Fe3O4@mSiO2 core-shell nanocomposite capped with disulfide gatekeepers for enzyme-sensitive controlled release of anti-cancer drugs

Article abstract of DOI:10.1039/c4tb01788a

Multifunctional nanocarriers based on the magnetic Fe₃O₄ nanoparticle core and bis-(3-carboxy-4-hydroxy phenyl) disulfide (R-S-S-R₁) modified mesoporous silica shell (Fe₃O₄@mSiO₂@R-S-S-R₁) were synthesized for cancer treatment through passive targeting and enzyme-sensitive drug release. Anti-cancer drug doxorubicin (DOX) was used as the model cargo to reveal the release behavior of the system. The drug loading system (DOX-Fe₃O₄@mSiO₂@R-S-S-R₁) retains the drug until it reaches the tumor tissue where glutathione reductase (GSH) can degrade the disulfide bonds and release the drug. Furthermore, the grafting amount of R-S-S-R₁ can be used to adjust the release performance. All the release behaviors fit the Higuchi model very well and the release kinetics are predominated by disulfide bond degradation and mesoporous structure. With good bioactivity and targeted release performance, the system could play an important role in the development of intracellular delivery nanodevices for cancer therapy.

Full text of DOI:10.1039/c4tb01788a

Journal of
Materials Chemistry B
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Fe O @mSiO core–shell nanocomposite capped
3
4
2
with disulfide gatekeepers for enzyme-sensitive
controlled release of anti-cancer drugs†
Cite this: DOI: 10.1039/c4tb01788a
a
a
b
b
b
b
a
Chunyu Yang, Wei Guo, Liru Cui, Na An, Ting Zhang, Gang Guo,* Huiming Lin*
a
and Fengyu Qu*
Multifunctional nanocarriers based on the magnetic Fe
3
O
4
nanoparticle core and bis-(3-carboxy-4-
@mSiO @R–S–S–R ) were
hydroxy phenyl) disulfide (R–S–S–R ) modified mesoporous silica shell (Fe
1
O
3 4
2
1
synthesized for cancer treatment through passive targeting and enzyme-sensitive drug release. Anti-
cancer drug doxorubicin (DOX) was used as the model cargo to reveal the release behavior of the
system. The drug loading system (DOX–Fe
tumor tissue where glutathione reductase (GSH) can degrade the disulfide bonds and release the drug.
Furthermore, the grafting amount of R–S–S–R can be used to adjust the release performance. All the
3 4 2 1
O @mSiO @R–S–S–R ) retains the drug until it reaches the
1
Received 29th October 2014
Accepted 20th November 2014
release behaviors fit the Higuchi model very well and the release kinetics are predominated by disulfide
bond degradation and mesoporous structure. With good bioactivity and targeted release performance,
the system could play an important role in the development of intracellular delivery nanodevices for
cancer therapy.
DOI: 10.1039/c4tb01788a
www.rsc.org/MaterialsB
as “gatekeepers” for MSNs to show their well-controlled release
performance. The controlled-release process can be regulated
Introduction
The development of diverse kinds of nanoscale drug delivery either by external stimuli such as thermal, light, electrostatic,
1
2
3
4
systems such as polymers, micelles, liposomes, dendrimers
magnetic actuation, and photoirradiation, or by internal stimuli
5
16–20
and inorganic materials for cancer treatment has received such as pH and enzymes.
For instance, Yang and co-workers
considerable attention and has become a major eld in medical constructed a novel cancer theranostic hybrid platform, based
research in recent years. Among these, the increasing interest in on mesoporous silica-coated gold nanorods gated by sulfona-
mesoporous silica nanoparticles (MSNs) has been greatly tocalix[4]arene switches, for biofriendly near-infrared (NIR)
21
enhanced because of their exible and robust properties, light-triggered cargo release in a remote and stepwise fashion.
including easy modication, excellent chemical stability, and Zhu et al. successfully demonstrated a pH-triggered controlled
6
–10
outstanding biocompatibility.
tunable morphology/pore size, high pore volume and large conditions, showing a valuable pH-responsive strategy for the
Moreover, the uniform and drug release system by the dissolution of ZnO nanolids in acidic
22
surface area for MSNs ensure high loading of various drug delivery of anticancer agents.
molecules as well as smart transporting.
11–14
However, pure
The disulde bond is systemically nontoxic and stable in
MSN materials always face some practical applicability limita- blood circulation, and it can only be degraded by reduced
tions due to the premature or burst drug release within several glutathione or other thiol compounds with certain concentra-
1
5
23,24
hours aer incubation in vitro. Therefore, the intriguing tions.
Furthermore, the concentration of GSH is oen
27,28
concept of stimulus-responsive gatekeeping was introduced to elevated to 2–10 mM (ref. 25 and 26) in tumor tissues,
about
regulate the cargo release and to optimize the application of twice that compared to normal tissues; thus, the disulde bond
MSNs in nanomedicine. Presently, nanoparticles, organic is more attractive in its use in the targeted release on tumor
molecules and supramolecular nanovalves have been employed tissues. For example, Yang et al. described the preparation of
core–shell multi-sensitive composite nanoparticles with a
poly(N-vinylcaprolactam-s-s-methacrylic acid) (P-(VCL-s-s-MAA))
a
Department of Photoelectric Band Gap Materials Key Laboratory of Ministry of shell to reveal the sensitive release behavior for cancer
Education, Harbin Normal University, Harbin 150025, China. E-mail: qufengyu@
15
treatment.
Strongly magnetic (Fe O or g-Fe O ) nanoparticles with low
hrbnu.edu.cn; linhuiming@hrbnu.edu.cn; Tel: +86 451-88060653
b
3
4
2 3
College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin
toxicity have been most intensively studied as targeted and
1
†
1
50025, China. E-mail: guogang19761126@sina.com
Electronic supplementary information (ESI) available. See DOI:
0.1039/c4tb01788a
29–32
magnetic resonance imaging agents.
However, pure iron
oxide is prone to aggregation due to anisotropic dipolar
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attraction and rapid biodegradation when they are exposed to 80 mL ethanol, 60 mL distilled water and 140 mL hexane. The
33,34
ꢀ
biological systems directly.
The core–shell structure with resulting solution was heated to 70 C and maintained at that
iron oxide nanoparticles as the core and mesoporous silica as temperature for 4 h. When the reaction was complete, the upper
the shell not only can overcome the limitations of pure iron organic layer containing the iron–oleate complex was washed
oxide nanoparticles but also can combine the advantages of the three times with 30 mL distilled water in a separatory funnel.
two to improve the performance in the eld of targeted drug Aer washing, hexane was evaporated off, resulting in the iron–
35,36
delivery.
Due to the collateral damage and adverse side oleate complex in a waxy solid form.
effects of most cancer drugs, targeting drug delivery systems
3
7
have attracted much attention for cancer therapy. For Synthesis of Fe
example, Yang et al. designed novel brous-structured meso-
3 4
O nanoparticles
3 4
Fe O nanoparticles were prepared using a literature proce-
porous silica microspheres (denoted as Fe O /FMSMs), which
39
3
4
dure. 36 g (40 mmol) of the iron–oleate and 5.7 g of oleic acid
exhibited a sustained drug release prole, sufficient magnetic
responsivity and redispersibility to the external magnetic eld.
In addition, Wang and coworkers synthesized a biocontrollable
drug release system with PAH/PSS multilayers on Fe O /mSiO ,
3 4 2
which showed magnetic-targeting and pH-controllable release
behavior.
With all of these considerations in mind, we synthesized a
Fe O @mSiO nanocarrier consisting of a magnetic Fe O
3 4
nanoparticle core and a mesoporous silica (mSiO ) shell, which
(20 mmol, 90%) were dissolved in 200 g of 1-octadecene (90%)
ꢀ
at room temperature. The reaction mixture was heated to 320 C
ꢀ
ꢁ1
with a constant heating rate of 3.3 C min , and then kept at
that temperature for 30 min. When the reaction temperature
ꢀ
reached 320 C, a dramatic reaction occurred and the initial
transparent solution became turbid and brownish black. The
resulting solution, containing the nanocrystals, was then cooled
to room temperature, and 500 mL of ethanol was added to the
solution to precipitate the nanocrystals, which were collected by
centrifugation and then dispersed in chloroform.
3
4
2
2
showed a passive targeting property (Fe
with enzyme-sensitive controlled release. As shown in Scheme
, in the rst step, the core–shell Fe @mSiO nanomaterials
3 4
O target) associated
1
3
O
4
2
Synthesis of Fe O @mSiO nanoparticles
3
4
2
were prepared as the drug carriers. At the same time, the
synthesized bis-(3-carboxy-4-hydroxy phenyl) disulde was
modied with an amino silane coupling agent (3-amino-
propyltriethoxysilane), denoted as (R–S–S–R ). Aer the drug
DOX) loading, the enzyme-sensitive R–S–S–R was employed to
O @mSiO as the blocking agent to
3 4 2
inhibit premature drug release. It is known that the high
expression of glutathione reductase (GSH) in tumor tissue
promotes the degradation of –S–S–, thereby allowing the release
of DOX.
3 4
In a typical procedure, 0.5 mL of the Fe O nanocrystals in
ꢁ1
chloroform (10 mg mL ) were poured into 8 mL of 0.2 M
aqueous CTAB solution and the resulting solution was stirred
vigorously for 30 min. The formation of an oil-in-water micro-
emulsion resulted in a turbid brown solution. Then, the mixture
1
(
1
gra outside of the Fe
ꢀ
was heated up to 60 C for 30 min to evaporate the chloroform,
38
3 4
resulting in a transparent black Fe O /CTAB solution. Next, 20
mL of distilled water was added to the obtained black solution
and the pH value of the mixture was adjusted to 8–9 by using 0.1
M NaOH. Aer that, 100 mL of 20% TEOS in ethanol was injected
six times at 30 min intervals. The reaction mixture was reacted
for 24 h under violent stirring. The obtained Fe O @mSiO NPs
were centrifuged and rinsed with ethanol repeatedly to remove
the excess precursors and CTAB molecules, and they were then
dispersed in ethanol (8 mL).
Experiment and methods
Materials
3
4
2
Unless specied, all of the chemicals were analytical grade and
were
used
without
further
purication.
Cetyl-
trimethylammonium bromide (CTAB), tetraethyl orthosilicate
Synthesis of bis-(3-carboxy-4-hydroxy phenyl) disulde
(
TEOS),
3-[4,5-dimethylthialzol-2-yl]-2,5-diphenyltetrazolium
(R–S–S–R)
0
bromide (MTT), doxorubicin hydrochloride (DOX$HCl), 2 -(4-
ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5 -bi-1H-benzimidazole,
trihydrochloride
0
The disulde was prepared from 5-ASA through the preparation
40,41
0
of the xantogenate derivative (see Fig. S1†).
round bottomed ask, 5-aminosalicyclic acid (5.0 g, 0.03 mol,
eq.) was suspended in water (17 mL) and acidied with
In a three necked
(Hoechst
33342),
N,N -dicyclohexyl-
carbodiimide (DCC), 4-dimethylaminopyridine (DMAP), (3-
aminopropyl)triethoxysilane (APTES), sodium oleate, oleic acid,
1
concentrated hydrochloric acid (13 mL). The mixture was then
1-octadecene, 5-aminosalicyclic acid, sodium nitrite, potassium
ꢀ
cooled to 0 C. A solution of sodium nitrite (2.3 g, 0.03 mol,
xantogenate, dichloromethane, ethyl acetate, and petroleum
ether were obtained from Aladdin, China. Ferric trichloride
hexahydrate (FeCl $6H O), ethanol, n-hexane and triethylamine
1
eq.) in water (16 mL) was added dropwise to the acidic solu-
ꢀ
tion, keeping the temperature below 5 C, and the mixture was
stirred for 1.5 h. The reaction pH was then raised to 5 using
3
2
were purchased from Tianjin Chemical Corp. of China.
ꢀ
sodium hydroxide (50%) under a temperature below 5 C.
Potassium xantogenate (15.70 g, 3 eq.) was dissolved in water
Synthesis of iron–oleate complex
(15 mL) under nitrogen at room temperature: the cooled dia-
In a typical synthesis of the iron–oleate complex, 10.8 g of iron zonium solution was added dropwise to the solution. The
chloride (FeCl
3
$6H
2
O, 40 mmol) and 36.5 g of sodium oleate solution turned red and nitrogen gas was released. The reaction
(120 mmol, 95%) were dissolved in a mixture composed of mixture was stirred for an additional hour at room temperature.
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3 4 2 1
Scheme 1 Illustration of the preparation and controlled release process of DOX–Fe O @mSiO @R–S–S–R .
0
Dichloromethane was added and the mixture was acidied When it was completely dissolved, 2.269 g (0.011 mol) of N,N -
using 1 M hydrochloric acid. The organic phase was separated, dicyclohexylcarbodiimide (DCC) was added and then main-
extracted with brine, separated, dried and evaporated under tained at that temperature for 1 h. Then, 4.807 g (0.022 mol) of
reduced pressure. The residue was puried by ash column (3-aminopropyl)triethoxysilane (APTES) and 0.1222 g (0.001
chromatography (PE : EA ¼ 5 : 1) to give the xantogenate mol) of 4-dimethylaminopyridine (DMAP) were added dropwise
product (5.24 g, 62.16%). The product was dissolved in ethanol to the solution, and the reaction mixture was reacted for 28 h
(
(
22 mL) to give a red colored solution. Potassium hydroxide with stirring.
3.41 g, 3 eq.) was added into this solution. The solution was
stirred for 5 h, then acidied with 1 M HCl and extracted with
ethyl acetate. The organic layer was separated, dried and evap-
orated. The crude product was puried by ash column chro-
matography on silica gel (PE : EA ¼ 1 : 1) to obtain the disulde
3 4 2 1
Drug loading and synthesis of DOX–Fe O @mSiO @R–S–S–R
Fe
3
O
4
@mSiO
2
(60 mg) and DOX (3 mg) were added to the
ꢀ
ethanol solution (3 mL) and stirred at 25 C for 12 h. Next, 150,
2
50 and 500 mL supernatant uid of R–S–S–R
mixed solution. The obtained solid (named as DOX–Fe
mSiO @R–S–S–R -1, DOX–Fe @mSiO @R–S–S–R -2, DOX–
Fe O @mSiO @R–S–S–R -3, respectively) was centrifuged, and
1
was added to the
(
1.42 g, 12.85%). The NMR spectrum of as-synthesized R–S–S–R
3 4
O @
is shown in Fig. S2.†
2
1
3
O
4
2
1
3
4
2
1
1
Synthesis of R–S–S–R–APTES (R–S–S–R )
washed several times with ethanol solution. The loading
In a typical procedure, 3.718 g (0.011 mol) of R–S–S–R was dis- amount of DOX was determined by UV/vis spectroscopy at 480
solved in 50 mL of dimethyl sulfoxide at room temperature. nm. The loading efficiency (LE wt%) of DOX can be calculated
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by using the formula (1). The experiment was repeated three microplate reader (Synergy™ HT, BioTek Instruments Inc,
times.
USA).
m
ðoriginal DOXÞ ꢁ mðresidual DOXÞ
LE wt% ¼ m
ꢂ 100%
(1)
ðFe O @mSiO Þ þ mðoriginal DOXÞ ꢁ mðresidual DOXÞ þ mðRꢁSꢁSꢁR1Þ
3
4
2
Drug release
Characterization
Gating protocol was investigated by studying the release proles Powder X-ray patterns (XRD) were recorded on a SIEMENSD
of DOX from the DOX–Fe @mSiO @R–S–S–R at pH 6.5 PBS 5005 X-ray diffractometer with Cu Ka radiation (40 kV, 30 mA).
3
O
4
2
1
buffer solution with 10 mM GSH or without GSH. Briey, The nitrogen adsorption/desorption, surface areas, and median
DOX–Fe O @mSiO @R–S–S–R (30 mg) was dispersed in 5 mL pore diameters were measured using a Micromeritics ASAP
3
4
2
1
of media solution and sealed in a dialysis bag (molecular weight 2010M sorptometer. The surface area was calculated according
cutoff 8000), which was submerged in 50 mL of media solution. to the conventional BET method and the adsorption branches
At the interval time, the solution was taken out to determine the of the isotherms were used for the calculation of the pore
release amount by UV.
parameters using the BJH method. Fourier transform infrared
FTIR) spectra were recorded on a Perkin-Elmer 580B Infrared
(
Spectrophotometer using the KBr pellet technique. A UV-vis
spectrum was used to describe the amount of drug release
Cell culture
HeLa cells (cervical cancer cell line) and human umbilical vein
endothelial cells (HUVEC) were grown in monolayers in Dul-
becco's Modied Eagle's Medium (DMEM, Gibco) supple-
mented with 10% (v/v) fetal bovine serum (FBS, Tianhang
bioreagent Co., Zhejiang) and penicillin/streptomycin (100 U
(SHIMADZU UV2550 spectrophotometer). Transmission elec-
tron microscopy (TEM) images were recorded on TECNAI F20.
Zeta potential and dynamic light scattering (DLS) were carried
out with a ZetaPALS Zeta Potential Analyzer. The magnetic
properties of samples were characterized with a Vibrating
Sample Magnetometer (Lake Shore 7410).
ꢁ1
ꢁ1
mL and 100 mg mL , respectively, Gibco) in a humidied 5%
ꢀ
CO
2
atmosphere at 37 C.
Confocal laser scanning microscopy (CLSM)
Results and discussion
To check cellular uptake, HeLa cells were cultured in a 12–well Morphology and structure
chamber slide with one piece of cover glass at the bottom of
X-ray diffraction patterns of Fe O @mSiO , DOX–Fe O @
3
4
2
3 4
each chamber in the incubation medium (DMEM) for 24 h. The
mSiO @R–S–S–R -1, DOX–Fe O @mSiO @R–S–S–R –2, and
2
1
3
4
2
1
cell nucleus was labeled by Hoechst 33342. DOX–Fe O @
3
4
DOX–Fe
3
O
4
2 1
@mSiO @R–S–S–R -3 powders are presented in
mSiO @R–S–S–R -2 was added into the incubation medium at
2
1
Fig. 1. As can be seen in Fig. 1, all the samples reveal only one
ꢁ1
the concentration of 100 mg mL for 6 h incubation in 5% CO2
ꢀ
at 37 C. Aer the medium was removed, the cells were washed
twice with PBS (pH 7.4) and the cover glass was visualized under
a laser scanning confocal microscope (FluoView FV1000,
Olympus).
Cell viability
The viability of cells in the presence of nanoparticles was
investigated using
a 3-[4,5-dimethylthialzol-2-yl]-2,5-diphe-
nyltetrazolium bromide (MTT, Sigma) assay. The assay was
performed out in triplicate in the following manner. For the
MTT assay, HeLa cells and HUVEC were seeded into 96-well
4
plates at a density of 1 ꢂ 10 per well in 100 mL of media and
grown overnight. The cells were then incubated with various
concentrations of Fe
3 4 2 3 4 2 1
O @mSiO , Fe O @mSiO @R–S–S–R -2
and DOX–Fe O @mSiO @R–S–S–R -2 for 24 h. Aerwards, cells
3
4
2
1
ꢁ1
were incubated in media containing 0.5 mg mL of MTT for 4
h. The precipitated formazan violet crystals were dissolved in
Fig. 1 Low-angle XRD patterns of (a) Fe
@mSiO @R–S–S–R -1, (c) DOX–Fe @mSiO
@mSiO @R–S–S–R -3.
3
O
4
@mSiO
2
, (b) DOX–Fe
3
-
ꢀ
100 mL of 10% SDS in 10 mmol HCl solution at 37 C overnight.
O
4
2
1
3
O
4
2
@R–S–S–R
1
-2, and
The absorbance was measured at 570 nm by a multi-detection (d) DOX–Fe
3
O
4
2
1
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diffraction peak at about 2q ¼ 2.26 , suggesting they all possess
the mesoporous structure. Moreover, aer drug loading and
R–S–S–R graing, the diffraction intensities of DOX–Fe O @
1
3 4
mSiO @R–S–S–R undergo an obvious decrease. In addition,
2
1
with increase in the R–S–S–R
Fe @mSiO , there is a decrease in the diffraction intensity of
DOX–Fe @mSiO @R–S–S–R s, which is consistent with a
previous report.
1
that is graed onto the
3
O
4
2
3
O
4
2
1
42
The morphologies, particle sizes, and pores were investi-
gated through TEM analysis. As displayed in Fig. 2A, Fe O
3
4
nanoparticles show the dispersed and uniform spherical
morphology with an average diameter about 20 nm in size.
3 4 2 3 4
Fe O @mSiO reveals the obvious Fe O core encapsulated by a
20 nm silica shell with a worm-like porous structure (Fig. 2B),
which agrees with the corresponding XRD analysis (Fig. 1). As
illustrated in Fig. 2C, the gra of the organic “gate” results in a
rough surface and less dispersion of these nanoparticles.
The pore structure and related textural properties of
Fe O @mSiO
and DOX–Fe O @mSiO @R–S–S–R s were
3 4 2 1
3
4
2
investigated
through
nitrogen
adsorption–desorption
measurements. The corresponding adsorption isotherms and
the pore size distribution curves are depicted in Fig. 3. From
Fig. 3A, Fe
isotherm and a steep capillary condensation step at a relative
pressure of P/P
¼ 0.2–0.4. The typical H4 hysteresis loop is
observed, testifying the mesoporous structure of Fe O @mSiO .
3 4 2
O @mSiO displays the typical IV adsorption
0
3
4
2
As can be seen in Fig. 3A, there is a much smaller uptake of
DOX–Fe O @mSiO @R–S–S–R in comparison to its counter-
3
4
2
1
part (Fe
3 4 2
O @mSiO ). This also makes the surface area and pore
2
ꢁ1
3
ꢁ1
volume decrease from 326 m g and 0.285 cm g of Fe
3
-
@
2
ꢁ1
3
ꢁ1
O
4
@mSiO
2
to 115 m g and 0.118 cm g of DOX–Fe
3
ꢁ1
O
4
2
ꢁ1
3
mSiO
2
@R–S–S–R
1
-1, 63.1 m
@R–S–S–R
g
and 0.0839 cm
g
of Fig. 3 (A) Nitrogen adsorption–desorption isotherms and (B) pore size
2
ꢁ1
3
DOX–Fe
3
O
4
@mSiO
2
1
-2, 43.4 m g and 0.0605 cm
3 4 2 3 4 2 1
distribution for (a) Fe O @mSiO , (b) DOX–Fe O @mSiO @R–S–S–R -1,
ꢁ1
(c) DOX–Fe O @mSiO @R–S–S–R -2, and (d) DOX–Fe O @
g
of DOX–Fe O @mSiO @R–S–S–R -3, respectively (Table 1).
3
4
2
1
3
4
3
4
2
1
2 1
mSiO @R–S–S–R -3.
Furthermore, as displayed in Table 1, it is worth mentioning
that with the highest packages of R–S–S–R , DOX–Fe
mSiO @R–S–S–R -3 possesses the lowest surface area and pore
volume.
The FTIR absorption spectrum measurement was carried out
to investigate the presence of R–S–S–R graing aer
the modication. The corresponding FT-IR spectra of R–S–S–R,
R–S–S–R–APTES, Fe @mSiO and Fe @mSiO @R–S–S–R
are illustrated in Fig. 4. As depicted in Fig. 4A, the absorption
1
3 4
O @
2
1
1
3
O
4
2
3
O
4
2
1
ꢁ1
bands at 1689 and 1662 cm
are assigned to the C]O
stretching vibration of dicarboxylic acids, and the O–H defor-
mation vibration and C–O stretching vibration bands at 1440
ꢁ
1
and 1290 cm also can be clearly observed. Furthermore, the
ꢁ1
absorption bands at 1200 and 1599 cm are assigned to the
C–O stretching vibration and C]C stretching vibration of
phenol, respectively. Moreover, the absorption band of S–S at
ꢁ
1
5
35 cm appears in R–S–S–R, conrming that R–S–S–R has
been successfully synthesized. Aer the link of APTES, two new
ꢁ1
peaks at 1078 (Si–O stretching vibration) and 1579 cm (N–H
formation vibration) appear, conrming that R–S–S–R–APTES
Fig. 2 TEM images of (A) Fe
mSiO @R–S–S–R -2.
3 4 3 4 2 3 4
O , B) Fe O @mSiO , and C) Fe O @
2
1
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Table 1 Pore parameters of the samples
2
ꢁ1
3
ꢁ1
Samples
BET (m g
)
V
p
(cm g
)
Pore size (nm)
Fe
3
O
4
@mSiO
2
326
115
63.1
43.4
0.285
0.118
0.0839
0.0605
2.42
2.39
2.37
2.33
DOX–Fe
DOX–Fe
DOX–Fe
3
3
3
O
O
O
4
4
4
@mSiO
@mSiO
@mSiO
2
2
2
@R–S–S–R
@R–S–S–R
@R–S–S–R
1
1
1
-1
-2
-3
has been successfully synthesized. As shown in Fig. 4B, Drug loading and release proles
comparing Fe O @mSiO @R–S–S–R with Fe O @mSiO , the
3
4
2
1
3
4
2
To investigate the sensitive controlled release kinetics of the
DOX–Fe O @mSiO @R–S–S–R system, DOX was selected as
3 4 2 1
the model drug to evaluate the loading and controlled release
behaviors. The actual loading capacities of DOX are calculated to
ꢁ
1
obvious absorption bands at 1661 cm , which are assigned to
the C]O stretching vibration of acid amide, can verify the
successful graing of R–S–S–R
In addition, the hydrodynamic diameters of Fe
and Fe @mSiO @R–S–S–R -2 were measured using a Zeta
1 3 4 2
on Fe O @mSiO .
3 4 2
O @mSiO
be 1.23 ꢃ 0.4, 1.60 ꢃ 0.3 and 2.16 ꢃ 0.5 wt% for DOX–Fe
3 4
O @
3
O
4
2
1
mSiO @R–S–S–R -1, DOX–Fe O @mSiO @R–S–S–R -2 and
2
1
3
4
2
1
Potential Analyzer. As displayed in Table 2, the hydrodynamic
diameter of Fe O @mSiO centers at 82.0 nm which is larger
DOX–Fe O @mSiO @R–S–S–R -3, respectively. The in vitro
3
4
2
1
3
4
2
release prole of DOX from DOX–Fe
PBS buffer (pH 6.5) in response to GSH (10 mM in PBS) is shown in
Fig. 7A. As can be seen in Fig. 7A, without GSH, DOX–Fe
mSiO @R–S–S–R nanoparticles release little cargo, which is
3 4 2 1
O @mSiO @R–S–S–R in
than that observed from TEM because of the hydrate layer in
aqueous environment; moreover, it increases to 107.4 nm aer
3 4
O @
the functional gra with the R–S–S–R
corresponding zeta-potential was further used to monitor the
surface change between Fe @mSiO and Fe @mSiO
R–S–S–R . From Fig. 5, Fe @mSiO shows a zeta potential of
15.01 ꢃ 1.17 mV derived from the negative charge of surface
1
shell. Furthermore, the
2
1
below 25% at 24 h. However, DOX can be released freely with
the aid of GSH. As displayed in Fig. 7A, it takes 4 h to reach
3
O
4
2
3
O
4
2
@
1
3
O
4
2
45.16%, 36.50%, and 10.90% and about 24 h to reach the maximal
ꢁ
amount 94.89%, 69.06%, and 42.76% for DOX–Fe O @
3
4
Si–OH, which increases to 5.22 ꢃ 1.91, 8.94 ꢃ 0.91, and 10.45 ꢃ
mSiO
DOX–Fe
release is ascribed to the activity of the “gate”. It is known that,
S–S– is a typical sensitive bond to some reducing agents, such
as GSH, which can induce the bond breaking and “gate” open
and drug release. Without GSH, R–S–S–R blocks the pores of
2
@R–S–S–R
1
-1, DOX–Fe
3
O
4
@mSiO
2 1
@R–S–S–R -2 and
1
.26 mV for Fe O @mSiO @R–S–S–R -1, Fe O @mSiO @
3 4 2 1 3 4 2
3
O
4
@mSiO
2
@R–S–S–R
1
-3, respectively. The selective
R–S–S–R
1
-2, and Fe
3
O
4
@mSiO
2
@R–S–S–R
1
-3, respectively, due
. Based
has been
to the decrease of surface Si–OH substituted by R–S–S–R
on the above investigation, it is clear that R–S–S–R
successfully graed on the surface of Fe @mSiO
1
–
1
3
O
4
2
.
1
Fig. 6 presents the magnetization characterization of
mSiO encapsulating the cargo within the pores. Furthermore,
2
Fe O @mSiO @R–S–S–R -1, Fe O @mSiO @R–S–S–R -2, and
3
4
2
1
3
4
2
1
the release performance of DOX–Fe O @mSiO (without a
3
4
2
Fe O @mSiO @R–S–S–R -3 at room temperature. The hyster-
3
4
2
1
“
gate”) in pH 6.5 with and without GSH was also studied. As
illustrated in Fig. 7A, the release of DOX from DOX–Fe
mSiO is faster than that from DOX–Fe @mSiO @R–S–S–R
Moreover, there is no obvious difference between the DOX
release from DOX–Fe @mSiO with or without GSH. Based
esis loops (Fig. 6) indicate the super paramagnetism of all the
materials. Furthermore, the saturation magnetizations (M ) of
-2, and
-3 are about 20.9, 15.1, and 9.08 emu
3 4
O @
s
2
3
O
4
2
1
.
Fe
Fe
3
O
O
4
4
@mSiO
@mSiO
2
@R–S–S–R
@R–S–S–R
1
3 4 2 1
-1, Fe O @mSiO @R–S–S–R
3
1
2
1
3
O
4
2
ꢁ
g
, respectively, and are ascribed to the non-magnetic mSiO
2
on the above investigation, the controlled drug release relies on
the “–S–S– gate” sensitivity to GSH. Without GSH or the “–S–S–
and R–S–S–R
1
.
3 4 2 3 4 2 1
Fig. 4 FTIR spectra of (A) R–S–S–R and R–S–S–R–APTES and (B) Fe O @mSiO and Fe O @mSiO @R–S–S–R .
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Table 2 Hydrodynamic size of the samples
the hydrodynamic diameter increases from 107.4 to 110.3 nm,
ascribed to the breaking of –S–S– outside Fe O @mSiO @
3
4
2
Hydrodynamic size
distribution (nm)
R–S–S–R -2. Furthermore, the zeta potential also reduced from
1
Samples
5
.22 ꢃ 1.91, 8.94 ꢃ 0.91, and 10.45 ꢃ 1.26 mV to ꢁ2.64 ꢃ 1.78,
Fe
Fe
Fe
3
O
3
O
3
O
4
4
4
@mSiO
@mSiO
@mSiO
2
2
2
82.0
107.4
ꢁ0.97 ꢃ 1.14, and 1.25 ꢃ 1.84 mV, respectively, due to the
@R–S–S–R
@R–S–S–R
1
-2
breaking of –S–S– to form –SH (Fig. 5).
1
-2 aer GSH treatment 110.3
To further investigate the release behavior, the release data
43,44
are analyzed by the Higuchi model.
As is well known, drug
release kinetics from an insoluble, porous carrier matrix are
frequently described by the Higuchi model, and the release rate
can be described by the following equation:
1
/2
Q ¼ k ꢂ t
(2)
where Q is the quantity of drug released from the materials, t
denotes time, and k is the Higuchi dissolution constant.
According to the model, for a purely diffusion-controlled
process, the linear relationship is valid for the release of rela-
tively small molecules distributed uniformly throughout the
44
carrier.
As illustrated in Fig. 7B, DOX–Fe
and DOX–Fe @mSiO @R–S–S–R -2 exhibit a two-step release
0–8 h and 8–24 h) based upon the Higuchi model. Compared
with the other two samples, DOX–Fe O @mSiO @R–S–S–R -3
3 4 2 1
O @mSiO @R–S–S–R -1
3
O
4
2
1
(
3
4
2
1
just displays a one-step release within 24 h. In the rst 8 h,
DOX–Fe @mSiO @R–S–S–R -1 possess the highest dissolu-
tion constant k (the slope of the tting line), followed by
3
O
4
2
1
Fig.
R–S–S–R
Fe @mSiO
GSH, Fe @mSiO
with GSH, Fe @mSiO
.5 with GSH.
5
Zeta potential test of Fe
-1, Fe @mSiO @R–S–S–R -2, Fe
@R–S–S–R -1 after R–S–S–R
@R–S–S–R -2 after R–S–S–R
@R–S–S–R -3 after R–S–S–R
3
O
4
@mSiO
@mSiO
degraded in pH 6.5 with DOX–Fe
degraded in pH 6.5 R–S–S–R
degraded in pH
2
,
Fe
3
O
4
@mSiO
2
@
1
3
O
4
2
1
3
O
4
2
@R–S–S–R
1
-3,
O
4
@mSiO
2
@R–S–S–R
1
-2 and DOX–Fe
3
O
O
4
4
@mSiO
@mSiO
2
2
@
@
3
O
4
2
1
1
3
3
O
4
2
1
1
1
-3. This is because when DOX–Fe
3
3
O
4
2
1
1
R–S–S–R
s immerses in the release media with GSH, it induces
1
6
–
S–S– breaking and drug release. With the lowest amount of
R–S–S–R , the “gatekeeper” was degraded most quickly, making
1
the highest dissolution constant k as well as the fastest release rate
of DOX–Fe
8–24 h), the release rates of DOX–Fe
and DOX–Fe @mSiO @R–S–S–R -2 decrease, and tend to be
3 4 2 1
O @mSiO @R–S–S–R -1. In the second release step
(
3 4
O
@mSiO @R–S–S–R -1
2
1
3
O
4
2
1
similar to each other. It is believed that, in the rst release step,
most drug molecules release outside aer the “gatekeeper” is
broken. Thus, the rst release step depends mainly upon the
degradation of –S–S– and the second release step is determined
just by the mesoporous structure of the host. However, with
highest amount of R–S–S–R
slow, which is associated with the mesoporous structure
controlling the resistant release; therefore, DOX–Fe
mSiO @R–S–S–R -3 displays a rst-step release behavior for 24
h. To sum up, the amount of “gate” (R–S–S–R ) can be used to
1
, the breaking of the “gatekeeper” is
3 4
O @
2
1
1
regulate the release performance of the system.
In vitro cytotoxic effect and cellular uptake
Fig. 6 Representative hysteresis loop measurements of the obtained
(
(
a) Fe
c) Fe
3
O
4
@mSiO
@mSiO
2
@R–S–S–R -1, (b) Fe
1
@R–S–S–R -3.
1
3
O
4 2
@mSiO @R–S–S–R
1
-2, and To investigate the cellular uptake of the sample, DOX–Fe
3 4
O @
3
O
4
2
mSiO @R–S–S–R -2 was incubated with HeLa cells at the
2
1
ꢁ1
concentration of 100 mg mL for 6 h. The cellular uptake and
subsequent localization of the sample is shown in Fig. 8. As
gate”, controlled drug release performance can be obtained. depicted in Fig. 8, nanoparticles are localized in the cytoplasm
The sensitive releases were further studied by the analysis of the aer 6 h incubation with HeLa cells, which proves the fast
hydrodynamic diameters and zeta-potentials before and aer cellular uptake ability of the sample. This is ascribed to small
3 4 2 1
Fe O @mSiO @R–S–S–R s were treated by GSH. From Table 2, particle size (65 nm), which is benecial in entering the cell and
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Paper
Fig. 7 Release profiles of DOX from (A) DOX–Fe
3
O
4
@mSiO
-1, (d) DOX–Fe
in pH 6.5 without GSH, (f) DOX–Fe
-3; (B) Higuchi plot for the release of DOX from DOX–Fe
-1, (b) DOX–Fe @mSiO @R–S–S–R -2, and (c) DOX–Fe
2
in pH 6.5 (a) with GSH, (b) without GSH, and DOX–Fe
@mSiO @R–S–S–R -2 (e) DOX–Fe
@mSiO @R–S–S–R -1, (g) DOX–Fe
@mSiO @R–S–S–R
@mSiO @R–S–S–R -3.
3
O
4
@mSiO
@mSiO @R–S–S–R
@mSiO @R–S–S–R -2, and (h)
in pH 6.5 with GSH, (a)
2
@R–S–S–R
1
in pH
6
.5 with GSH (c) DOX–Fe
3
O
4 2
@mSiO @R–S–S–R
1
3
O
4
2
1
3
O
4
2
1
-3, and
DOX–Fe
DOX–Fe
DOX–Fe
O
3 4
O
3 4
O
3 4
@mSiO
@mSiO
@mSiO
2
2
2
@R–S–S–R
@R–S–S–R
@R–S–S–R
1
1
1
3
O
4
2
1
3
O
4
2
1
3
O
4
2
1
3
O
4
2
1
3
O
4
2
1
45,46
enhancing the drug efficacy.
In addition, DOX can also be
The investigation of the cytotoxicity of the synthesized drug
found in cytoplasm aer 6 h incubation and benets from the carrier is signicant for its potential biomedical applications.
fast cellular uptake ability of these nanocomposites and the low Only nontoxic carriers are suitable for drug delivery. Here, the
47
pH endosomal environment. Importantly, the morphology of the cellular toxicity of Fe O @mSiO , Fe O @mSiO @R–S–S–R -2,
3
4
2
3
4
2
1
HeLa cells was not inuenced by the addition of DOX–Fe O @ and DOX–Fe O @mSiO @R–S–S–R -2 nanoparticles toward
3
4
3
4
2
1
mSiO @R–S–S–R -2, also illustrating the good biocompatibility HeLa cells were determined by means of a standard MTT cell
2
1
of the nanocomposites.
assay. It could be seen that both pure Fe
3 4 2 3
O @mSiO and Fe -
O
4
@mSiO @R–S–S–R -2 show no signicant cytotoxic effect on
2
1
ꢁ
1
the HeLa cells in a range of concentrations (3.125–50 mg mL ).
As can be seen in Fig. 9, the cell viability is 86.14% even aer the
3 4 2 1
concentration of Fe O @mSiO @R–S–S–R -2 reaches 50 mg
ꢁ
1
mL , while that of DOX–Fe O @mSiO @R–S–S–R -2 decreases
3
ꢁ
4
2
1
1
to 58.79% death at 50 mg mL . This can be explained by the fact
that the nanoparticles can diffuse into cells rapidly, followed by
the enzyme (GSH) inducing release of the anticancer drug DOX to
3 4 2 1
make the higher cytotoxicity of DOX–Fe O @mSiO @R–S–S–R -2.
In order to validate the specicity of the enzyme dependent
ꢁ
1
Fig. 8 CLSM images of HeLa cells after incubation with 100 mg mL
Fig. 9 Cell viability of HeLa cells incubated with different amounts
@mSiO (gray), Fe @mSiO @R–S–S–R -2 (pink), and
@mSiO @R–S–S–R -2 (cyan), and human umbilical vein
-2 (green), (D) Hoechst 33342 labeled cell nucleus endothelial cells (HUVEC) incubated with different amounts of
blue), and (E) merged. DOX–Fe @mSiO @R–S–S–R -2 (violet) for 24 h.
DOX–Fe
DOX fluorescence in cells (red), (C) FITC labeled DOX–Fe
mSiO @R–S–S–R
3
O
4
@mSiO
2
@R–S–S–R
1
-2 for 6 h. (A) HeLa cells (bright), (B) of Fe
3
O
4
2
3
O
4
2
1
3
O
4
@
DOX–Fe
3
O
4
2
1
2
1
(
3
O
4
2
1
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Journal of Materials Chemistry B
drug release, DOX–Fe
3
O
4
@mSiO
2
@R–S–S–R
1
-2 incubated with 11 L. Yuan, Q. Tang, D. Yang, J. Z. Zhang, F. Zhang and J. Hu, J.
a non-cancerous cell line (HUVEC) is presented as the control.
As illustrated in Fig. 9, it shows a very low cytotoxic effect (about 12 X. F. Guo, Y. S. Kim and G. J. Kim, J. Phys. Chem. C, 2009, 113,
8.40%) on the HUVEC even when the concentration of the cells 8313–8319.
reaches 50 mg mL due to the lack of GSH to enhance DOX 13 M. Manzano and M. Vallet-Regi, J. Mater. Chem., 2010, 20,
Phys. Chem. C, 2011, 115, 9926–9932.
2
ꢁ
1
release.
5593–5604.
1
1
4 Y. J. Wang and F. Caruso, Chem. Mater., 2005, 17, 953–961.
5 B. S. Chang, D. Chen, Y. Wang, Y. Z. Chen, Y. F. Jiao,
X. Y. Sha and W. L. Yang, Chem. Mater., 2013, 25, 574–585.
Conclusion
In summary, we have demonstrated an enzyme-responsive 16 M. W. Ambrogio, C. R. Thomas, Y.-L. Zhao, J. I. Zink and
controlled-release system using a smart switch (R–S–S–R ) gated J. F. Stoddart, Acc. Chem. Res., 2011, 44, 903–913.
core–shell Fe O @mSiO nanomaterial for targeted drug 17 S. Angelos, N. M. Khashab and Y.-W. Yang, J. Am. Chem. Soc.,
1
3
4
2
delivery. Owing to the degradation of the “gate,” the cargo
release is triggered by GSH, which is a specic enzyme that has 18 B. S. Chang, X. Y. Sha, J. Guo, Y. F. Jiao, C. C. Wang and
been proved to be highly expressed at the tumor microenvi- W. L. Yang, J. Mater. Chem., 2011, 21, 9239–9247.
ronment. The in vitro efficacy of the nanocomposites were 19 E. Aznar, M. D. Marcos, R. Martinez-Manez, F. Sancenon,
2009, 131, 12912–12914.
conrmed using HeLa cells and a MTT assay and CLSM were
carried out, revealing that the nanocarrier can rapidly enter into
J. Soto, P. Amoros and C. Guillem, J. Am. Chem. Soc., 2009,
131, 6833–6843.
the cells and has no obvious cytotoxic effect on HeLa cells at a 20 Y. Zhu, W. Meng, H. Gao and N. Hanagata, J. Phys. Chem. C,
ꢁ1
concentration of 50 mg mL . Furthermore, the drug molecules
can be transported into cells just aer 6 h incubation with 21 H. Li, L. L. Tan, P. Jia, Q. L. Li, Y. L. Sun, J. Zhang, Y. Q. Ning,
HeLa. Considering the high specicity and good controlled- J. H. Yu and Y. W. Yang, Chem. Sci., 2014, 5, 2804–2808.
release performance, DOX–Fe @mSiO @R–S–S–R can be 22 F. Muhammad, M. Y. Guo, W. X. Qi, F. X. Sun, A. F. Wang,
potential candidate for targeted cancer
2011, 115, 13630–13636.
3
O
4
2
1
employed as
treatment.
a
Y. J. Guo and G. S. Zhu, J. Am. Chem. Soc., 2011, 133, 8778–8781.
23 I. Ojima, Acc. Chem. Res., 2008, 41, 108–119.
2
4 I. Ojima, X. D. Geng, X. Y. Wu, C. X. Qu, C. P. Borella,
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Acknowledgements
Financial support for this study was provided by the National
Natural Science Foundation of China (21471041, 21171045, 25 N. S. Kosower and E. M. Kosower, Int. Rev. Cytol., 1978, 54,
1101046, 21441002), the Natural Science Foundation of Hei- 109–160.
longjiang Province of China ZD201214, and the Technology 26 S. J. Yu, C. L. He, J. X. Ding, Y. L. Cheng, W. T. Song,
2
development pre-project of Harbin Normal University (12XYG-
1).
X. L. Zhuang and X. S. Chen, So Matter, 2013, 9, 2637–2645.
27 J. A. Cook, H. I. Pass, S. N. Iype, N. Friedman, W. Degraff,
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