Photoresponsive cyclodextrin-covered nanocontainers and their sol-gel transition induced by molecular recognition

Article abstract of DOI:10.1002/anie.200803880

Springing the trap: Cyclodextrin-covered mesoporous silica nanoparticles with photocleavable linkers exhibit photoinduced release characteristics and a sol-gel transition that is induced by molecular recognition (see picture). Upon exposure to UV light, t

Full text of DOI:10.1002/anie.200803880

Angewandte
Chemie
DOI: 10.1002/anie.200803880
Supramolecular Chemistry
Photoresponsive Cyclodextrin-Covered Nanocontainers and Their
Sol-Gel Transition Induced by Molecular Recognition**
Chiyoung Park, Kyuho Lee, and Chulhee Kim*
Stimuli-responsive nanomaterials have attracted much atten-
tion as controlled nanodevices, actuators, and biomedical
materials because of their ability to change their physical or
chemical properties in response to external triggers.[1–3] In
particular, nanocontainers with stimuli-responsive functions
can provide unique benefits for precise, controlled release
under specific conditions.[4] However, although traditional
nanocarriers such as liposomes and polymer micelles have
suffered from their instability, mesoporous silica particles (Si-
MPs) provide a rigid framework with a porous reservoir that
can encapsulate a large amount of guest molecules. Therefore,
the use of Si-MPs that have a gate function for controlled
release can provide a unique opportunity for biomedical
applications.[5] To date, several types of supramolecular
nanovalve systems for the controlled release of guests under
suitable conditions have been reported to act as stimuli-
responsive nanocontainers.[6] For this purpose, the surfaces of
nanocontainers have been tethered with supramolecular
functional motifs that are switchable by various stimuli, for
example, redox and pH changes, enzymes, and heat, which
can open and close the pore on demand.[6] Several research
groups have reported mesoporous silica systems with photo-
responsive gate functions.[6a,7] In addition, Si-MPs capped
with “gatekeepers” such as nanoparticles, polymers, and
dendrimers also exhibited controlled release characteristics in
response to stimuli.[5b,8]
Herein, we describe a novel cyclodextrin(CD)-covered
nanocontainer system that can exhibit photoresponsive
release characteristics and contains a photocleavable linker.
In addition to the photocontrolled release properties, we
Figure 1. Schematic illustration of the synthesis of cyclodextrin-covered
nanocontainers (Si-MP-4) and the photocontrolled release of guest
molecules from the pores. The pores of Si-MP-0, Si-MP-1, and Si-MP-2
are filled with CTAB. The inset shows FE-SEM images of Si-MP-4.
report the formation of the nanocontainer hydrogel that is
induced by molecular recognition. The CD-covered nano-
container system consists of the Si-MPs as a reservoir for
guest molecules, an o-nitrobenzyl ester moiety as a photo-
cleavable linker, and the CD “gatekeeper” that can close the
gate of the pore of Si-MPs (Figure 1).
Conditions: 1) 3-aminopropyltriethoxysilane; 2) succinic anhydride and
triethylamine; 3) removal of CTAB, N,N’-diisopropylcarbodiimide and
4-(dimethylamino)pyridine; 4) calcein, CuSO4, sodium ascorbate, and
mono-6-azido-b-CD.
We prepared Si-MP-0, which has an approximate diam-
eter of 60 nm (pore diameter ꢀ2 nm), as a nanocontainer for
guest molecules (Figure 1).[9] The average pore diameter was
measured by using powder X-ray diffraction (PXRD) and
Barret–Joyner–Halenda analysis. The structure of the Si-MPs
was further confirmed by using transmission electron micro-
scopy (TEM) and field emission scanning electron micro-
scopy (FE-SEM; see Figure S1 in the Supporting Informa-
tion). The TEM and PXRD analyses revealed that the Si-MPs
exhibit a well-ordered porous structure with a hexagonal
arrangement (Figure S1 in the Supporting Information). The
FE-SEM analysis showed that the Si-MPs are not only
uniform in size but also possess spherical shapes (Figure S1b
in the Supporting Information). The surface functionalization
of Si-MPs was monitored by FTIR spectroscopy (Figure S2a
in the Supporting Information).[9]
[*] C. Park, K. Lee, Prof. Dr. C. Kim
Department of Polymer Science and Engineering
Inha University, Incheon 402-751 (South Korea)
Fax: (+82)32-865-5178
E-mail: chk@inha.ac.kr
[**] This work was supported by the Korea Research Foundation (KRF-
2007-313-D00205) and the Korea Science and Engineering Foun-
dation through National Nuclear Technology Program (2007). C.K.
also thanks the Korea Health 21 R&D Project (A062254) for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803880.
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The surface of Si-MP-0 was functionalized with amine
from the pores of Si-MP-4 was monitored by fluorescence
measurements. The fluorescence intensity of the solution of
Si-MP-4 at 515 nm was monitored over time (Figure 2). In the
dark, only a very weak fluorescence intensity was observed,
because of self-quenching of calcein molecules in the pores of
Si-MP-4 (Figure 2 inset). As shown in Figure 2b, the calcein
molecules entrapped in the pores of Si-MP-4 were not
released in the dark because the pore gate was closed by
the CD moiety on the particle surface. When Si-MP-4 was
exposed to UV light after 24 hrs in the dark, we observed a
remarkable increase in the fluorescence intensity, which
suggests that the entrapped calcein molecule was released
from the pore of Si-MP-4 because the photolysis of o-
nitrobenzyl ester moiety on the surface of Si-MP-4 triggers
the opening of the pore gate of Si-MP-4 (Figure 2a,b). We
also observed periodic release of calcein molecules from Si-
MP-4 in response to successive UV irradiation over short time
periods (Figure S3 in the Supporting Information).
Si-MP-4 can be utilized as a building block for the
formation of photoresponsive physical hydrogels because the
surface of Si-MP-4 is covered with CDs, which provide the
inclusion sites for hydrophobic molecules. In particular, the
host–guest interaction between CDs and the polymers that
bear alkyl units can be exploited for noncovalent network
formation.[12] For this purpose, six-arm poly(ethylene glycol)
with dodecyl end groups (6-PEG-C12) that can be included
into the hydrophobic cavity of a-CD or b-CD, was prepared
by the coupling of six-arm PEG-succinimidyl succinate with
dodecylamine (Figure 3a).[9] Upon addition of Si-MP-4 into
an aqueous solution of 6-PEG-C12, the mixture formed a
hydrogel (Si-MP-4-gel) as a result of the network formation of
the inclusion complex between b-CD of Si-MP-4 and the
dodecyl group of 6-PEG-C12 (Figure 3b). The Si-MP-4-gel
composed of Si-MP-4 and 6-PEG-C12 changed to a sol upon
addition of a-CD as a competitive host in which the dodecyl
moiety is preferentially included to remove 6-PEG-C12 from
the b-CD moiety of Si-MP-4-gel (Figure 3b). The fluores-
cence intensity of Si-MP-4-sol was not higher than that of Si-
MP-4-gel, which suggested that the calcein molecule was not
released from the hydrogel system (Figure 4). However, after
UV irradiation (l = 350 nm) of Si-MP-4-sol, the fluorescence
intensity of Si-MP-4-sol-UV increased (Figure 4), which
indicated that the calcein molecules entrapped in the pores
were released (Figure 3b).
groups by treatment with 3-aminopropyltriethoxysilane to
obtain Si-MP-1. The carboxylic acid terminated Si-MP (Si-
MP-2) was obtained by the reaction of Si-MP-1 with succinic
anhydride in the presence of triethylamine (Figure 1). The
surfactant template (n-cetyltrimethylammonium bromide,
CTAB) was removed from Si-MP-2 by heating the methanol
solution of Si-MP-2 (MeOH/HCl 100:1) at reflux for
24 hours.[10] The FTIR spectrum of Si-MP-2 exhibits absorp-
tion bands in the regions of amide I (1635 cmÀ1), amide II
(1560 cmÀ1), and at 1720 cmÀ1, which arise from the carbonyl
stretching modes.[9] Si-MP-3 was prepared by coupling Si-MP-
2 with 1.[9] The product was purified by centrifugation and
washing with DMF. The FTIR spectrum of Si-MP-3 showed
sharp bands at 2100 cmÀ1 and 3296 cmÀ1 respectively, which
[9]
ꢁ
À
arise from the alkyne C C and C H stretching modes.
Calcein guest molecules were loaded into the pores of
silica particles by soaking Si-MP-3 in a solution of calcein in
phosphate buffered saline (PBS, pH 7.4). Mono-6-azido-b-
CD was then added into the mixture to produce calcein-
loaded Si-MP-4, in which the pores were capped by cyclo-
dextrins, by the Huisgen 1,3-dipolar cycloaddition
(Figure 1).[9,11] The excess calcein and catalyst were removed
by filtration, centrifugation, and washing with PBS buffer
solution (pH 7.4). After purification, the resulting particles
were resuspended in PBS at pH 7.4. The absorption spectrum
of Si-MP-4 showed an absorption of calcein at 504 nm, which
indicated that calcein molecules were loaded in the Si-MP-4
pores (Figure 2a). The self-quenching induced by calcein
Figure 2. a) Absorption spectrum of Si-MP-4 in PBS (the inset shows
absorption spectra of Si-MP-4 in response to UV irradiation). b) Time-
dependent change in fluorescence intensity (at lem =515 nm) of
Si-MP-4 in PBS (lex =490 nm). The inset shows fluorescence
spectra of Si-MP-4 before and after UV irradiation.
In summary, we have demonstrated that the introduction
of a photocleavable linker and a CD “gatekeeper” by click
chemistry on the surface of Si-MPs provided a unique route to
mesoporous particles, which are capable of releasing guest
molecules from the CD-blocked pore under photocontrol.
Upon exposure to UV light, the guest molecules were
released from the pore because of removal of the CD
“gatekeeper”, which was linked on the surface of Si-MP-4
through a photocleavable o-nitrobenzyl ester moiety. Fur-
thermore, Si-MP-4 could form a hydrogel through the net-
work formation of the b-CD/6-PEG-C12 inclusion complex.
The sol–gel transition and the guest-release characteristics of
Si-MP-4-gel were controlled by the combination of the
competitive host–guest interaction and photostimulus. We
expect that the Si-MPs system described here can be used as a
aggregation within the pores of Si-MP-4 results in only a weak
fluorescence signal of calcein being observed. The FE-SEM
analysis of Si-MP-4 revealed that the particles were spherical,
with an average diameter of 60 nm (Figure 1). The loading of
calcein in Si-MP-4 was visualized by confocal laser scanning
microscopy (Figure S2 in the Supporting Information).
Upon exposure of the Si-MP-4 solution to UV light (l =
350 nm), the absorption signal at 282 nm decreased and the
absorption signal at 344 nm increased as a result of photo-
cleavage of the o-nitrobenzyl moiety (Figure 1 and 2a). We
subsequently investigated the photoresponsive release char-
acteristics of Si-MP-4. The release of calcein guest molecules
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stirred at room temperature for 3 days. The resulting particles were
then filtered and purified by centrifugation (9500 rpm, 20 min) and
washing with H2O/MeOH.
Release experiments: Si-MP-4 was placed on the bottom of a
quartz cuvette which was then filled with PBS (pH 7.4). The
photocleavage was induced by irradiation with UV light (l =
350 nm), which was then turned off. The fluorescence intensity of a
solution of Si-MP-4 at 515 nm was measured as a function of
irradiation time.
Fluorescence measurements: All fluorescence measurements
were performed using a Shimadzu RF-5301PC spectrofluorophotom-
eter. The emission and excitation slit widths were set at 3 nm with
lex = 490 nm.
PXRD experiment: PXRD patterns were recorded at room
temperature on a Rigaku model RINT-2000 counter diffractometer
with a CuKa radiation source (Operated at 40 kV, 40 mA).
BET: The pore size was measured at 77 K on a Quantachrome
instrument.
TEM analysis: TEM images were obtained using a Philips CM
200 instrument operated at an acceleration voltage of 120 kV. For the
preparation of dispersed samples in water, a drop of sample solution
(100 mgLÀ1) was placed onto a 300-mesh copper grid coated with
carbon. About 2 min after deposition, the grid was touched with filter
paper to remove surface water. The samples were air dried before
measurement.
SEM analysis: Field emission scanning electron microscopy (FE-
SEM, Hitachi S-4200) was carried out on a field emission gun FE-
SEM instrument (accelerating voltage: 10–15 kV and pressure range:
0.8–0.9 Torr). The FE-SEM samples were prepared by transferring a
drop of sample solution onto a 200 mesh carbon-coated copper grid or
a silicon wafer. About 5–10 min after deposition, excess water was
removed by touching the edge of the substrate with filter paper. The
samples were air dried before measurement.
Figure 3. a) Chemical structure of 6-PEG-C12. b) Schematic illustration
of the photoresponsive release of guest molecules from the pores of
Si-MP-4 and sol–gel transitions induced by molecular recognition.
Received: August 6, 2008
Revised: November 19, 2008
Published online: January 9, 2009
Keywords: cyclodextrins · gels · molecular recognition ·
.
nanostructures · supramolecular chemistry
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