Controlled release using mesoporous silica nanoparticles functionalized with 18-crown-6 derivative

Article abstract of DOI:10.1039/c1jm11334h

Mesoporous silica nanoparticles were functionalized with an 18-crown-6 group as a gate molecule and the releasing capacity as a drug delivery system was controlled by the exchange reaction of "host-guest complex" with alkaline metal ions.

Full text of DOI:10.1039/c1jm11334h

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COMMUNICATION
Controlled release using mesoporous silica nanoparticles functionalized with
18-crown-6 derivative†
*
Young Lan Choi, Justyn Jaworski, Moo Lyong Seo, Soo Jin Lee and Jong Hwa Jung
Received 30th March 2011, Accepted 15th April 2011
DOI: 10.1039/c1jm11334h
supports with suitable coordination is a promising starting point for
applying the versatility of supramolecular ideas to the design of
nanoscopic devices and a method for bringing molecular and
supramolecular concepts to new advances in the field of nanosciences.
With these ideas in mind, we describe the mesoporous silica
immobilized with 18-crown-6 derivative as a cation-responsive release
system. Since the stoichiometric ratios of 18-crown-6 derivative
complexed with cations is strongly dependent on the size of cations,
the 18-crown-6 derivative was selected as the gate molecule. The
release rate of the curcumin cargo molecule from mesoporous silica
nanoparticles immobilized with 18-crown-6 derivatives could be
efficiently controlled by using different stoichiometries of coordina-
tion complexes with Cs+ and K+ ions. In the current study, the
selected model drug was curcumin (or diferuloylmethane), one of the
best-characterized chemopreventive agents. Since curcumin has
strong absorption and fluorescent emission properties,11 we can
monitor the operation of the controlled release by following the
changes in its luminescent property. This system is not only quite
simple compared to previous reported methods, but it also allows
easy control of the release rate of a cargo molecule by change in the
concentration of K+ ion.
Mesoporous silica nanoparticles were functionalized with an
18-crown-6 group as a gate molecule and the releasing capacity as
a drug delivery system was controlled by the exchange reaction of
‘‘host–guest complex’’ with alkaline metal ions.
The goal of drug delivery is to administer medicinally active mole-
cules with high specificity to diseased cells in a targeted and controlled
manner.1,2 Recently, mesoporous silica nanoparticles were described
as an appealing class of drug delivery vehicles, due to their sophisti-
cated design and mode of action.3 Increasing evidence has shown that
the nanoparticles are not cytotoxic and that those on the order of
100–200 nm in diameter can be taken up by cellular endocytosis and
transported into acidic lysosomes.2
Recently, in the field of gated nanochemistry, photochemically,
electrochemically and ionically controlled gate-like elements have
been incorporated into 3D MCM-41 scaffolds via tethering molec-
ular or supramolecular gating ensembles on the pore outlets of the
mesopores.4–7 For instances, Stoddart and Zink et al. presented
supramolecular redox-controlled nanovalves containing grafted
pseudorotaxanes and bistable rotaxanes in the pore outlets of mes-
ostructured silica thin films and they reported pH-driven systems
containing dialkylammonium threads anchored to MCM-41 and
capped with dibenzo-24crown-8.4 Some other release stimuli involve
coordination features, auto-modulated systems and specific irrevers-
ible reactions such as cleavage of specific bulky groups or taps.8–10 For
instance, in a recent publication operational controlled hydrolysis was
demonstrated by taking advantage of enzyme specificity through
rupture of an ester-like stopper.8
Scheme 1 shows the strategy of the cation-responsive release
system on the mesoporous silica surface. Mesoporous silica nano-
particles were uniformly covered with 18-crown-6 functional groups
(1), as coordination binding sites for Cs+ and K+, and attached to the
surface by covalent bonds. The 18-crown-6 moiety of 1 formed the
sandwich-type complex with Cs+ by a 2 : 1 ratio.12 On the other hand,
the 18-crown-6 moiety of 1 forms a complex with K+ by a 1 : 1
ratio.12 Cs+ ions readily bind to the 18-crown-6 groups on the mes-
oporous surface to form a ‘‘host–guest’’ coordination bond, in which
the mesopores are closed. Subsequently, K+ can be exchanged with
the Cs+ ion, because the stability constant of K+ ion is much higher
than that of Cs+ ion. The 18-crown-6 moiety of 1 forms a 1 : 1
complex with K+; this causes the mesopores to open. Thus, curcumin
molecules harbored within the mesoporous silica nanoparticles can
be released into the solution phase with K+ ion.
From these examples, it is apparent that most of the guest-release
controls on gate-like scaffolding have been reported by using light-
redox or pH-driven systems. In contrast, it is clear from the literature
that examples of guest release controlled in response to cations in
aqueous solution have still never been reported. However, the design
of such systems for certain cation species could be of interest for the
design of complex functional materials driven by the presence of
cations. In relation to this field, the combination of mesoporous
The synthetic procedure for the preparation of the 18-crown-6
derivative 1 (Scheme S1†) functionalized mesoporous silica nano-
particles is as follows; the mesoporous silica particles were prepared
through the sol–gel process by the previously reported method.13
Before removal of a template, the 18-crown-6 group, used as a gate,
was attached to the external surface of mesoporous silica nano-
particles in a sol–gel grafting reaction. The surfactant template was
Department of Chemistry and Research Institute of Natural Science,
Gyeongsang National University, Jinju, 660-701, Korea. E-mail:
jonghwa@gnu.ac.kr
† Electronic supplementary information (ESI) available: Spectroscopic
data and experimental conditions. See DOI: 10.1039/c1jm11334h
7882 | J. Mater. Chem., 2011, 21, 7882–7885
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Scheme 1 Schematic representation for the drug delivery system by using mesoporous silica nanoparticles: (a) preparation of mesoporous silica
nanoparticle, (b) immobilization of 1 as gate molecule, (c) encapsulation of curcumin (2), (d) complex formation of 18-crown-6 moiety with Cs+ ion and
(e) release of curcumin (2) upon addition of K+ ion.
removed by ethanol extraction; then, the silica particles obtained in
the sol–gel reaction were characterized by transmission electron
microscopy (TEM), 13C cross-polarization magic-angle-spinning
(CP-MAS) solid-state NMR spectroscopy, BET isotherms, TOF-
SIMS, X-ray photoelectron spectroscopy (XPS) and powder X-ray
diffraction (PXRD).
(iii) the signals resonating around 100, 115, 125 and 148 ppm can be
attributed to the characteristic carbon peaks of azobenzene moiety.
Mesoporous silica nanoparticles before and after functionalization of
1 were further confirmed by XPS (Fig. S5†). The XPS spectrum of
mesoporous silica nanoparticles before immobilization of 1 shows
Si2P and O1S binding energy (Fig. S5a†), whereas C1S and N1S for
carbon and nitrogen appeared for C-MS (Fig. S5b†). The absorption
and emission bands of C-MS in the solid state appeared at 350 nm;
this resulted in a yellow color (Fig. S6†). In addition, the N2
adsorption–desorption isotherms obtained at 77 K (Fig. S7†) showed
a typical type IV isotherm; in this, the observed step could be related
to nitrogen condensation inside the mesopores by capillarity. The
pore size and surface area of the silica nanoparticles before immo-
bilization of 1 were determined to be 4.48 nm and 1157.20 m2gꢁ1,
respectively (Fig. S7a†). After immobilization of 1, the pore size and
surface area of the silica nanoparticles were determined to be 4.48 nm
and 960.66 m2gꢁ1, respectively (Fig. S7b†). These were slightly smaller
than those observed before immobilization of 1. From the above
experimental data, we clearly concluded that the 18-crown-6 deriva-
tive (1) was attached onto the external surface of mesoporous silica
nanoparticles by covalent bonding. In addition, we measured the
density of 1 attached to the external surface of mesoporous silica
nanoparticles by TGA. 30% of 1 was attached onto the external
surface of mesoprous silica nanoparticles (Fig. S8†).
Fig. 1 shows the TEM image of silica particles after 18-crown-6
derivative (1) immobilization with a covalent bond. The 18-crown-6-
immobilized mesoporous silica nanoparticles (C-MS) exhibited
a typical mesopore structure of 4.48 nm with 100–500 nm of particle
size, which had hexagonal structure. The nanoparticles also show
XRD patterns typical of the hexagonal mesoporous silica. An inter-
planar spacing (d100) of ꢀ4.48 nm was calculated from these patterns
(Fig. S1†).
The spectroscopic observations provide direct evidence for the
attachment of 18-crown-6 derivative (1) onto the external surface of
silica nanoparticles. The IR and TOF-SIMS results were consistent
with bond formation; the IR spectrum of C-MS showed strong new
bands at 3010, 2970, 1350 and 1250 cmꢁ1, which originated from
molecule 1. This was consistent with 1 residing on the silica particle
(Fig. S2†). The TOF-SIMS spectrum of C-MS displayed fragments
attributable to 1 (m/z ¼ 473.25), thereby providing evidence that 1
was anchored onto the surface of the silica particles (Fig. S3†). After
immobilization of 1, examination of the 13C CP-MAS solid NMR
spectrum of C-MS (Fig. S4†) shows that (i) the signals resonating
around 70 ppm can be attributed to the characteristic peak of the
ethyl ether 1, 2 and 3; (ii) the signal resonating around 20–60 ppm can
be assigned to the characteristic peaks of carbon on the alkyl chain;
In order to determine the binding affinity and stoichiometry of 1
1
complex with Cs+ and K+, H NMR titrations of the 18-crown-6
derivative (1) were carried out upon the addition of Cs+ and K+ ions
in DMSO-d6 (Fig. S9 and S10†). The formation constant (Kf) for 1
complex with Cs+ is ca. 1.25 ꢂ 104 Mꢁ1,14 which shows 2 : 1 stoi-
chiometry. On the other hand, the value of Kf for 1 complex with K+
is ca. 5.20 ꢂ 104 Mꢁ1,14 which has 1 : 1 complex structure. These
results suggest that C-MS complex with Cs+ is exchangeable with K+
in aqueous solution.
To include a model drug molecule, curcumin (10 mM) was added
to a dispersed solution of C-MS (10 mg) and stirred for 1 h. The final
curcumin-loaded C-MS (C-C-MS) solid was isolated by centrifuga-
tion and washed with ethanol to eliminate the residual curcumin. C-
C-MS was characterized by TGA, fluorometry, FT-IR and solid 13
C
NMR. The emission band of the C-C-MS solid appeared at 530 nm
by fluorometry. The IR spectrum of C-C-MS showed new bands at
Fig. 1 (A) Photograph and (B) TEM image of 18-crown-6 derivative (1)
attached onto mesoporous silica particles (C-MS).
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3300, 3050 and 1700 cmꢁ1, which originated from curcumin
(Fig. S11†). In addition, the 13C CP-MAS spectrum of C-C-MS
included new peaks at 40, 58, 90, 104, 118, 142, 158,182 and 195 ppm
(Fig. S12†). The estimated loading was 20% of curcumin per gram of
C-MS by TGA observation (Fig. S13†).
As mentioned above, the 18-crown-6 moiety of 1 formed
a complex with Cs+ by a 2 : 1 stoichiometry. Thus, we selected Cs+ as
a stopper ion. C-C-MS (10 mg) was suspended in Cs+ solution (0.7
equiv.). Then, the solid product was isolated by centrifugation and
washed with water to remove the free Cs+. The physically adsorbed
curcumin on the external surface of the mesoporous silica nano-
particle would be removed for precise releasing experiments. In
addition, our previous experiments confirmed that the curcumin
loaded on the inside of mesoporous silica was not released to the
outside of the mesopore.
Fig. 3 Concentration dependence of K+ ion for the release profiles of
cargo molecule 2 from C-MS upon (10 mg) in the presence of Cs+ (0.7
equiv) upon addition of KCl; (a) 0, (b) ¼ 1.0, (c) ¼ 2.0 and (d) ¼ 3.0
equivalents in aqueous solution.
To investigate the delivery system of C-C-MS, we used lumines-
cence spectroscopy to monitor the release of the cargo molecule,
curcumin (2), upon the addition of K+ ion in aqueous solution. The
emission intensity of cargo 2 was negligible before the triggered
release from this system. When the concentration of K+ was adjusted
from 0 to ꢀ3.0 equivalents, the emission intensity of curcumin in
solution gradually increased, indicating that cargo molecule 2 had
been released into the aqueous phase (Fig. 2). In addition, we
measured the luminescence properties of curcumin in the presence of
K+ and Cs+. However, we could not find any influences in curcumin
with K+ and Cs+, because we used a small amount of K+ and Cs+ in
compared to curcumin. In addition, most of K+ was bound to 1
attached onto mesoporous silica particles. Thus, the Cs+ bound to the
18-crown-6 group on the external surface of C-C-MS was de-com-
plexed by K+, in which the K+ ion became coordinated to the 18-
crown-6 group by 1 : 1 complex structure, and opened the pores on
the surface of the C-MS.
addition of 3.0 equivalent of K+ in compared to the concentration of
Cs+, approximately 100% of cargo 2 was efficiently released into the
aqueous phase over 90 min. The results indicate that the rate of the
release of cargo 2 depends directly on the concentration of K+ ion,
with higher release rates occurring at larger concentrations of K+ ion.
In conclusion, we developed a mesoporous silica-based cation
responsive release system, based on the ‘‘host–guest’’ concept. The
curcumin molecules loaded into pores of C-MS were effectively
released by de-complexation of the coordination bonds between the
18-crown-6 group of C-MS and Cs+ upon the addition of K+.
Therefore, this system, based on the complexation of host and guest
molecules, may be a promising method for developing custom-made
controlled-delivery devices specifically triggered by target molecules.
Acknowledgements
Finally, we investigated the releasing capacity of the hollow silica
particles at different concentrations of K+ ion. The amount of cur-
cumin (2) released from C-C-MS was determined by measuring the
fluorescence emission intensity of the supernatant before and after the
addition of K+ ion. The release profiles were expressed in weight
percentages of cargo 2 at different concentrations of K+ (Fig. 3). The
release of cargo 2 was negligible for 210 min in the absence of K+ ion;
this indicated that cargo 2 remained in the pores of the silica nano-
particles. However, upon the addition of 1.0 equivalent of K+, up to
45% of cargo 2 was gradually released over 170 min. Upon the
This work was supported by a grant from the NRF (grant no.
2010-0016306) and the World Class University (WCU) Program
(R32-2008-000-20003-0) supported by Ministry of Education,
Science and Technology.
References
1 D. Schrama, R. A. Reisfeld and C. Baker, Nat. Rev. Drug Discovery,
2006, 5, 147.
2 M. Davis, Z. Chen and D. M. Shin, Nat. Rev. Drug Discovery, 2008, 7,
771.
3 (a) F. Torney, B. G. Trewyn, V. S.-Y. Lin and K. Wang, Nat.
Nanotechnol., 2007, 2, 295; (b) B. G. Trewyn, I. I. Slowing, S. Giri,
H.-T. Chen and V. S.-Y. Lin, Acc. Chem. Res., 2007, 40, 846; (c)
S. Angelos, E. Johansson, J. F. Stoddart and J. I. Zink, Adv. Funct.
Mater., 2007, 17, 2261; (d) K. M. L. Taylor, J. S. Kim, W. J. Rieter,
H. An, W. Lin and W. Lin, J. Am. Chem. Soc., 2008, 130, 2154; (e)
ꢀ
F. Casasus, E. Climent, M. D. Marcos, R. Martınez-Manez,
F. Sancenon, J. Soto, P. Amoros, J. Cano and E. Ruiz, J. Am.
ꢀ~
ꢀ
ꢀ
Chem. Soc., 2008, 130, 1903.
4 T. D. Nguyen, K. C.-F. Leung, M. Liong, C. D. Pentecost,
J. F. Stoddart and J. I. Zink, Org. Lett., 2006, 8, 3363.
5 L. Du, S. Liao, H. A. Khatib, J. F. Stoddart and J. I. Zink, J. Am.
Chem. Soc., 2009, 131, 15136.
6 H. Meng, M. Xue, T. Xia, Y.-L. Zhao, F. Tamanoi, J. F. Stoddart,
J. I. Zink and A. E. Nel, J. Am. Chem. Soc., 2010, 132, 1290.
ꢀ
ꢀ
ꢀ
ꢀ~
ꢀ
7 C. Coll, L. Mondragon, R. Martınez-Manez, F. Sancenon,
ꢀ
ꢀ
M. Dolores Marcos, J. Soto, P. Amoros and E. Perez-Paya, Angew.
Chem., Int. Ed., 2011, 50, 2138.
Fig. 2 Controlled release profile of cargo molecule 2 from C-MS (10 mg)
in the presence of Cs+ (0.7 equiv.) upon addition of K+ ion (0–3 equiv-
alents) in aqueous solution.
8 Q. Zhang, K. Ariga, A. Okabe and T. Aida, J. Am. Chem. Soc., 2004,
126, 988–989.
7884 | J. Mater. Chem., 2011, 21, 7882–7885
This journal is ª The Royal Society of Chemistry 2011

View Article Online
9 D. Jin, K. W. Park, K. Song, J. G. S. Kim, M. L. Seo and J. H. Jung,
J. Mater. Chem., 2011, 21, 1039.
12 R. M. Izatt, K. Park, J. S. Bradshaw and R. L. Bruening, Chem. Rev.,
1991, 91, 1039.
10 C. Chen, J. Geng, F. Pu, X. Yang, J. Ren and X. Qu, Angew. Chem.,
Int. Ed., 2010, 49, 1–6.
13 A. Galarneau, H. Cambon, F. D. Renzo, R. Ryoo, M. Choi and
F. Fajula, New J. Chem., 2003, 27, 73–79.
11 A. Duvoix, B. Romain, D. Sylvie, S. Michael, M. Franck, H. Estelle,
D. Mario and D. Marc, Cancer Lett., 2005, 223, 181.
14 K. A. Conners, Binding Constants, The Measurement of Molecular
Complex Stability, Wiley, New York, 1987.
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