Microporous and Mesoporous Materials 150 (2012) 83–89

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Microporous and Mesoporous Materials

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

Chitosan enclosed mesoporous silica nanoparticles as drug nano-carriers:

Sensitive response to the narrow pH range
Fang Chen, Yingchun Zhu ⇑
Key Lab of Inorganic Coating Materials, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai 200050, PR China

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

Article history: Most pH-sensitive drug delivery systems have been reported to respond to wide ranges of pH or target
Received 3 May 2011 tissues the pH of which vary considerably, whereas these systems are not able to target diseased tissues
Received in revised form 27 July 2011 like inflammatory tissues and tumor cells (pH 6.8) due to the extremely slight differences between pH of
Accepted 29 July 2011
normal tissues (pH 7.4) and them. Consequently, ingenious pH-responsive drug delivery systems are
Available online 22 September 2011
desired to target this kind of abnormal tissues. In the present study, we fabricated a novel pH-sensitive
drug delivery system with a 22% loading capacity, which released about 65% and 35% model drug in pH
Keywords:
6.8 and 7.4 after 24 h, respectively. In pH 7.4 release medium, chitosan molecules are orderly aggregated
pH-responsive
Controlled-release
state, which efficiently hinder the release of the guest molecules from nanocarriers. However, in pH 6.8
Chitosan release medium, chitosan chains are heavily and flexibly entangled in gel state, which is good for the
Mesoporous silica nanoparticle release of guest molecules. The drug delivery system could reduce the drug nonspecific reaction with nor-
Drug delivery system mal cells but remaining the curative effect.
Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction
The pH-responsive drug delivery systems [1–12] are gaining
increasing interest in targeting particular sites where pH is differ-
ent from that of others. It has been well known that pH in human
bodies is diverse, for example, pH of stomach is in the range of 1.0–
2.5, small intestine pH is from 5.5 to 6.5, colon pH is about 6.5 [13],
normal tissues pH is around 7.4 [14] and inflammatory tissues and
tumor cells pH is approximately 6.8. Consequently, pH-responsive
controlled-release delivery systems enable drug concentration to
be different from place to place in the drug administration route.
However, many present works on pH-responsive drug delivery sys-
tems are focused on the gastrointestinal tract, which are designed
to easily release drugs under conditions of strong acid (approach to
the pH of stomach) or protect oral drugs against the acidic environ-
ment in the stomach. Very few reported pH-responsive drug deliv-
ery systems are efficiently capable of targeting diseased tissues like
inflammatory and tumor cells by responding to the extremely
slight pH difference between them and normal tissues. Here, we
attempted to fabricate a pH-responsive drug delivery system that
can release drugs under pH of the inflammatory and tumor cells
(pH 6.8) more easily than pH of normal tissues (pH 7.4). This sys-
tem can efficiently reduce the drug nonspecific reactions in normal
tissues while maintain the effectiveness of medicinal treatment for
inflammatory and tumor cells. Thereby it is highly significant for
drugs that are detrimental to normal cells and consequential to re-
duce the huge pain of cancer patients who are receiving chemo-
therapy. To develop such an ingenious pH-responsive drug
delivery system, mesoporous silica nanoparticles (MSN1) are cho-
sen as drug carriers and chitosan (CTS2) are chosen as pH-responsive
functional molecules.
CTS has been widely used in drug delivery systems because of
its unique properties such as non-toxicity, biocompatibility, biode-
gradability and so on [15]. Moreover, there are large quantities of
amino groups on chains of CTS, whose ionization provides CTS
molecules with the pH-sensitive feature. Over the last few decades,
many studies [16–23] have reported the application of CTS in pH-
responsive drug delivery systems. However, very few of them are
used to target the diseased tissues. Herein, considering that the
acid dissociation constant (pKa) of CTS is around 6.3–7.0 [24],
which provides CTS different dispersing states in the near neutral
pH range from 6.8 to 7.4, CTS is used in this study. Moreover, to
maintain good stability of the drug delivery system, CTS is only
used as high pH-sensitive functional biomacromolecules and
MSN are chosen to be the drug nano-carriers [25,26].
In the present work we report on the fabrication of CTS directly-
wrapped onto MSN and CTS wrapped by c-methacryloxypropyltri-
methoxysilane (MPS3) as well as their in vitro release experiments
which are conducted under pH 6.8 and 7.4 buffer solutions. To the

1
MSN: mesoporous silica nanoparticles.
⇑ Corresponding author. Tel./fax: +86 21 5241 2632. 2
CTS: chitosan.
3
E-mail addresses: cfang@student.sic.ac.cn (F. Chen), yzhu@mail.sic.ac.cn (Y. Zhu). MPS: c-methacryloxypropyltrimethoxysilane.

1387-1811/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.micromeso.2011.07.023
84 F. Chen, Y. Zhu / Microporous and Mesoporous Materials 150 (2012) 83–89

Fig. 1. Illustrations of (a) fabricating processes, (b) release mechanism of both IBU@MSN-C and IBU@MSN-MPS-C and (c) the structure of hydrated CTS under pH 7.4. IBU is
released easily under pH 6.8 where CTS are heavily entangled, while blocked by orderly aggregated CTS under pH 7.4.

best of our knowledge, this is the first time to wrap CTS outside MSN
and to be applied in controlling the amount of released drugs at near
neutral pH environment. The illustrations of the whole fabricating
process (a), release mechanism of IBU@MSN-C4 and IBU@MSN-
MPS-C5 (b) and structure of hydrated CTS in pH 7.4 solution (c) are
depicted in Fig. 1.
(NH4NO3, AR), CTS (deacetylation degree >92%, BR), tetraethyl ortho-
silicate (TEOS, AR), ethanol (CH3CH2OH, CP) and all other materials
are commercially available and were used as received. Deionized
water was applied for all reactions and treatment processes.
2.2. Fabrication of mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSN, see Table 1) were pre-

2. Experimental
pared by cetyltrimethyl ammonium bromide (CTAB)-templated,
base-catalyzed condensation reaction of tetraethyl orthosilicate
2.1. Materials
(TEOS), which was according to a literature procedure [27] with
minor modification. Briefly, 0.2 g CTAB was dissolved in a solution
Cetyltrimethyl ammonium bromide (CTAB, AR), sodium
of 96 ml water and 1.4 ml TMS, stirred and heated. As soon as the
hydroxide (NaOH, AR), n-hexane (C6H14, AR), disodium hydrogen
temperature reached 80 °C, 0.7 ml 2 M NaOH (aq) was added to the
phosphate (Na2HPO4, AR), potassium dihydrogen phosphate
solution and stirred for another 30 min. After that, 1.4 ml TEOS was
(KH2PO4, AR) were purchased from Sinopharm Chemical Reagent
added dropwise at a proper rate to the solution. Then the reaction
Co., Ltd. Pharmaceutical grade Ibuprofen (IBU6) provided by
mixture was stirred vigorously at 80 °C for another 2 h. The result-
Zhengzhou Xing people Chemical Products Co., Ltd. were used as
ing white precipitate was air-cooled for a while and then isolated
model drugs. 1,3,5-trimethylbenzene (TMS7, AR), ammonium nitrate
by filtration, washed with abundant ethanol and dried. The struc-
4
ture-templating CTAB and TMS molecules in the pores were re-
IBU@MSN-C: chitosan-wrapped ibuprofen loaded mesoporous silica
moved by solvent extraction [28]: 0.4 g NH4NO3 had been
nanoparticles.
5
IBU@MSN-MPS-C: chitosan-wrapped ibuprofen loaded MPS-coupled MSN. resolved in 150 ml 95% ethanol aqueous solution, 1 g nanoparticles
6
IBU: ibuprofen. were suspended into the solution, and then the mixture was stirred
7
TMS: 1,3,5-trimethylbenzene. for 5 h at 60 °C. The solvent-extracted nanoparticles were then
 F. Chen, Y. Zhu / Microporous and Mesoporous Materials 150 (2012) 83–89
Table 1
List of the denotations of fabricated samples.
Samples structure Denotation
Mesoporous silica nanoparticles MSN
Ibuprofen (IBU) loaded in mesoporous silica IBU@MSN
nanoparticles
IBU loaded chitosan-wrapped mesoporous silica IBU@MSN-C
nanoparticles
IBU@MSN-C after in vitro release IBU@MSN-CR
IBU@MSN coupled by c- IBU@MSN-MPS
methacryloxypropyltrimethoxysilane
Chitosan-wrapped IBU@MSN-MPS IBU@MSN-MPS-C
isolated by filtration, washed with abundant ethanol for several
times and dried.
2.3. Ibuprofen loading
Loading IBU into the pores of MSN was carried out by soaking
0.1 g MSN in 30 ml IBU n-hexane solution (40 mg/ml) in a flask.
The mixture was stirred for 2 days at room temperature. Then
the IBU loaded MSN (IBU@MSN8) was separated by filtration and
washed with hexane, dried under atmosphere. The loading capacity
was calculated by measuring the difference in weight of totally dried
solid before and after the loading.
2.4. Coupling to Ibuprofen loaded mesoporous silica nanoparticles
0.1 g IBU@MSN was added into 4 ml toluene and 0.1 ml MPS
and stirred at the room temperature for 12 h. Then IBU@MSN-
MPS9 was gained after filtration, rinsing and drying.
2.5. Chitosan wrapping
Twenty milliliter 0.6% w/v CTS acetic acid aqueous (10% v/v)
solution was prepared and the pH was adjusted to 6.0 with 1 M
NaOH, then 0.1 g IBU@MSN or IBU@MSN-MPS was added into it
and stirred. After stirring for 36 h, the mixture was centrifugated,
suspended, washed with deionized water twice and dried. Then
the resulting products IBU@MSN-C or IBU@MSN-MPS-C were
obtained.
2.6. In vitro release of IBU
The in vitro simulated release of IBU was executed by soaking
equal weight samples in pH 6.8 and 7.4 buffer solutions. Firstly,
samples were pressed into discs with a 3 MPa pressure for about
1 min and soaked into release medium preheated to 37 °C. The
releasing temperature was kept at 37 °C. Then the IBU-release
medium (5.0 ml) was extracted for UV–vis analysis at given time
intervals and replaced with the same volume of fresh buffer solu-
tion, which was preheated to 37 °C.
2.7. Characterization
Transmission electron microscopy (TEM) images were obtained
with a field-emission transmission electron microscope (JEOL JEM-
2100F, Japan). X-ray diffraction (XRD) patterns were recorded on a
D/max 2550V diffractometer (Rigaku, Japan) with CuKa radiation
(k = 1.542 Å). Fourier transform infrared (FTIR) analysis was carried
out using KBr discs in the region of 4000–400 cm1 by a SHIMA-
DZU (IR Affinity-1, Japan). Thermo gravimetric (TG) and differential
8
IBU@MSN: ibuprofen loaded mesoporous silica nanoparticles.
9
IBU@MSN-MPS: ibuprofen loaded MPS-coupled mesoporous silica nanoparticles.
85
scanning calorimetric (DSC) curves were taken with a simulta-
neous thermal analyzer (NetzschSTA409PC, Germany) at a heating
rate of 5 °C/min in flowing air. N2 adsorption–desorption isotherm
curves, BET surface areas and pore volumes were measured with
an accelerated surface area and porosimetry system (Micromeritics
ASAP2010, USA). Ultraviolet–visible (UV–vis) absorption spectra
were performed on a UV2300 Spectrophotometer (TECHCOMP,
China) using a pair of quartz cuvettes (12.4  12.4  45 mm3).
The pH value was measured on a pH meter with the precision of
0.1 (PHS-25, Shanghai Precision & Scientific Instrument Co. Ltd.,
China).
3. Results and discussion
3.1. Fabrication and characterization of MSN, IBU @ MSN-C and
IBU@MSN-MPS-C
In this study, original nanocarriers MSN was fabricated and
loaded with IBU firstly. Then the obtained IBU@MSN was made
to react with MPS. CTS were wrapped onto samples IBU@MSN or
IBU@MSN-MPS through the hydrogen bonding between silanol
(IBU@MSN) or carbonyl (IBU@MSN-MPS) and amine of CTS as illus-
trated in Fig. 1. Briefly, MSN was fabricated by CTAB-templated,
base-catalyzed condensation reaction according to literature [27].
After IBU loaded, IBU@MSN was dispersed in mixture of toluene
and MPS to obtain sample IBU@MSN-MPS. Then, CTS were
wrapped by soaking IBU@MSN or IBU@MSN-MPS in CTS sol. TEM
images of template-removed MSN (a), IBU@MSN-C (b) and
IBU@MSN-MPS-C (c) are shown in Fig. 2. The synthesized MSN
are uniform nanospheres with regular array of channels, where
diameter is in the range of 90–140 nm (Fig. 2a). In the correspond-
ing small angle XRD (SAXRD) pattern (Fig. 2d), three peaks ob-0
served pcan
ffiffiffi be indexed on a hexagonal unit cell with a 48.5 Å A
(2d100/ 3). From Fig. 2c and d, it can be seen that the edge of both
IBU@MSN and IBU@MSN-MPS were sealed by a thin layer of CTS,
which is owing to the lack of chemical reaction between CTS and
IBU@MSN or IBU@MSN-MPS and CTS were adsorbed through the
hydrogen bonding between amide (CTS) and silanol (MSN) or car-
bonyl group (MPS) (see Fig. 1).
To confirm the loading of IBU and wrapping of CTS, FTIR were
used to probe the secondary structures. Fig. 3 shows the FTIR spec-
tra of samples MSN (a), IBU@MSN (b), IBU@MSN-C (c), IBU@MSN-
MPS-C (d), IBU (e) and CTS (f). The peaks at 1636, 797, 967, 1087
and 1237 cm1 in all curves are attributed to the stretching vibra-
tion of O–H, the flexible vibrations of Si–O, the stretching vibration
of Si–OH and Si–O–Si, respectively [29]. The peak at 1723 cm1
only appeared in absorption spectrum of IBU@MSN-MPS-C is
attributed to the C@O stretching vibration of MPS. The adsorption
spectra of IBU@MSN, IBU@MSN-C and IBU@MSN-MPS-C show the
adsorption bands of IBU at about 1710, 1515 and 1412 cm1 which
are caused by the C@O stretching vibration, C@C vibration of the
phenyl ring and the C–H bond vibration. Therefore, it indicates that
IBU is present in IBU@MSN, IBU@MSN-C and IBU@MSN-MPS-C. Be-
sides, the absorption spectra of both IBU@MSN-C and IBU@MSN-
MPS-C show the adsorption bands of native CTS at about 1652
and 1560 cm1 which are attributed to the amide I and amide II
infrared absorbance, and this result indicates the presence of CTS
in fabricated IBU@MSN-C and IBU@MSN-MPS-C. These results
can also be ensured by the thermal analysis. Furthermore the con-
tent of IBU and CTS in IBU@MSN, IBU@MSN-C can be calculated by
the drug loading capacity and thermal analysis data.
Fig. 4 shows (a) TG curves and (b) DSC curves of IBU, CTS, MSN,
IBU@MSN, IBU@MSN-C and IBU@MSN-MPS-C. In the TG curves
(Fig. 4a), two-level-step profile is observed from samples
IBU@MSN and IBU@MSN-C and three-level-step profile is observed
from the sample IBU@MSN-MPS-C. The weight loss at 70–130 °C
86 F. Chen, Y. Zhu / Microporous and Mesoporous Materials 150 (2012) 83–89
Fig. 2. TEM images of fabricated (a) template-removed MSN, (b) IBU@MSN-C and (c) IBU@MSN-MPS-C and (d) the corresponding small angle XRD (SAXRD) of MSN.
Fig. 3. FTIR spectra of samples MSN (a), IBU@MSN (b), IBU@MSN-C (c), IBU@MSN-
MPS-C (d), IBU (e) and CTS (f).
and 200–600 °C originates from the evaporation of water , the
clean burn of IBU and CTS in air atmosphere, respectively. The
weight losses between 200 and 600 °C of samples IBU@MSN and
IBU@MSN-C are about 30%, which indicates that the wrapped
CTS is equal to the leaked IBU during the wrapping process. Before
the CTS wrapping process, the drug loading capacity of IBU@MSN is
about 30%, while the drug loading capacity of IBU@MSN-C is about
22% after CTS wrapped (see Section 3.2). Consequently, the amount
of wrapped CTS outside MSN is about 8%. The step at around 500 °C
in TG curve of IBU@MSN-MPS-C is attributed to the existing of
crosslinker MPS. Furthermore, the weight losses in the TG curves
are well related to the corresponding endothermic/exothermic
peaks in DSC curves (Fig. 4b). The endothermic peak in IBU DSC
curve at about 80 °C is due to the IBU melting, and the small endo-
thermic peaks found at temperature below 100 °C in the DSC
curves of CTS, IBU@MSN-C and IBU@MSN-MPS-C are due to the
evaporation of absorbed water. In the DSC curves of IBU@MSN,
IBU@MSN-C and IBU@MSN-MPS-C, small endothermic peaks can
be found at about 270 °C, which correspond to the IBU DSC curve.
While the exothermic peaks at temperature between 200 and
350 °C corresponds to the DSC curve of CTS. Hence, it can also be
clear from the TG curves and DSC curves that the drug loading
and CTS wrapping is successfully done through both the two meth-
ods depicted in Fig. 1a. Additionally, in Fig. 4b, the CTS degradation
temperatures of IBU@MSN-MPS-C, IBU@MSN-C and pure CTS are
around 380, 320 and 307 °C, it confirms that there are interactions
between CTS and IBU@MSN or IBU@MSN-MPS and furthermore the
interaction between CTS and IBU@MSN-MPS is stronger than that
between CTS and IBU@MSN.
3.2. Calculation of loading capacity
We calculated the drug loading capacity (LC) of both IBU@MSN
and IBU@MSN-C by weighing method and ultraviolet–visible
 F. Chen, Y. Zhu / Microporous and Mesoporous Materials 150 (2012) 83–89
Fig. 4. (a) TG curves and (b) DSC curves of IBU, CTS, MSN, IBU@MSN, IBU@MSN-C
and IBU@MSN-MPS-C.
(UV–vis) spectroscopy. Firstly, the weights of totally dried MSN be-
fore and after the loading process were measured cautiously and Eq.
(1) was used to calculate the LC of MSN. The resulted loading capac-
ity of MSN (LCMSN) is about 29.7%.
m1  m0
LCMSN ¼
m1
Herein, m0 and m1 mean the weight of MSN before and after
loading process.
Afterward, the leaked IBU during the wrapping process is mea-
sured by UV–vis spectrophotometer (Fig. 5). We applied the data of
absorption peak at 264 nm (ABS) in Fig. 5 into IBU standard curve
equation and calculated the content of leaked IBU (mleaked
IBU = C  V, V – volume of the mixture). And then the loading
capacity of IBU@MSN-C (LCMSN-C) was obtained by using Eq. (2),
which was about 22.4%.
LCMSN  mIBU@MSN  mleaked MSN
LCMSN-C ¼
mIBU@MSN  mleaked MSN
Herein, mIBU@MSN means the weight of IBU@MSN used during
the wrapping process.
3.3. In vitro drug release and the release kinetics study of IBU@MSN-C
In vitro pH-responsive release experiments were carried out by
soaking samples in buffer solution at 37 °C. Fig. 6 displays the
in vitro pH-responsive release of IBU from IBU@MSN and
IBU@MSN-C in pH 6.8 and 7.4 buffer solutions, respectively.
Fig. 6 shows that the amounts of released IBU from IBU@MSN in
pH 6.8 solution (hollow red circles) is about 22% for 1 h and 90%
for 24 h, whereas the released IBU from IBU@MSN in pH 7.4 solu-
tion (hollow black circles) is around 25% for 1 h and 92% for 24 h.
The amount of released IBU in pH 7.4 is slightly higher (2%) than
87
Fig. 5. Ultraviolet–visible spectrum of the supernatant obtained after the CTS
wrapping process, and it indicates the leakage of drug from IBU@MSN during the
wrapping process.
ð1Þ Fig. 6. In vitro IBU-release profiles of the IBU@MSN and IBU@MSN-C drug delivery
systems.
that in pH 6.8, which is due to the carboxylic acid group and hydro-
phobic property of IBU molecule (i.e. a-Methyl-4(2-methylpropyl)
benzeneacetic acid) [30]. The amounts of released IBU from
IBU@MSN-C in pH 6.8 release medium (solid red circles) is about
22% for 1 h and 65% for 24 h, while released IBU from IBU@MSN-
C in pH 7.4 release medium (solid black circles) is about 20% for
1 h and 35% for 24 h. Comparing to IBU@MSN, IBU released by
IBU@MSN-C changes dramatically with the pH. IBU released from
ð2Þ IBU@MSN-C in pH 6.8 release medium after 24 h was about 30%
more than that in pH 7.4. This provides the ingenious pH-respon-
sive controlled-release system targetability to diseased tissues
such as inflammatory and tumor cells where pH is slightly lower
than normal tissues, which is of great physiological significance.
The result is caused by the CTS layer which owns different dis-
persing states in pH 6.8 and 7.4 aqueous solutions (see Fig. 1b).
CTS owns three different states which are sol, gel and precipitate.
And the morphologies of their chains are in slightly entangled
semirigid state, heavily entangled flexible state and orderly aggre-
gated state, respectively [24]. When CTS are soaked into aqueous
solution with pH 7.4, the hydrogen bonding is strong and the
amide groups don’t carry any charge, so there is no electrostatic
repulsion exists between CTS molecules, and CTS are in orderly
aggregated state (see Fig. 7). In this case, the chains crystallize
in an orthorhombic unit cell with dimensions a = 8.95(4),
88 F. Chen, Y. Zhu / Microporous and Mesoporous Materials 150 (2012) 83–89
Fig. 7. Different states of CTS. CTS are orderly aggregated under pH 7.4 and gelated
under pH 6.8.
b = 16.97(6), c (fiber axis) = 10.34(4) Å [31]. This crystal structure
can efficiently block the pore outlet and hinder the release of IBU
which is approximately 1.0285 nm and diameter is around
0.5237 nm [32]. While CTS are soaked into pH 6.8 release med-
ium, the hydrogen bonding is weaker than that in alkaline envi-
ronment and CTS molecules exist in the gel network state,
which is less efficiently block the pore outlet and less influence
the release of IBU (see Fig. 1). To understand the release behavior
of samples in buffer solution with different pH, the release kinet-
ics of IBU@MSN and IBU@MSN-C were studied.
The release kinetics was studied by fitting the Peppas equation.
MSN could be considered as non-swellable spherical sample. And
according to Peppas [33,34], the diffusional exponent (n) in Peppas
equation Mt/M1 = ktn of non-swellable spherical sample should be
equal to 0.43 when the release behavior complies with typical Fic-
kian diffusion driven by the concentration gradient of IBU. Fig. 8
shows the release-kinetics profiles of the IBU@MSN and
IBU@MSN-C in pH 6.8 and 7.4. From Fig. 8, it is clear that the Pep-
pas equation is fitted well to the release behavior of sample
IBU@MSN in both pH 6.8 and 7.4. However, the diffusional expo-
nents of IBU@MSN-C in pH 6.8 and 7.4 were respectively 0.37
and 0.17, which represented the non-typical Fickian diffusion. It
indicated that the IBU diffusion from IBU@MSN-C was hindered
in both pH 6.8 and 7.4 solution and the block effect was stronger
in pH 7.4 release medium. In pH 7.4 aqueous solution, CTS chains
crystallize in an orthorhombic unit cell with dimensions
b = 16.97, c (fiber axis) = 10.34 Å, [24,31] and hinder the diffusion
of IBU molecules through the outlets of MSN, while in pH 6.8 aque-
ous solution, CTS are in gel state and the meshes are bigger than
IBU molecules, hence the block effect is weaker and the diffusion
exponent in pH 6.8 is bigger than that in pH 7.4.
Fig. 8. Release-kinetics profiles of the IBU@MSN and IBU@MSN-C.
Fig. 9. N2 adsorption–desorption isotherm curves of MSN, IBU@MSN, IBU@MSN-C
and IBU@MSN-CR.
3.4. Material characterization before and after storage and release
The effect of CTS-wrapping and IBU molecules storage in the
structures of mesoporous silica nanoparticles can be characterized
by N2 adsorption–desorption isotherms techniques. Fig. 9 shows
the N2 adsorption–desorption isotherm curves of MSN, IBU@MSN,
IBU@MSN-C and IBU released IBU@MSN-C (IBU@MSN-CR10), and
the data of BET surface areas and BJH pore volumes are listed in
Table 2. The type IV isotherm curve with an obvious step between
0.3 and 0.4 of P/P0 indicates that MSN possess a well-defined meso-
porous structure. When IBU molecules have been loaded, sharp
reduction of the adsorption capacity of samples IBU@MSN reveals
that a large number of IBU molecules have been loaded in the meso-
porous channels. Therefore, the calculated surface area SBET reduces
to 149 from 1215 m2/g, moreover the pore volume Vp falls from
2.23 to 0.82 cm3/g as indicated in Table 2. After samples IBU@MSN
have been wrapped with CTS, the amount of nitrogen adsorption fur-
ther decreases due to the sealing effect of the outside CTS layer.
10
IBU@MSN-CR: chitosan-wrapped Ibuprofen loaded mesoporous silica nanoparti
cles after release for 72 h.
 F. Chen, Y. Zhu / Microporous and Mesoporous Materials 150 (2012) 83–89
Table 2
The structure parameters of sample.
Sample SBET (m2/g) Vp (cm3/g)
MSN 1215 2.23
IBU@MSN 149 0.82
IBU@MSN-C 47 0.48
IBU@MSN-CR 330 0.99
Fig. 10. In vitro IBU-release profiles of the IBU@MSN-MPS and IBU@MSN-MPS-C.
Consequently, Vp falls from 0.82 to 0.48 cm3/g. However, the
IBU@MSN-CR (see [9]) develops some mesopore structure after re-
lease which is indicated by the hysteresis between the nitrogen
adsorption and desorption branch and the SBET and Vp significantly
increase, from 47 to 330 m2/g and 0.48–0.99 cm3/g, respectively.
Due to the remaining of CTS outside MSN, the SBET and Vp don’t return
back to the structure parameters of MSN. Hence, the storage of IBU
molecules in MSN and the release of IBU molecules from
IBU@MSN-C are both confirmed in this N2 adsorption–desorption
measurements.
3.5. In vitro drug release IBU@MSN-MPS-C
Fig. 10 displays the in vitro pH-responsive release of IBU from
IBU@MSN-MPS and IBU@MSN-MPS-C in pH 6.8 and 7.4 buffer
solutions. In the first hour, the amount of accumulated released
IBU from IBU@MSN-MPS in pH 7.4 release medium is about 21%,
whereas that from IBU@MSN-MPS-C in pH 6.8 and 7.4 release
media are around 17% and 16%. Ten hours later, the amount of
accumulated released IBU from IBU@MSN-MPS in pH 7.4 release
medium is about 56%, whereas that from IBU@MSN-MPS-C in pH
6.8 and 7.4 release media are around 37% and 34%. The amount
of accumulated released IBU from IBU@MSN-MSP-C in pH 6.8 re-
lease medium is only 3% higher than that in pH 7.4 release med-
ium. It is suggested that CTS molecules did not reside close
enough to the surface of the IBU@MSN-MPS, thereby making the
hinder function of CTS less useful in pH 7.4 release medium.
4. Conclusions
In conclusion, CTS-wrapped mesoporous silica nanoparticles
were obtained. The layer of CTS on nanocarriers is adsorbed by
hydrogen bonding between CTS and MSN or MSN-MPS. With IBU
as the model drug, we studied the in vitro release properties of sam-
ples IBU@MSN, IBU@MSN-C and IBU@MSN-MPS-C in a narrow pH
range from pH 7.4 to 6.8, and the results indicated that the release
of IBU was sensitive to the release medium pH value. The most
89
released IBU amount was achieved in pH 6.8, which is perfect ap-
proach to the pH value around some tumor cells and inflammatory
tissues. Besides, the pH-sensitivity of IBU@MSN-C is better than that
of IBU@MSN-MPS-C, which could be attributed to that the silane
coupling agent make CTS can’t reside close enough to surface of
the nano-carriers. Given the pharmacological studies of IBU indi-
cated that apart from the frequent poor water solubility, gastrointes-
tinal side effects and limited therapeutic uses by the necessity to
deliver the drug to specific sites of target organ or tissue, the
achievement by this IBU@MSN-C pH-responsive release system is
significant and it can provide a promising control-release manner
to achieve a good therapeutic effect for localized drug delivery.
Acknowledgments
This work was supported by the China NSFC (50772125), the
Shanghai STCSM (11XD1405600), and the CAS (KGCX2-YW-210-
03).
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