pH-responsive supramolecular nanovalves based on cucurbit[6]uril pseudorotaxanes

Article abstract of DOI:10.1002/anie.200705211

An open and closed case: pH-controllable nanovalves that operate in water have been produced by attaching [2]pseudorotaxanes to the surface of mesoporous silica nanoparticles. The nanovalves are able to contain guest molecules (rhodamine B, red circles) w

Full text of DOI:10.1002/anie.200705211

Communications
DOI: 10.1002/anie.200705211
Molecular Devices
pH-Responsive Supramolecular Nanovalves Based on Cucurbit[6]uril
Pseudorotaxanes**
Sarah Angelos, Ying-Wei Yang, Kaushik Patel, J. Fraser Stoddart,* and Jeffrey I. Zink*
The ability to control the release of molecules from meso-
porous silica nanoparticles promises to have far-reaching
is the ability of CB[6] to form inclusion complexes with a
variety of polymethylene derivatives, especially diamino-
alkanes: the stabilities of these 1:1 complexes are highly pH-
[
1]
consequences for drug-delivery applications. Both molec-
ular and supramolecular nanovalves, which regulate the
release of guest molecules from nanopores of mesostructured
silica nanoparticles, and operate under a range of stimuli
[
10,11]
dependent.
The pH-dependent complexation/decom-
plexation behavior of CB[6] with diaminoalkanes has enabled
the preparation of dynamic supramolecular entities which can
[
2,3]
[3]
[4]
[7,10–13]
including pH,
competitive binding, light, and redox
be controlled by pH.
Another important characteristic
to catalyze 1,3-dipolar cycloaddi-
[
5]
[12,14]
control, have been designed and their successful operation
of CB[6] is its ability
[
6]
[7]
[15]
demonstrated in organic solvents. These systems are based
upon the switching of components that have been tethered to
the nanoparticle surfaces, such that access to the entrances of
the nanopores can be opened and gated on demand. Since
most of the traditional nanovalve designs have been based on
tions, such that the reaction between an azide-substituted
ammonium ion and an alkyne-containing ammonium ion
yields a disubstituted 1,2,3-triazole derivative encircled by a
CB[6] ring. In view of these particular properties of CB[6], we
set about to employ it as a catalyst for the formation of
monolayers of [2]pseudorotaxanes on the surfaces of meso-
porous silica nanoparticles so as to generate ultimately pH-
responsive, biocompatible nanovalves capable of executing
different missions.
[
8]
[9]
[
2]pseudorotaxanes and bistable [2]rotaxanes that rely
upon donor–acceptor and hydrogen-bonding interactions
between the ring and stalk components, they are limited
[
7]
largely to use in organic solvents. However, to realize the
potential of nanovalves in therapeutic applications, it is
imperative that they not only employ biocompatible compo-
nents but that they also operate under physiological con-
ditions. For nanovalves to be viable in biological environ-
ments, a recognition and binding motif which operates in
aqueous media has to be identified, and then tried and tested.
Herein, we describe a pH-responsive nanovalve that relies on
the ion–dipole interaction between cucurbit[6]uril (CB[6])
and bisammonium stalks, and operates in water.
[1–6,16]
Mesoporous silica has proven
to be an excellent
support for the formation of dynamic nanosystems, including
nanovalves, because it is chemically stable and optically
transparent. In this current study, [2]pseudorotaxanes con-
sisting of bisammonium stalks and CB[6] rings were con-
structed (Figure 1a,b) on the surface of mesoporous silica
nanoparticles, and the pH-dependent binding of CB[6] with
the bisammonium stalks is exploited to control the release of
guest molecules from the pores of the silica nanoparticles. At
neutral and acidic pH values, the CB[6] rings encircle the
bisammonium stalks tightly, thereby blocking the nanopores
efficiently when employing tethers of suitable lengths.
Deprotonation of the stalks upon addition of base results in
spontaneous dethreading (Figure 1b,c) of the CB[6] rings and
unblocking of the silica nanopores.
CB[6], a pumpkin-shaped polymacrocycle with D6h sym-
metry consisting of six glycouril units strapped together by
pairs of bridging methylene groups between nitrogen
[
10]
atoms, has received considerable attention because of its
highly distinctive range of physical and chemical properties.
Of particular interest in the field of supramolecular chemistry
The silica supports employed were approximately 400-
nm-diameter spherical particles which contain ordered 2D
hexagonal arrays of tubular pores (pore diameters of ca. 2nm
with a lattice spacing of ca. 4 nm) prepared by using a base-
[
+]
[+]
[
*] S. Angelos, Dr. Y.-W. Yang, K. Patel, Prof. J. F. Stoddart,
Prof. J. I. Zink
California NanoSystems Institute and
Department of Chemistry and Biochemistry
University of California, Los Angeles
05 Hilgard Avenue, Los Angeles, CA 90095-1569 (USA)
Fax: (+1)310-206-1843
E-mail: stoddart@chem.ucla.edu
zink@chem.ucla.edu
Homepage: http://stoddart.chem.ucla.edu
[
17]
catalyzed sol–gel method. The nanopores were templated
by cetyltrimethylammonium bromide (CTAB) surfactants,
and tetraethylorthosilicate (TEOS) was used as the silica
precursor. Empty nanopores were obtained by removal of the
templating agents by solvent extraction. The ordered struc-
ture and particle morphology were confirmed (Figure 2) by
X-ray diffraction (XRD) and scanning electron microscopy.
This system was designed (Scheme 1a) such that the
nanovalve components could be assembled in a stepwise,
divergent manner from the nanoparticle surface outwards.
Following solvent extraction, the nanoparticles were heated
under reflux in an aminopropyltriethoxysilane (APTES)
solution, which afforded the amino-modified nanoparticles
1. These nanoparticles were recovered by vacuum filtration
4
http://www.chem.ucla.edu/dept/Faculty/jzink/
+
[
] These authors have contributed equally and both should be
considered first author.
[
**] This research was supported by a Nanoscale Interdisciplinary
Research Team (NIRT) grant (ESC-0103559) and a DMR (0346610)
grant from the National Science Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2
222
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Angewandte
Chemie
showed
new
absorption
ꢁ1
bands at 2131 and 3296 cm ,
which correspond to the
alkyne CꢂC and CꢁH stretch-
ing modes, respectively. In
the FTIR spectrum of the
nanoparticles {3ꢀCB[6]}, the
ꢁ
1
band at 1632cm
corre-
sponding to the CB[6] C=O
stretching mode confirms the
attachment of monolayers of
[
2]pesudorotaxanes to the
surfaces of the silica nano-
particles. The existence of the
alkyne CꢂC stretching band
ꢁ1
at 2131 cm infers that not
all of the tethered alkyne
groups are involved in
CB[6]-catalyzed 1,3-cycload-
ditions, presumably because
of the steric hindrance
between the [2]pseudorotax-
anes congregated on the sur-
face of the silica nanoparti-
cles.
Figure 1. Graphical representations of operating supramolecular nanovalves {3ꢀCB[6]} and {6ꢀCB[6]}. The
alkyne-functionalized mesoporous silica nanoparticles MCM-41 are loaded (a!b) with rhodamine B (RhB)
molecules, and capped (a!b) with CB[6] during the CB[6]-catalyzed alkyne-azide 1,3-dipolar cycloadditions,
followed by washing away the excess of substrates. RhB molecules are released (b!c) by switching off the
ion–dipole interactions between the CB[6] rings and the bisammonium stalks upon raising the pH value.
Real-time measurements
on the release of RhB have
been carried out to monitor
before being washed and dried extensively. They were then
resuspended in MeOH in the presence of propargyl bromide
and heated under reflux overnight to obtain the alkyne-
terminated nanoparticles 2. Next, the empty nanopores in 2
were loaded with fluorescent guest molecules by soaking the
nanoparticles in a 0.5 mm solution of rhodamine B (RhB) for
the operation of the nanovalve. Dye-loaded, CB[6]-capped
nanoparticles were washed extensively with MeOH and H O
2
to remove adsorbed molecules from the surface. A portion of
the washed nanoparticles (ca. 15 mg) was placed in the
bottom corner of a cuvette, and H O (12mL) was added
2
carefully. A 10 mW, 514 nm probe beam, directed into the
water above the nanoparticles, was used to excite the dye
molecules as they are released from the nanoparticles. The
emission spectrum of RhB was recorded as a function of time
at one-second intervals. The nanovalves were opened by
adjusting the solution to pH 10 through the addition of 2m
NaOH. Plots of the dissolved dye intensities as a function of
time (the release profiles are shown in Figure 3) indicate an
increase in the amount of dye released upon base activation,
thus demonstrating that the nanovalves do indeed open at
high pH values.
5
h. The preparation of the nanovalves was completed by
means of an interfacial CB[6]-catalyzed 1,3-dipolar cyclo-
addition of the silica-supported alkyne function and 2-
azidoethylamine to yield CB[6]/disubstituted 1,2,3-triazole
[
2]pseudorotaxanes {3ꢀCB[6]} spread all over the silica
surface.
[
6]
In keeping with the development of prototypical nano-
valves, the design of the components usually needs to be
optimized to achieve the best possible performance. The
situation is no different with the [2]pseudorotaxane
{
{
3ꢀCB[6]}. The release profile (Figure 3a) reveals that
3ꢀCB[6]} exhibits appreciable leakiness prior to base
activation. We suspected that the CB[6] rings in the
[
2]pseudorotaxanes do not reside close enough to the surface
Figure 2. a) The XRD pattern and b) SEM image of the mesoporous
silica nanoparticles {3ꢀCB[6]}.
of the mesoporous silica nanoparticles when the nanovalves
are closed, thereby making it possible for the RhB molecules
to escape prior to base activation. Previous research
[5c]
The surface functionalization of silica nanoparticles and
the construction of the CB[6]-capped nanovalves was moni-
tored by FTIR spectroscopy (see the Supporting
Information). The FTIR spectrum of the nanoparticle 2
revealed that the critical factors affecting nanovalve activa-
tion include 1) the size of the nanovalve components, 2) the
positioning of the nanovalves relative to the orifices of the
nanopores, and 3) the length of the linker. The outer diameter
Angew. Chem. Int. Ed. 2008, 47, 2222 –2226
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2223

Communications
[
10]
of the CB[6] ring which is 1.4 nm, might be expected to be
large enough to gate the approximately 2-nm-diameter pore
and thus prevent RhB molecules from escaping. In the
synthetic approach summarized in Scheme 1a, solvent extrac-
tion of the sol–gel prior to modification of the silica nano-
particles with amino groups enables the linkers to bind to the
pore interiors as well as to the surfaces of the nanoparticles.
We suspect, nonetheless, that the bulky CB[6] rings in
{
3ꢀCB[6]} do not penetrate deep enough inside the nano-
pores, which leaves the nanovalves prone to leakage. Thus, to
seal the nanovalves, a shorter linker was employed so that the
CB[6] rings would be positioned closer to the surface of the
mesoporous silica and so block the nanopore orifices more
efficiently. A shorter linker was attached to the silica surface
in two steps (Scheme 1b). The nanoparticles were first of all
derivatized with chloromethyltriethoxysilane (CMTES) to
afford the nanoparticles 4, which were then treated with
NaNH to produce the amino-modified nanoparticles 5. The
2
remaining steps of the synthesis of the nanovalve with the
shorter linkers were similar to those described earlier
(
Scheme 1a) for the nanoparticles with the longer linkers.
Figure 3. The release of the RhB guest molecules monitored by
following the luminescence intensity of the solution of a) nanoparticles
with longer linkers {3ꢀCB[6]} and b) nanoparticles with shorter linkers
{
6ꢀCB[6]} (blue trace). Control experiments without changing the
pH value (red trace) were also performed. Whereas (a) exhibits
substantial leakage, as indicated by the premature rise in lumines-
cence intensity, (b) shows no leakage.
The use of the shorter linker curtails the length of the stalk of
the pseudorotaxane in {6ꢀCB[6]} such that the CB[6] ring is
positioned about 0.2nm closer to the surface of the silica
nanoparticle. This subtle change in linker length tightens up
the nanovalves sufficiently to prevent leakage, and the release
profile illustrated in Figure 3b is observed.
A concern regarding the operation of these nanovalves is
the stability of the silica supports under the high pH
conditions required for the nanovalve to function. Activation
of the nanovalves relies on deprotonation of the primary
alkylammonium and secondary dialkylammonium centers
(
pK ꢃ 10) so as to disrupt the ion–dipole interactions
a
responsible for the binding of the CB[6] rings. To verify that
the silica mesostructure and particle morphology are able to
withstand the exposure to base (NaOH), which is required for
the activation of the nanovalves, scanning electron micro-
scopy (SEM) images and X-ray diffraction patterns of the
functionalized nanoparticles were compared (see the
Scheme 1. Synthetic route to mesoporous silica nanoparticles function-
alized with CB[6]/dialkylammonium pseudorotaxanes. i) and iv) pro-
pargyl bromide, MeOH, 508C, overnight; ii) and v) 0.5 mm RhB, H O,
2
RT, 5 h; then CB[6], 2n HCl, RT, 3 days; iii) NaNH , PhMe, heat under
2
reflux, 12 h.
2
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Angewandte
Chemie
Supporting Information) before and after exposure to base.
No noticeable differences in either the nanoparticle morphol-
ogy or mesostructure were observed, which indicates that the
structure of the nanoparticle supports is preserved during the
controlled release process.
(100 mg) in CMTES (1 mm) to dry toluene (10 mL) and heating under
[5c]
reflux for 12h to give the intermediate nanoparticles 4.
After
adding NaNH (0.02mmol), the reaction mixture was heated at reflux
2
for another 12h. The aminomethyl-modified nanoparticles 5 were
collected by filtration, washed thoroughly with toluene, and dried
under vacuum. They were characterized by means of FTIR, XRD,
SEM, and DLS.
On reflection, the production of CB[6]-based nanovalves,
which employ biocompatible components and operate in
water, has been achieved. The nanovalves rely on ion–dipole
interactions between the CB[6] rings and the bisammonium
stalks attached to the mesoporous silica nanoparticles and can
be operated quite simply by raising and lowering the
pH value. A modular approach has been developed that
relies on the interfacial CB[6]-catalyzed 1,3-cycloaddition of
alkyne- and azide-terminated subunits in the final steps of the
syntheses of the nanovalves. Now that the validity of
exploiting ion–dipole interactions for the design of nano-
valves has been established, we anticipate that nanovalves
based on CB[6] rings as the gatekeepers will play a significant
role in the future of functionalized mesoporous silica nano-
{6ꢀCB[6]}: Nanoparticles 5 were first modified with propargyl
bromide by heating under reflux in MeOH under N for 24 h to obtain
2
the alkyne-terminated silica nanoparticles. Loading with RhB and
completion of the nanovalve synthesis was achieved as described for
nanovalve {3ꢀCB[6]}. They were characterized by means of FTIR,
XRD, and SEM (see the Supporting Information).
Controlled release experiments: The dye-loaded, CB[6]-capped
nanoparticles (15 mg) were placed in the corner of a cuvette, and
distilled H O (12mL) was added carefully. A 10 mW, 514 nm
2
excitation beam was directed into the solution above the nano-
particles, and the RhB emission spectrum was recorded as a function
of time. Release profiles were obtained by plotting the luminescence
intensity of RhB at the emission maximum (578 nm) as a function of
time. Activation of the nanovalves was accomplished by adjusting the
pH value of the solution to 10 by adding 2m NaOH solution. The
solution in the cuvette was stirred gently throughout the controlled
release experiment.
[18]
particles for biotechnological and medical applications.
Furthermore, it is conceivable that these pH-responsive
supramolecular nanovalves can be tuned to operate under
gentler pH stimulation by identifying bisammonium ion
Received: November 12, 2007
Published online: February 14, 2008
centers with pK values that will enable the development of
a
CB[6]-based nanovalves for in vivo applications using the
[
19]
Keywords: heterogeneous catalysis · host–guest systems ·
mesoporous materials · molecular devices · surface chemistry
natural variations in pH that exist
diseased cells in living systems.
within healthy and
.
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Experimental Section
1
: Bare mesoporous silica nanoparticles templated by cetyltrimethyl-
ammonium bromide (CTAB) were synthesized according to a
[
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2
afforded the alkyne-modified MCM-41. Extensive washing of the
product with MeOH and drying under vacuum resulted in silica
nanoparticles 2. The nanoparticles were characterized by means of
FTIR, XRD, SEM, and dynamic light scattering (DLS; see the
Supporting Information).
{
3ꢀCB[6]}: Loading of the pores with rhodamine B (RhB) was
carried out by soaking the alkyne-modified porous silica nano-
particles 2 in an aqueous solution of RhB (0.5 mm) for 5 h at RT. A
concentrated solution of HCl (12m, 15 mL) containing an excess of
CB[6] and 2-azidoethylamine (see the Supporting Information for the
synthesis) was then added to the above mixture. The resulting mixture
was stirred for 3 days at RT. The loaded, capped nanoparticles were
collected by filtration and washed thoroughly with water to give
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3ꢀCB[6]}, which was characterized by means of FTIR, XRD, and
SEM (see the Supporting Information and Figure 2).
: The bare nanoparticle surface was derivatized with chlorome-
[7] The pH-controlled release of guest molecules entrapped in the
nanopores of mesoporous silica nanoparticles that have been
blocked by surface-grafted, pH-responsive, polyethyleneimine/
cyclodextrin poly-pseudorotaxanes has already been described
5
thyltriethoxysilane (CMTES) by adding a suspension of nanoparticles
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Communications
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