molar
ratio of 200, 100, 50 and 33, respectively. Part of TS-n-as sample
was calcined at 773 K for 5 h in air to remove the template, and
the obtained composite was named as TS-n. SBA-15 is prepared
for comparison according to the literature [21].
2.2.3. Detection of heparin
An amount of 50 mg of heparin sodium of was dissolved in
50 mL phosphate-buffered saline (PBS) solution (pH = 7.2–7.6 con-
taining 0.02 M phosphate and 0.15 M sodium chloride) to obtain
the standard heparin solution. 0.005% toluidine blue solution was
prepared by adding 25 mg of o-toluidine blue, 2.5 mL of 2 M HCl
and 1 g of NaCl in 500 mL of distilled water. Standard heparin dilu-
tions with concentration of 0.5, 1, 2, 4, 6, 8, 10, 12, 14 lg mL 1 were
diluted from the standard heparin solution. Ten tubes were used
for this assay. Among them one tube was utilized as the blank.
Each tube was added with 2.5 mL of toluidine blue solution, and
then 2.5 mL of heparin solutions with different concentration were
added to these tubes, while 2.5 mL of PBS solution was added to
the blank tube. All the tubes were shaken vigorously for 30 s.
5 mL of hexane was added to each tube and then shaken violently.
This was done to extract the heparin-dye complex formed in tube
1–9. For each tube, the absorbance was measured at 620 nm using
the visible spectrophotometer. To perform the adsorption of
heparin [5,6]: 100 mg powder-like sample was added into a tube
containing 5 mL PBS solution with 50 mg heparin, and then the
tube was kept in the fridge at 277 K for 72 h. After the sample
was washed with 10 mL PBS solution for three times, it was put
into another 10 mL PBS solution to assess the release of heparin.
The release amount of heparin at different time was determined
by toluidine blue method [22], and release profiles were obtained
by plotting the release amount vs. time. For the adsorption of
heparin in dilute solution [6], 100 mg of SBA-15 or TS-50 powder
sample was added into a tube containing 10 mL PBS solution with
1–50 mg heparin, as mentioned above.
2.2.4. Adsorption and release of ibuprofen (IBU)
50 mg of TS-n samples was added in 5 ml of hexane solution of
IBU (10 mg ml 1) for 72 h at 277 K. The residual IBU concentration
of solution was detected by using a UV–visible spectrophotometer
(UV1750) at a wavelength of 272 nm, and the loaded vessels were
dried under vacuum at 313 K. Then 20 mg of the vessel was
immersed into 5 ml of PBS buffer solution (pH = 7.4) at 310 K.
The solution was taken at given time to analyze the amount of
IBU, and the sample was soaked with 10 ml of new PBS solution.
To visualize the efficiency of Ti institutors in SBA-15 for improving
adsorption and release drug, the performance of vessel was calcu-
lated by per square meter of surface area instead of per gram.
2.2.5. Liquid adsorption of nitrosamines
A total of 20 mg of powder sample were added into a tube
containing 1.1 mL of a dichloromethane solution of NPYR. After
the static adsorption of 24 h at 277 K, the solid was separated
and the residual NPYR in solution was detected by an improved
spectrophotometric method [23].
3. Results
3.1. 1Characterization of Ti-SBA-15 series samples
Fig. 1 illustrates the XRD patterns of Ti-SBA-15 samples with
different T-contents. TS-200 and TS-100 samples clearly showed
three well-resolved peaks that could be indexed as (1 0 0), (1 1 0),
and (2 0 0) diffractions associated with the p6mm hexagonal sym-
metry, similar to that of SBA-15 in 2h position, peak intensity, and
line-width. This similarity means the existence of highly ordered
meso-structure on these Ti-containing analogs. When the amount
of titanium additive increased, however, the (1 1 0) and (2 0 0)
peaks on the XRD patterns of TS-50 and TS-33 samples became less
resolved, meanwhile the intensity of (1 0 0) peak declined obvi-
ously, demonstrating the less ordering of meso-structures. This
phenomenon is not unexpected, since it is generally accepted that
the maximum Ti/Si content in the initial gel should be less than
0.015 in order to obtain high-quality Ti-SBA-15 materials [13].
Fig. 2a displays the N2 adsorption–desorption isotherms of
SBA-15 and Ti-SBA-15 samples to further characterize their
structural change. SBA-15 exhibited a type IV isotherm with the
sharp capillary condensation at high relative pressure, along with
H1-type hysteresis loop that indicated the uniform mesopores.
TS-n samples remained the pore structure of SBA-15, but the shape
of hysteresis loop was changed more or less. Besides, addition of
titanium isopropoxide in the synthesis of SBA-15 clearly influenced
the surface area and pore volume of resulting sample though the Ti
content of the solids was negligible. Usually the BET surface area of
SBA-15 varies in the range of 500–1000 m2 g 1 since its porous
property is greatly dependent on synthesis conditions [21,24,25],
hence here the SBA-15 possessed a surface area of 754 m2 g 1.
Impregnation of Ti in SBA-15 lowered the surface area of samples
to 588 cm3 g 1. Especially, TS-200 sample owned a 2% reduced sur-
face area and an 8% shrunk pore volume, and its most probable
pore size decreased from 9 to 7.7 nm. As the initial ratio of Si/Ti
in synthesis declined from 100 to 33, the reduced ratio of BET sur-
face area of resulting sample TS-100, TS-50 and TS-33 was 3.3%,
22%, and 18.7%, respectively. In contrast, their pore volume was
increased slightly from 7% (TS-33) to 22% (TS-200). The average
Intensity (a. u.)
SBA-15
TS-200
TS-100
TS-50
TS-33
1 2 3 4 5 6
2 θ (degrees)
Fig. 1. XRD patterns of SBA-15 and the TS-n samples.
 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49 43

7
a b
SBA-15
Volume adsorbed (cm g at STP) 3 -1
150 cm g at STP 6 TS-200
TS-100

Pore volume (cm g )

TS-50

-1
5 TS-33
-1

3
3

SBA-15 4

TS-200 3

TS-100
2
TS-50
1
TS-33
0
0.2 0.4 0.6 0.8 1.0 0 10 20 30 40
Relative pressure (P/P0) Pore diameter (nm)

Fig. 2. The nitrogen adsorption–desorption isotherms (a) and pore size distribution (b) of SBA-15 and TS-n series samples.

pore size of TS-200, TS-100 and TS-33 was lowered from 9.0 nm to
about 7.6 nm meanwhile their pore size distribution was wider
than that of SBA-15. TS-100 sample became the exception whose
pore diameter was similar as that of parent SBA-15. These irregular
structural variations of Ti-containing SBA-15 mirror the strong
effect of titanium component on the synthesis of meso-structure
[14], which realizes the structural tailor of the mesoporous vessel.
The TEM images in Fig. 3 further confirmed the ordered meso-
porous structure of TS-n samples. TS-200 and TS-100 samples
showed the high ordered hexagonal arrays of mesopores with large
uniform pore sizes, but the regularity of TS-50 was considerably
declined in which some channels were bended with rough surface.
When the added molar ratio of Ti/Si equaled to 0.03, the pore struc-
ture of TS-33 became less ordered (Fig. 3d), and some parts lost the
channel structure and became warm-like while some possessed
criss-cross pore-structures, which was consistent with the results
of XRD tests (Fig. 1).
UV–vis spectroscopy is used to characterize the coordination
states of the Ti species incorporated in SBA-15, and the bands at
200–230, 330 and 260–290 nm are usually taken as the evidence
for isolated framework Ti, anatase particles, and octahedrally coor-
dinated Ti species with low dispersion, respectively [26]. Fig. S1a
depicts the UV spectra of TS-n samples, and all of them presented
a band at 210 nm that indicated the titanium in a distorted
tetrahedral coordination [13], further proving the incorporation
of titanium in the framework of mesoporous silica [13,27]. No
extra-framework anatase TiO2 was observed in these spectra,
because of the absence of the signal between 350 and 400 nm
[28]. On the other hand, there was no signal of Ti detected on
the XPS spectrum of TS-50 or TS-33 sample (Fig. S3), either, which
excluded the possibility of surface enrich of Ti component and con-
firmed the incorporation of titanium ions in the framework [29]:
these samples had the Si/Ti of about 4000 (Table 1), hence their
Ti-content was lower than the detection limitation of XPS (about
0.1% of surface concentration) [30].
IR spectra of SBA-15 and its Ti-containing analogs are presented
in Fig. S1b. These spectra illustrated two bands at 800 and
1057 cm 1 that could be associated with Si–O bonding [31]. In
addition, a band centered at 962 cm 1 was generally attributed
to the overlapping of vibrations of Ti–O–Si and Si–OH bonds

100 nm 50 nm

50nm 50nm
Fig. 3. TEM images of the surfactant-free samples (a) TS-200, (b) TS-100, (c) TS-50 and (d) TS-33.
44 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49

Table 1
Textural properties of Ti-SBA-15 composites and their adsorption performances.

Samples SBA-15 TS-200 TS-100 TS-50 TS-33 TS-50-Ha AS-100[6]

Initial Si/M – 200 100 50 33 50 100
Final Si/M – 15923 8333 3773 4901 – 308
NM (lmol g 1, A) – 1.0 1.9 4.2 3.2 – 5.2
Zeta potential (mV) 40.3 37.2 33.7 30.6 31.4 36.5 33.1
SBET (m2 g 1) 754 737 729 588 613 338 675
Vp (cm3 g 1) 0.9 1.1 1.0 1.0 0.97 0.58 0.76
DBJH (nm) 9.0 7.7 9.2 7.6 7.4 10 8.4
Wall thickness (nm) 2.1 3.5 2.5 3.6 3.3 – 2.8
Ads. amount (mg g 1) 30.0 53.6 70.2 82.5 62.4 –
(mg g 1)b 20.5 41.7 65.0 73.0 43.8 –
Nhep (lmol g 1, B)c – 8.93 11.7 13.8 10.4 – 93
A/B (%) – 11.2 16.2 30.4 30.8 – –
1
Released at 4th day (mg g , C) 12.4 6.5 8.2 8.4 5.3 – –
At 60th day (mg g 1, D) 15.4 15.3 19.3 35.0 16.4 – –
C/D (%) 80.5 42.5 42.0 24.0 32.3 –
Adsorbed IBU (mg g 1) 75 113 131 140 93 –
Released at 2 h (%) 67 60 40 19 –
Adsorbed NPYR (mg g 1) 42 59 61 83 54 –
(mmol g 1) 0.42 0.59 0.61 0.83 0.54 –
a
This sample has been adsorbed heparin.
b
This is the data calculated from the result of TG measurements of the samples adsorbed heparin.
c
The average molar weight of heparin is estimated to be 6000.

[32,33]. A slight strengthened 962 cm 1 band was observed in the
spectra of TS-n composites, mirroring the more Ti–O–Si bonding in
these titanosilicate materials.
Both initial and final molar ratio of Si/Ti, Zeta potential of sam-
ples, and their adsorption capabilities are summarized in Table 1.
Actually, the incorporated titanium in SBA-15 was much less than
that of the initial gels, possibly due to a portion of Ti precursor that
remained in the acidic solution [13], and the former tardily rose as
the latter increased, with the exception of TS-33 whose Ti-content
was slightly lower than that of TS-50 instead. However, even so lit-
tle of titanium incorporated into SBA-15 still dramatically changed
the Zeta potential of the sample. TS-n composites exhibited a less
negative Zeta-potential than that of SBA-15 ( 40.3 eV), from
37.4 eV (TS-200) to 31.4 eV (TS-33), since the surface negative
charge of support could be adjusted by introduction of metal com-
ponent [6]. Adsorption of heparin made the mesoporous vessel to
exhibit more negative Zeta-potential. For instance the data of
TS-50-H ( 36.5 eV) was quite more negative than that of TS-50
( 30.6 eV), because heparin is a negative charged molecule [34].
The variation of surface negative charge of mesoporous vessel
affected the adsorption of heparin, and the less negative charge
would be beneficial for the adsorption [6]. TS-33 sample was also
the exception whose Zeta-potential data ( 31.4 eV) was less
negative than that of TS-100 ( 33.7 eV) but its adsorption capacity
was inferior to that of TS-100 (Table 1), which implies the
existence of other factors affecting the adsorption of heparin on
Ti-containing SBA-15.
3.2. Adsorption and release of heparin by Ti-SBA-15 composites
As TS-50 sample exhibited the highest adsorption capacity of
heparin, it was selected to explore further the promotion of tita-
nium substitute on adsorption of negative charged drug. Thus,
TS-50 and SBA-15 samples were chosen to adsorb heparin in a
diluted solution (Fig. 4a). SBA-15 could hardly adsorb heparin in
the solution with a concentration of 0.1 mg mL 1, and it trapped
a trace amount as the concentration rose to 0.2 and 0.3 mg mL 1.
When the concentration of heparin exceeded 0.4 mg mL 1, notice-
able adsorption was observed in SBA-15 and the adsorbed amount
rose as the concentration further increased (Fig. 4a). Based on these
results, it is apparent that the driving force of heparin adsorption in
mesoporous silica is the concentration difference between the
solution and the vessel [5], and such promotion only emerges in
the solution with a relatively high concentration. In contrast,

SBA-15 90

75
TS-50 a b
Adsorbed amount (mg g-1)

Adsorbed amount (mg g -1)

75 TS-50

60
60

45 45

SBA-15
30 30

15 15

0 0
0 1 2 3 4
0.1 0.2 0.3 0.4 0.5 1 10
-1
Time (d)
Concentration of heparin (mg mL )
1
Fig. 4. Adsorption of heparin on the composite based on SBA-15 in (a) various dilute solution and (b) the solution of 10 mg mL .
 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49
TS-50 began to adsorb heparin in the solution with a rather low
concentration (0.1 mg mL 1), and its adsorption became efficient
once the concentration rose to 0.2 mg mL 1 as shown in Fig. 4a
where TS-50 trapped ten times more heparin (5.2 mg g 1) than
SBA-15 (0.4 mg g 1). As the heparin concentration of solution
was enhanced to 0.4 mg mL 1, 28.6 mg g 1 of heparin was
adsorbed by TS-50, 40% more than that by SBA-15 (20.3 mg g 1).
When the concentration of solution was further increased to
10 mg mL 1, TS-50 captured the heparin of 82.1 mg g 1 while
SBA-15 adsorbed 37.8 mg g 1. It is obvious that lowering the sur-
face negative charge (Zeta-potential) of mesoporous vessel by Ti
species availably promotes the adsorption of heparin in the dilute
solution, say, less than 0.3 mg mL 1. Fig. 4b describes the adsorp-
tion of heparin by SBA-15 and TS-50 in the solution of 10 mg mL 1.
The former captured the heparin of 17 mg g 1 in first 12 h and
another 12 mg g 1 in the succeeding 60 h, meanwhile the latter
adsorbed 32 and 53 mg g 1 in the corresponding times, thanks to
the incorporation of metal cation that accelerates the adsorption
of heparin in the mesoporous silica [6].
TG measurement confirms the heparin adsorption determined
by colorimetric toluidine blue method (Table 1 and Fig. S4). All of
TS-n samples adsorbed more heparin than parent SBA-15, and their
adsorption capacity increased as the Ti-content rose with the
exception of TS-33 (Table 1). However, the adsorbed amount of
heparin determined by TG technique was 9–29% smaller than that
by colorimetric toluidine blue method, due to the different detec-
tive mechanisms. The judgment of TG is based on the weight loss
during the combustion of heparin, but some fragments containing
sulfur and/or nitrogen are deposited on the sample even at the high
temperature; meanwhile colorimetric toluidine blue method is
based on chemical reaction which can recognize all of the heparin
molecules.
Fig. 5a displays the cumulative release of heparin from SBA-15
and its Ti-containing analogs. There was an obvious initial release
burst on the release curve of SBA-15; it released the heparin of
about 12 mg g 1 within the initial 4 days but only 3 mg g 1 during
the following 26 days. In contrast, a much slower release was
observed on TS-n composites for the first time. For TS-50 sample
whose final release amount of drug was about 35 mg g 1, it only
released 5 mg g 1 of heparin in the first 4 days, followed by a
evenly heparin-releasing in 20 days, and its release of heparin
was kept stable and slow in another 20 days. Similarly, an obvious
suppression of burst was observed at the beginning of the release
from TS-100 (Fig. 5a), though its release achieved the equilibrium
at 30th day. The release burst was avoided on TS-200 composite
so that it released more heparin after 4 days (9 mg g 1) than that
from SBA-15 (3 mg g 1). Likewise, the release of TS-33 was
40
SBA-15
TS-200
35
Released heparin (mg g )
TS-100
-1
30 TS-50
TS-33
25
20
15
10
5 20
0 0
0 10 20 30
Time (D)
Fig. 5. Release profiles of (a) heparin and (b) ibuprofen from TS-n series samples.
45
characterized with the suppressed release burst. To illustrate the
release rate of each sample, the release percentage of heparin is
plotted vs. the release time (Fig. S5). SBA-15 had the fastest release
rate of heparin due the lack of proper host–guest interaction. In
contrast, its Ti-modified analogs exhibited a more even release rate
for this drug.
3.3. Adsorption and release of ibuprofen and NPYR
Ibuprofen (IBU) was chosen as the probe owing to its similar
negative charged property (with acid group) but a much smaller
size (0.6 nm) than that of heparin [1,35], theoretically the mesop-
ores of SBA-15 and TS-n composites should be wide enough for its
adsorption therefore the adsorption and release of IBU will be
mainly affected by the electrostatic attraction from the vessel.
Uptake of IBU in the adsorption by TS-n samples was larger than
that by SBA-15 as expected, increasing from 75 to 113 then to
140 mg g 1 on SBA-15 to TS-200 then to TS-50. The Ti modifier
decreased the Zeta potential of SBA-15, facilitating the adsorption
of negative charged drug IBU indeed. However, TS-33 sample only
trapped 93 mg g 1 of IBU though its Ti-content was larger than
that of TS-200 and TS-100 (Table 1), which was attributed to its
distorted channel structure (Fig. 3d). The relative large amount of
titanium in the synthesis sol–gel leaded to the disordered structure
of TS-33 sample, in which some parts of the channel was degener-
ated like bottleneck so that IBU could not pass, similar to the
hindered adsorption reported on dealuminated Y zeolite due to
the block of the entrance to the cages by extra-framework Al spe-
cies [35].
Liquid adsorption of NPYR, a typical volatile nitrosamine with
negative-charged N–NO group and the molecular size of 0.42 nm,
confirmed the electrostatic function of TS-n composites and the
existence of small pores in TS-33. SBA-15 trapped 0.42 mmol g 1
of NPYR due to the weak adsorptive sites of silanol group, and
TS-n samples exhibited an enhanced capability owing to the Ti
modifier, because the adsorption of NPYR is sensitively affected
by host–guest electrostatic interaction [36]. As the Ti-content
increased from TS-200 to TS-50, the adsorbed NPYR increased from
0.59 to 0.83 mmol g 1 (Table 1). However, TS-33 sample showed a
declined capability (0.54 mmol g 1) although its Ti-content was
larger than that of TS-200 and TS-100, similar to the report of zeo-
lite A with narrow pore that hinders the entrance of NPYR [19].
This result indicates the distorted structure of TS-33 consisting of
some extra-fine micropores or gaps that forbid the diffusion of
NPYR.
The adjusted release of IBU was also observed on Ti-SBA-15
characterized with the suppressed burst effect. IBU was released
TS-50
a 140
b
Released ibuprofen (mg g )
-1
TS-100
120
100
TS-200
SBA-15
80
TS-33
60
40
40 50 60 0 10 20 30 40 50
Time (hour)
46 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49
extremely rapidly from SBA-15, 50% was released with 0.5 h, 67%
in 2 h and finished at 7 h (Fig. 5b). In contrast, the released ratio
in 2 h for TS-200, TS-100 and TS-50 was 60%, 40% and 19%
respectively. Especially the cumulative ibuprofen release was 46%
after 4 h and 70% after 8 h. After 48 h, all ibuprofen molecules
were released from TS-n vessel (Fig. S5b), this performance of con-
trolled slow release was faster than dealuminated faujasites did
(96–102 h) [35], but similar to that of amorphous microporous sil-
ica [37]. All TS-n samples released more IBU than SBA-15 did. For
instance, the amount from TS-50 (140 mg g 1) was 86.7% more
than that from SBA-15 (75 mg g 1) due to the larger adsorption
capacity of TS-50. It is proven that the specific electrostatic func-
tion of Ti-SBA-15 is also efficient to realize the evenly release of
small poorly soluble drug such as ibuprofen.
In order to see the difference on the release kinetics more
clearly, graphs in concentration vs. log concentration along with
concentrations vs. log t are plotted as shown in Figs. S6 and S7.
Released concentration of heparin or IBU had an evident positive
correlation with log C, and the released concentration of heparin
or IBU increased a lot with the introduction of titanium. Moreover,
the results in Fig. S7a show that release rate of heparin by TS-n
samples was much slower than that by SBA-15 samples. Especially,
released concentration of the drug and log t is almost in linearity
relation on TS-50 sample, indicating that burst effect has been suc-
cessfully suppressed by titanium modification.
4. Discussion
Judged from the aforementioned results, it is apparent that
titanium has been successfully substituted into the framework of
SBA-15 despite of the small amount. Proper amount of titanium
additive in synthesis had little effect on the pore structure of
resulting composite such as TS-200 and TS-100, and their titanium
content gently rose with the enhanced titanium concentration in
initial gels (Table 1). However, continuative increased titanium
source in synthesis changed the uniform mesopores to less ordered
pores in composite TS-50 and TS-33 (Fig. 3), due to the salt effect
caused by titanium isopropoxide. At the meantime, the Ti-content
of TS-33 was lower than that of TS-50 instead, which is resulted
from the relative high concentration of titanium source [14]. In
general the assembly of the mesoporous silica organized by tri-
block copolymer species in acid media occurs through a (S0H+)
(X I+) pathway [34]. Salt plays a role of structure maker during
the micellization of PEO-PPO-PEO block copolymers because of
its self-hydration through hydrogen bonding [38], which, however,
in turn reduces P123 solubility, critical micellar concentration, crit-
ical micellar temperature, and cloud point of the copolymer [38].
As the result, the surface area and pore volume of resulting com-
posite would be lowered [39]. Rather, a slightly thicker channel
Scheme 2. The possible influence of Ti-containing framework on the release of heparin.
wall was formed on TS-n samples (Table 1), which might impact
their release performance of heparin [6] and other drugs.
Unlike parent SBA-15 whose almost 80% of the released heparin
went out within the first 4 days, TS-n samples exhibited the sub-
stantially altered release kinetics with a much slower rate and
extended release duration. Especially, the proportion of heparin
released from TS-50 composite within the first 4 days was lowered
to 24%, indicating the remarkable suppression of burst phenome-
non which relates to the structure and surface electrical modifica-
tions of sample. A low Ti-content of initial gel usually leads to a
material with titanium tetrahedrally coordinated into the silica
framework [14] so the titanium was incorporated in SBA-15 to
form a high dispersion; and most of them were isolated in the
composite [13], according to the XPS detection (Fig. S3). Such
incorporation properly changes the surface negative charge
(Zeta-potential) of the vessel, fabricating a beneficial microenvi-
ronment for heparin. Compared with other substitute like alumi-
num [6], titanium has some specific features for fabrication of
versatile mesoporous drug releaser. The first one is to moderately
improve heparin adsorption in SBA-15 sorbent. Adsorption of
bio-molecules in mesoporous silica is dominated by weak physical
forces such as van der Waals or dispersion forces [40], and the spe-
cific elelctronegativity of titanium could moderately adjust the
surface charge of SBA-15 and gently elevated the adsorption of
heparin, avoiding too much bio-molecules to be crowd inside the
channel. Likewise, the moderate attraction for heparin made the
trapped protein arduous to desorb. If the heparin molecule encap-
sulated around Ti species was properly bolted inside the channel, it
would retard the diffusion of other heparin molecules, hence the
burst release was significantly suppressed (Scheme 1).
The second function of Ti-substitution on SBA-15 is to distort
the channels of vessel (Fig. 3). These distorted channels still pos-
sessed the mesoporous’ characters but became tortuous while
the pore wall was rugged (Scheme 2), which inevitably enlarge
the collision probability of adsorbates with the wall of adsorbent,
delaying desorption of heparins [5,6], since drug release is mainly
dependent on their diffusion coefficient through the pores [9]. Here
the Ti-content of initial gels in synthesis was of great concern,
since it determined whether the subtle ‘‘critical state’’ could be
established or not. Less Ti-additive failed to reach this borderline
state of disorder while more Ti-additives would cause too serious
structural damage in SBA-15 (Fig. 3). Also, specific synthesis is nec-
essary to prepare subtle mesoporous drug releaser, since Ti substi-
tution into SBA-15 framework is highly affected by synthesis
conditions and the critical titanium loading is mainly influenced
by synthesis temperature, hydrothermal treatment time and sili-
con precursor concentration [14]. Firstly, we used TEOS rather than
TMOS as the siliceous source although TMOS could cause the faster
condensation rate of silicate species, yielding a high local curved
energy that is beneficial for control of morphology [41]. Unlike
 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49
the effort of keeping the hydrolysis of siliceous source synchronous
with that of titanium source [13], we adjusted them to have a
slight difference by use of TEOS to control the connection of Ti with
Si, since the rate of hydrolysis and condensation influences the for-
mation, growth, arrangement and connection of the initial rod-like
particles in a great degree [41]. Secondly, the aging temperature of
373 K rather than 353 K was adopted because we wanted the sam-
ple with a relatively thin pore wall that was easily-distorted.
Thirdly, the synthesized TS-n sample was thoroughly washed to
remove extra framework Ti species. As the result, TS-n vessels kept
all of the Ti substitutes highly dispersed in the framework plus the
subtle distorted channel structure more or less, different from
some Ti-SBA-15 samples in which extra-framework Ti species
and well remained channel were reported [14]. Among them TS-
50 sample had a partly distorted and rough channels while TS-33
was changed to be the warm like structure plus the criss-cross
pores, however, the number of Ti substituted was limited in com-
parison with that in literature.
Proper electronegativity and optimal distribution of titanium
substitute delicately tune the loading and release of heparin in
SBA-15 vessel. Particularly, TS-50 composite represented the sub-
tle ‘‘critical state’’ in which the electrostatic induction only moder-
ately withdrew the negative charged drug, while slightly distorted
channels just retarded its movement instead of stopping its diffu-
sion. Thanks to the synergy of electrostatic and geometric factors,
TS-50 not only released the heparin more than that AS100 did,
but also in a more evenly style (Fig. 5a), although its Si/M ratio
was ten time larger than that of AS100 (Table 1).
Since Ti-substitution changed the surface area of SBA-15
composites, it is better to assess their performance of adsorption
and release by normalized as nmol m 2 instead of per gram of
sample. Assuming Ti-SBA-15 kept the original property of parent
SBA-15, this assess is emphasized on the relation between the
increased adsorption or release of heparin by TS-n and its
Ti-content (Table S1), in order to deeply comprehend the efficiency
of Ti-substitutes and their distribution in the vessel. The Ti density
of TS-n sample was increased from TS-200 (1.36), TS-100 (2.60) to
TS-50 (7.14) but declined on TS-33 (5.22 nmol m 2), and the
corresponding more adsorbed heparin was 5.29, 9.19, 14.97 and
8.81 nmol m 2, respectively. Consequently, the improvement of
Ti-modifier in TS-n on the adsorption of heparin is calculated as
3.9 (TS-200), 3.5 (TS-100), 2.1 (TS-50) and 1.7 (TS-33). Since these
Ti-substitutes are highly dispersed without surface enrich accord-
ing to the tests of XRD and XPS, they should exhibit the same elec-
trostatic attraction for heparin so that their different performance
may result from their different microenvironment. Almost of the
5 30
0-4 d
5-10 d
Released Heparin (nmol m )
-2
4 11-24 d
25-45 d
3
2
1
0 0
SBA-15 TS-200 TS-100 TS-50 TS-33
Samples
Fig. 6. Absolute release amount of (a) heparin and (b) ibuprofen during different release period.
47
Ti-substitutes in TS-200 seem to exert their function because
TS-200s pore structure was same as that of SBA-15. Those titanium
species in TS-100 were not so lucky as that in TS-200 because part
of them were buried in the deep layer of pore wall so that they
could not attract heparin; similar situation appeared on TS-50 on
which more Ti species were located inside the pore wall. As more
Ti-substitutes were jointed into TS-33, its channels were seriously
distorted and some channels were blocked and inaccessible for
heparin as aforementioned hence its Ti improvement was further
declined. To check this hypothesis of Ti-modifiers distribution in
TS-n, similar calculation was carried out on the adsorption of
ibuprofen. The IBU molecule has two negative charged oxygens
in carboxyl group, one is -0.604 and another is 0.716 a.u., along
with a relatively small molecular size so that it is easily attracted
and moves towards the attractor inside the mesoporous channels
without geometric confinement so long as the attractor is accessi-
ble. The more adsorbed IBU by TS-n sorbent was 262.1 (TS-200),
393.2 (TS-100), 674.8 (TS-50) and 257.3 nmol m 2 (TS-33), respec-
tively, and the improvement of Ti substitute could thus be calcu-
lated as 192.7 (TS-200), 151.2 (TS-100), 94.5 (TS-50) and 49.3
(TS-33). Roughly, these data was about 4:3:2:1. Accordingly, the
accessibility of Ti-substitutes was really different in the different
TS-n composites, and some of them were located inside the pore
wall and thus inaccessible for IBU. The influence of rough and
crooked channels was found on the liquid adsorption of NPYR
whose negative charge ( 0.197 a.u.) was smaller than IBU. There
were 0.23 (TS-200), 0.26 (TS-100), 0.36 (TS-50) and 0.20 nmol m 2
(TS-33) more NPYR to be adsorbed by TS-n sample in comparison
with that by SBA-15, and the improvement of Ti substitute was
calculated as 169.1 (TS-200), 100.0 (TS-100), 50.4 (TS-50) and
38.3 (TS-33), which equaled to 0.87 (TS-200), 0.66 (TS-100), 0.53
(TS-50) and 0.78 (TS-33) of that for IBU due to the weaker
negativity of NPYR. Roughly the Ti efficiency of TS-n was changed
to about 4:3:1.3:1, among the promotion of TS-50 declined the
most obviously because of its distorted channels that hindered
the movement of NPYR. In contrast, the criss-cross pore structures
of TS-33 (Fig. 3d) facilitated the entering of NPYR hence it avoided
the decrease of adsorption. Similarly, TS-200 and TS-100 kept the
expedite channels of SBA-15 so that the adsorption of NPYR was
primarily affected by the weak negative charge of itself. Utilization
of three different probes, heparin that is the strong negative
charged bulky one, IBU that is the strong negative charged small
one, NPYR that is a weak negative charged small molecule, in
liquid adsorption can well explore the electrostatic attraction and
surface roughness and /or tortuosity of channel of mesoporous
sorbents.
a 0-2 h b
2-9 h
25
Released IBU (nmol m-2 )
9-24 h
24-48 h
20
15
10
5
SBA-15 TS-200 TS-100 TS-50 TS-33
Samples
48 M.M. Wan et al. / Microporous and Mesoporous Materials 199 (2014) 40–49
The synergy of electrostatic attraction and geometric confine-
ment of TS-n also well adjusted the release of heparin. As showed
in Fig. 6a, SBA-15 released 2.7 nmol m 2 of heparin in the first
4 days, 0.5, 0.5 and 0.04 nmol m 2 of the drug in 5–10, 11–24,
and 25–45 days respectively, exhibiting an obvious burst phenom-
enon as that shown in Fig. 5a. Such burst was suppressed on TS-
200 whose absolute released amount in first 4 days and 5–10 days
was same. Moreover, reversed situation appeared on TS-50 vessel
whose data of 5–10 and 11–24 days were higher than that of first
4 days. Theoretically, the release of IBU was hardly confined by the
channel of TS-n vessels so that it should be mainly affected by dif-
fusion along with the possible electrostatic interaction of the sor-
bent. The absolute amount of IBU released from SBA-15 in first
2 h and 3–9 h was 13.4 and 3.2 nmol m 2 and none after then
(Fig. 6b). Yet, TS-200 released IBU till 25–28 h while the released
maximum from TS-50 appeared in 3–9 h and its obvious release
could keep in 28th hour. Due to its criss-cross pore structures,
TS-33 released more IBU (18.5 nmol m 2) than TS-50 did in the
first 2 h but less in the rest of time. It follows that this subtle ‘‘crit-
ical state’’ of mesoporous vessel is not only efficient for adsorption
and release of bulky drug like heparin thanks to the capacious
channel, but also impactful for release of small drug such as IBU.
In general, fine geometric confinement is required for small adsor-
bates since common mesoporous channels were too wide to hold
these small drugs so that the modified zeolite was employed
[35], but its microporous channel was inferior to mesopores for
adsorbing IBU. This contradictory is preliminary conquered here
by the subtle ‘‘critical state’’ of Ti-SBA-15 whose proper electro-
static attraction replaced the fine geometric confinement to hold
IBU while the moderately distorted channels delayed diffusion of
IBU, therefore its actual release performance was close to that of
microporous silica [37]. It is possible to fabricate a versatile meso-
porous vessel for drug release with the principle of ‘‘critical state’’,
based on the rational choice of appropriate modifier plus the opti-
mal synthesis.
5. Conclusion
(1) Titanium could be substituted into the framework of SBA-15
without formation of TiO2 or surface-enrich under specific
hydrothermal synthesis conditions.
(2) The proper Si/Ti ratio in initial gel was able to reduce the
surface negative charge (Zeta-potential) and appropriately
distort the mesoporous channels of Ti-SBA-15, fabricating a
versatile releaser for negative charged drugs. With the syn-
ergy of electrostatic and geometric modification, Ti-SBA-15
could adsorb much more heparin or IBU than parent SBA-
15 did, and released linearly more heparin with a longer
duration, significantly suppressing the burst release.
(3) Proper electrostatic attraction of the Ti-SBA-15 plus the
moderately distorted channels could delay the diffusion of
small drug like IBU to exert the function like that of fine geo-
metric confinement, and its actual release performance was
close to that of microporous silica.
(4) Liquid adsorption of different probes including heparin, IBU
and NPYR could well explore the electrostatic attraction and
surface roughness and/or channel tortuosity of mesoporous
sorbents, offering a new method to characterize mesoporous
materials.
Acknowledgments
NSF of China (21173117 and 21273106), Graduate School and
Analysis Center of Nanjing University financially supported this
research.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.micromeso.2014.
08.005.
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