Glucose- and pH-responsive controlled release of cargo from protein-gated carbohydrate-functionalized mesoporous silica nanocontainers

Article abstract of DOI:10.1002/anie.201300958

Learning to let go: Controlled release of cargo (purple cubes) from lectin (blue squares)-gated nanopores was achieved using mannose (green loops)-functionalized mesoporous silica (see scheme). The protein nanogates could be opened either by decreasing the pH of the buffer or by adding competing glucose (yellow rings) to release the cargo from the pores. Copyright

Full text of DOI:10.1002/anie.201300958

Angewandte
Chemie
DOI: 10.1002/anie.201300958
Drug Delivery
Glucose- and pH-Responsive Controlled Release of Cargo from
Protein-Gated Carbohydrate-Functionalized Mesoporous Silica
Nanocontainers**
Shanshan Wu, Xuan Huang, and Xuezhong Du*
To improve the therapeutic efficacy and to reduce adverse
side effects of drugs, one strategy is to design a target-specific
drug-delivery system that can transport an effective dosage of
delivery systems are highly desirable for practical applications
in disease-related environments.
Herein, we report the controlled release of cargo from
novel protein-gated carbohydrate-functionalized MSN nano-
containers. Carbohydrate–protein interactions play an impor-
tant role in a variety of cellular processes including cell
[1]
drug molecules to the targeted cells and tissues on time. For
drug-delivery systems, no premature release and stimuli-
responsive controlled release of the pharmaceutical cargo are
two very important prerequisites that impact the therapeutic
differentiation and adhesion, inflammation, metastasis, and
[2]
[15]
efficacy and cytotoxicity of the drug delivery. Mesoporous
silica nanoparticles (MSNs) have been used in delivery
systems as nanocontainers because of their excellent biocom-
patibility, high surface areas, large pore volumes, uniform and
tunable pore sizes, and a great diversity of surface function-
immune response.
However, monovalent carbohydrate–
protein interactions are inherently weak, with a binding
3
4
À1 [16]
constant of 10 –10 Lmol , and the interaction strength
and specificity can be improved with multivalent interactions
or several simultaneous binding events with a binding con-
[
3]
6
7
À1
[16]
alization, in comparison with traditional delivery systems,
which mainly depend on simple diffusion or degradation of
stant of 10 –10 Lmol or higher. Concanavalin A (Con A,
pI = 4.5–5.5, a tetrameric form under physiological condi-
[1]
[17]
[17b]
the nanocarriers. A variety of MSN-based controlled-
tions, 3.9 ꢀ 4.0 ꢀ 4.2 nm for the tetramer)
specifically binding mannose and glucose epitopes in the
is capable of
[
4]
release systems have been developed using nanoparticles
[
5a]
[5b]
[5c–f]
[5g]
2+
2+
(
CdS,
Fe O ,
Au,
and ZnO ), macrocyclic com-
presence of Mn and Ca ions but with higher affinity for
mannose. Carbohydrate-functionalized nanoparticles and
3
4
[6a–e]
[6f–k]
[17]
pounds (cyclodextrins
and cucurbiturils
), dendrim-
[
7]
[8]
[9]
ers, polymers, and biomacromolecules (proteins and
vesicles have been used for protein recognition and sensing
[
2,5c,10]
[18]
DNA
) responsive to various external stimuli, such as
through the multivalent carbohydrate–protein interactions.
[
5e,6a,f–i,10b]
[6i,j,8a]
[8,9]
[5-
pH,
competitive binding,
redox,
light,
Herein, MSNs were functionalized with mannose ligands at
optimized surface densities, tight Con A nanogates were then
constructed using multivalent carbohydrate–protein interac-
tions to encapsulate the cargo within the pores, and the cargo
was released by introducing an acidic environment, such as is
found in tumor cells and inflammatory tissue. pH-controlled
drug delivery could be important for cancer therapy, while
e,6k,7,8a]
[2,6c,d,j,11]
and enzymes.
Despite the significant progress
that has been made, the direct use of biomolecules as
gatekeepers is still in its infancy. Based on the biotin–avidin
complex, the strongest noncovalent interaction found in
1
3
15
À1
nature, with a binding constant of 10 –10 Lmol , avidin-
gated MSN nanocontainers have been constructed for
protease- and temperature (908C)-responsive controlled
release through proteolytic digestion and protein denatura-
[19]
also reducing side effects. In addition, the drug could also
be released by competitive binding of glucose when the
normal blood-glucose concentration becomes elevated, which
would have potential applications for diabetes therapy.
Controlled release from Con A-gated MSN nanocontain-
ers is shown in Scheme 1. MCM-41-type MSNs with cylin-
drical channels were used as the nanocontainers. Mercapto-
terminated mannose derivatives were synthesized (Support-
ing Information, Scheme S1), reacted with alkenyl-termi-
nated silanes using a thiol–ene click reaction (Scheme S2),
and finally the external surfaces of MCM-41 were function-
alized with mannose epitopes. Subsequent capping with
Con A encapsulated the cargo within the pores through the
multivalent carbohydrate–protein interactions. Rhodam-
ine 6G (Rh6G) was selected as a model drug for convenient
detection of the release, because its fluorescence emission
[
12]
tion. Based on an antibody and hapten interaction, anti-
body-gated MSN nanocontainers have been used for com-
[13]
petitive-binding-driven controlled release.
Similarly, glu-
cose oxidase-gated MSN nanocontainers were also designed
[
14]
on the basis of an enzyme-inhibition mechanism, and the
release could be triggered by glucose at very low concen-
À4
À1
trations (3.3 ꢀ 10 mmolL ). Biomacromolecule-gated MSN
[*] S. Wu, X. Huang, Prof. Dr. X. Du
Key Laboratory of Mesoscopic Chemistry (Ministry of Education),
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210093 (China)
E-mail: xzdu@nju.edu.cn
2
+
2+
remains unchanged not only in the presence of Ca , Mn ,
and Con A but also with a change of pH from 7.4 to 1.5
[
**] This work was supported by the National Natural Science
Foundation of China (21273112) and the Natural Science Founda-
tion of Jiangsu Province (BK2012719).
2
+
(Figure S1). Con A is a metalloprotein and requires Ca and
2
+
a transition metal ion such as Mn to bind to carbohy-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300958.
[16]
drates. The carbohydrate-binding activity is abolished upon
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ents. The organosilica species underwent a gradual change
2
1
from T to T with the increase of the surface density of
1
3
29
mannose. Combination of the C and Si NMR spectra
confirmed that the mannose-terminated silanes were cova-
lently immobilized on the MCM-41 surfaces.
FTIR spectroscopy was further used to characterize the
functionaliztion of the MSN surface and protein capping
(Figure S7). The removal of surfactants was confirmed by the
disappearance of three strong bands at 2923, 2853, and
À1
1
478 cm , owing to the CH stretching and bending vibra-
2
tions of CTAB. With MS1-1, MS1-2, and MS1-3, the weak
À1
bands at 2955 and 2855 cm were observed from the CÀH
stretching vibrations, while corresponding CÀO stretching
bands could not be distinguished from the strong SiÀOÀSi
À1
stretching bands at 1230–1000 cm . Upon capping with
Con A (without Rh6G loading for clarity), strong amide I
À1
and amide II bands at 1648 and 1540 cm were observed, but
the amount of Con A was highest at the middle surface
density of mannose ligands (MS1-2). Further thermogravi-
metric analysis indicated that the maximum weight-loss
percentage between the MS1 and Con A-capped MS1 series
was observed for MS1-2 (Figure S8), which further demon-
strates that the amount of Con A on MS1-2 was the highest,
which is favorable for tight closure of the MSN pores. It is
known that specific mannose–Con A interactions are
achieved by the access of the carbohydrate ligands to protein
Scheme 1. Illustration of the controlled release of cargo from Con A-
gated mannose-functionalized MSN nanocontainers in response to
changes in pH value and glucose concentration.
removal of these metal ions by dialysis under acidic con-
ditions, on the other hand, Con A exists as a dimer and/or
monomer below pH 5.5. We would expect the protein nano-
gates to release their cargo either upon exposure to acidic
environments or by competitive binding of glucose.
MCM-41 materials were synthesized using the base-
catalyzed sol-gel method, and then the cetyltrimethylammo-
nium bromide (CTAB) templates were removed. From the
scanning electron microscope (SEM) and transmission elec-
tron microscope (TEM) images of MCM-41 (Figure S2),
MSNs were 110 Æ 10 nm in diameter and contained hexago-
nally arranged pores. Upon modification of mannose-termi-
nated silane with an oligo(ethylene glycol) (OEG) spacer S1,
the mannose-functionalized MSNs were referred to as MS1.
MS1-1, MS1-2, and MS1-3 represented MSNs functionalized
with S1 at different surface densities, which were determined
2
+
2+
binding pockets in the presence of Ca and Mn ions. Low
surface-ligand density limits multivalent protein binding,
whereas high surface density could result in steric crowding
of the neighboring ligands, which would be unfavorable to
multivalent protein binding. It has been shown that the
amount of specifically bound proteins is closely related to the
surface density and spatial arrangement of the carbohydrate
ligands and is determined by the balance between these two
[
16c,d]
factors.
The zeta potential values of MCM-41, MS1-2, and
Con A-capped MS1-2 were À51.9, À33.4, and À13.1 mV,
respectively (Figure S9a), and the hydrodynamic diameters of
the corresponding nanoparticles were 112 Æ 7, 128 Æ 10, and
219 Æ 15 nm, respectively (Figure S9b). These indicate that
the Con A-gated MS1-2 with the highest protein loading was
well-dispersed in aqueous solution without significant aggre-
gation, taking into account the easily hydrated OEG-linked
mannose ligands and the dimensions and isoelectric point of
Con A (Type V, pI = 4.7).
by thermogravimetric analysis to be 0.137, 0.284, and
À1
0
.410 mmolg SiO (Figure S3), respectively. However, the
2
SEM and TEM images of MS1 and the Con A-capped MS1
series (Figure S4) did not show significant differences from
those of MCM-41, probably owing to the relatively small
dimensions of S1 and Con A and the conditions under which
the microscopic images were taken.
The small-angle powder X-ray diffraction (XRD) patterns
of MCM-41 after CTAB removal exhibited three well-
[
22]
resolved reflections, indexed as (100), (110), and (200)
Solid-state NMR spectra of MS1-1, MS1-2, and MS1-3
clearly confirm the functionalization of the surface with
(Figure S10), which is typical of a hexagonal mesoporous
structure. MS1-1, MS1-2, and MS1-3 also showed similar
XRD patterns to MCM-41, which indicates that the function-
alized mannose epitopes (with different surface densities) did
not influence the mesoporous structure of the silica matrix.
1
3
mannose ligands. In the solid-state C NMR spectra (Fig-
ure S5), two weak signals at d = 31.24 ppm and 35.52 ppm
were ascribed to the resonances of the two carbon atoms
directly connected to the sulfur atom, which confirms the
success of the thiol–ene click reaction. In the solid-state
However, none of the three peaks was detectable after
À1
loading with Rh6G (loading of 0.183 mmolg SiO , as
2
2
9
Si NMR spectra (Figure S6), the two resonances at d =
À50.56 ppm and À56.51 ppm corresponded to the organo-
silica T and T species, assigned to [RSiOSi(OH) ] and
determined by fluorescence spectroscopy) and capping with
Con A, owing to an effect from the filled pores.
1
2
The nitrogen adsorption–desorption isotherms of MCM-
41 showed typical type IV curves with a surface area of
2
[
20,21]
[
RSi(OSi) OH],
respectively. These two peaks resulted
2
2
À1
from silicon atoms covalently bound to the organic substitu-
1093 m g and an average pore size of 2.9 nm (Figure S11
2
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and Table S1). MS1-1, MS1-2, and MS1-3 decreased in surface
area and pore size with an increase in surface density of
mannose ligands, because the surface area was considerably
reduced and the pore was filled upon loading of Rh6G and
subsequent capping with Con A (Figure S12).
Fluorescence spectroscopy was used to check for any
premature release of Rh6G from Con A-gated MS1 systems
in the buffer solution (pH 7.4) before the pH trigger was
added (Figure 1a). The fluorescence emission of the Con A-
gated MS1 systems remained low and almost unchanged after
two hours, which indicated that the cargo remained entrapped
in the pores. The Con A-gated MS1 systems showed a good
ment enhanced protein binding. The long and flexible OEG
spacers played an important role in adjusting the local spatial
arrangement of the ligands and allowed for better binding of
the ligands for multivalent carbohydrate–protein interactions,
in contrast to the short linkers used in other MSN-based
[
6f]
delivery systems.
Upon decreasing the pH of the buffer, the fluorescence
emission of the Con A-gated MS1-2 system significantly
increased (Figure 2), which indicates that the protein nano-
gates opened and the cargo was released from the MSN pores.
The efficiency of release significantly increased from pH 7.4
to 5.5, and additionally to pH 3.5 and 1.5. Under acidic
Figure 2. Release profiles of Rh6G from Con A-gated MS1-2 at different
pH values.
2
+
2+
conditions, Ca and Mn ions were dialyzed out of the
protein binding pockets, resulting in removal of the Con A
proteins from the MS1-2 surface, in addition, the Con A
tetramers disassociated into dimers and monomers below
pH 5.5. Both of these factors caused the protein nanogates to
open and release their cargo to different extents dependent
on the pH value. The amount of cargo released could be
controlled in small steps with the continued stepwise decrease
in pH value of the buffer (Figure S18). After the release of
cargo at pH 1.5, the delivery system showed the same FTIR
spectrum as MS1-2 confirming the disappearance of the
amide I and amide II bands of the proteins (Figure S7); the
SEM and TEM images were nearly identical to those of MS1-
2 without visible morphological changes or pore collapse
(Figure S19); the XRD reflection peaks reappeared but with
reduced intensities (Figure S10); the surface area returned to
Figure 1. Release profiles of Rh6G from Con A-gated mannose-func-
tionalized MSNs with different surface ligand densities in tris-HCl
buffer solutions (pH 7.4): a) MS1 series; b) MS2 series together with
MS1-2 for comparison. Drawings show retention of cargo (a) and slow
release of some cargo (b) from the MSN pores.
blocking effect with minimal premature release of the dye,
especially for the Con A-gated MS1-2. Similarly, MSNs were
functionalized with mannose-terminated silanes without an
2
À1
2
À1
OEG spacer (S2) at different surface densities (0.164, 0.286,
642 m g from 51 m g , and the pore diameter was restored
to the original size of 2.5 nm of MS1-2 (Figure S12 and
Table S1). All of these changes indicate that the protein
nanogates of the delivery system opened and the cargo was
released under acidic conditions, although there was a small
amount of dye retained in the pores.
À1
and 0.443 mmolg SiO ; Figure S13) and were accordingly
2
referred to as MS2-1, MS2-2, and MS2-3 (Figure 1b). The
FTIR spectra (Figure S14), small-angle XRD patterns (Fig-
ure S15), and nitrogen adsorption–desorption isotherms
under different conditions for MS2 were recorded (Fig-
ures S16,S17 and Table S2). The Rh6G-loaded, Con A-gated
MS2 systems showed slight leakage over time before the pH
trigger was added, in comparison with the Con A-gated MS1
systems. The carbohydrate ligands protruding from the
biocompatible silica surfaces with a suitable spatial arrange-
Glucose is capable of specifically binding Con A in the
2
+
2+
presence of Mn and Ca ions but with lower binding
affinity than mannose. In the presence of glucose, the
fluorescence emission of the Con A-gated MS1-2 system
gradually increased with increasing glucose concentration
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Keywords: carbohydrates · controlled release · drug delivery ·
.
molecular devices · proteins
[
[
[
1] I. I. Slowing, J. L. Vivero-Escoto, C.-W. Wu, V. S.-Y. Lin, Adv.
Drug Delivery Rev. 2008, 60, 1278 – 1288.
2] C. Chen, J. Geng, F. Pu, X. Yang, J. Ren, X. Qu, Angew. Chem.
2
011, 123, 912 – 916; Angew. Chem. Int. Ed. 2011, 50, 882 – 886.
3] a) Y. Liu, W. Zhang, T. Pinnavaia, Angew. Chem. 2001, 113,
295 – 1298; Angew. Chem. Int. Ed. 2001, 40, 1255 – 1258; b) Y.
Han, D. Li, L. Zhao, F. Xiao, Angew. Chem. 2003, 115, 3761 –
765; Angew. Chem. Int. Ed. 2003, 42, 3633 – 3637.
1
3
[
4] a) M. W. Ambrogio, C. R. Thomas, Y.-L. Zhao, J. I. Zink, J. F.
Stoddart, Acc. Chem. Res. 2011, 44, 903 – 913; b) P. Yang, S. Gai,
J. Lin, Chem. Soc. Rev. 2012, 41, 3679 – 3698; c) Y.-W. Yang, Med.
Chem. Commun. 2011, 2, 1033 – 1049.
[
5] a) C.-Y. Lai, B. G. Trewyn, D. M. Jeftinija, K. Jeftinija, S. Xu, S.
Jeftinija, V. S.-Y. Lin, J. Am. Chem. Soc. 2003, 125, 4451 – 4459;
b) S. Giri, B. G. Trewyn, M. P. Stellmaker, V. S.-Y. Lin, Angew.
Chem. 2005, 117, 5166 – 5172; Angew. Chem. Int. Ed. 2005, 44,
Figure 3. Release profiles of Rh6G from Con A-gated MS1-2 in the
presence of different concentrations of glucose in tris-HCl buffer
solution (pH 7.4).
5038 – 5044; c) F. Torney, B. G. Trewyn, V. S.-Y. Lin, K. Wang,
Nat. Nanotechnol. 2007, 2, 295 – 300; d) J. L. Vivero-Escoto, I. I.
Slowing, C.-W. Wu, V. S.-Y. Lin, J. Am. Chem. Soc. 2009, 131,
because of competitive binding of glucose to the proteins
which drove the removal of proteins and the controlled
release of cargo (Figure 3). The normal concentration ranges
3462 – 3463; e) E. Aznar, M. D. Marcos, R. Martꢁnez-MꢂÇez, F.
Sancenꢃn, J. Soto, R. Casasffls, P. Amorꢃs, C. Guillem, J. Am.
Chem. Soc. 2009, 131, 6833 – 6843; f) R. Liu, Y. Zhang, X. Zhao,
A. Agarwal, L. J. Mueller, P. Feng, J. Am. Chem. Soc. 2010, 132,
1500 – 1501; g) F. Muhammad, M. Guo, W. Qi, F. Sun, A. Wang,
Y. Guo, G. Zhou, J. Am. Chem. Soc. 2011, 133, 8778 – 8781.
6] a) C. Park, K. Oh, S. C. Lee, C. Kim, Angew. Chem. 2007, 119,
À1
of glucose are 4–7 mmolL before a meal and less than
À1
1
0 mmolL about 1.5 hours after a meal. Thus, glucose in the
normal range could not trigger a significant release of cargo
because glucose is a weak competitor in comparison with
mannose, and it is difficult for glucose at low concentrations
to disrupt the multivalent mannose–Con A interactions. On
the other hand, high concentrations of glucose could give rise
to a slow release of cargo from the MSN pores, and the
amount of cargo released would increase with time for
application in a sustained release system. The mechanism of
controlled release by competitive binding is different from
that of the pH-responsive release. It is clear that the Con A-
gated MS1 systems have promise for applications in site-
specific drug release, relevant to tumors and diabetes.
In summary, Con A-gated mannose-functionalized MSN
delivery systems were constructed for the controlled release
of drugs. The Con A tetramers specifically bound the
functionalized mannose epitopes through multivalent carbo-
hydrate–protein interactions to encapsulate cargo within the
MSN pores. The long and flexible spacers linked with the
mannose ligands played an important role in adjusting the
local spatial arrangement of the ligands to favor multivalent
protein binding, as did the surface density of the ligands. The
optimized protein-gated delivery systems showed minimal
premature release of cargo. The protein nanogates could be
opened either by decreasing the pH value of the buffer or by
competitive binding of glucose at high concentrations,
releasing the cargo from the MSN pores on demand. These
Con A-gated MSN delivery systems are promising for in vivo
applications of site-specific drug release for the treatment of
tumors and diabetes.
[
1477 – 1479; Angew. Chem. Int. Ed. 2007, 46, 1455 – 1457; b) C.
Park, K. Lee, C. Kim, Angew. Chem. 2009, 121, 1301 – 1304;
Angew. Chem. Int. Ed. 2009, 48, 1275 – 1278; c) C. Park, H. Kim,
S. Kim, C. Kim, J. Am. Chem. Soc. 2009, 131, 16614 – 16615; d) K.
Patel, S. Angelos, W. R. Dichtel, A. Coskun, Y.-W. Yang, J. I.
Zink, J. F. Stoddart, J. Am. Chem. Soc. 2008, 130, 2382 – 2383;
e) D. P. Ferris, Y.-L. Zhao, N. M. Khashab, H. A. Khatib, J. F.
Stoddart, J. I. Zink, J. Am. Chem. Soc. 2009, 131, 1686 – 1688;
f) S. Angelos, Y. Yang, K. Patel, J. F. Stoddart, J. I. Zink, Angew.
Chem. 2008, 120, 2254 – 2258; Angew. Chem. Int. Ed. 2008, 47,
2222 – 2226; g) S. Angelos, N. M. Khashab, Y. Yang, A. Trabolsi,
H. A. Khatib, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2009,
131, 12912 – 12914; h) S. Angelos, Y. Yang, N. M. Khashab, J. F.
Stoddart, J. I. Zink, J. Am. Chem. Soc. 2009, 131, 11344 – 11346;
i) J. Liu, X. Du, J. Mater. Chem. 2010, 20, 3642 – 3649; j) J. Liu, X.
Du, X. Zhang, Chem. Eur. J. 2011, 17, 810 – 815; k) Y.-L. Sun, B.-
J. Yang, S. X.-A. Zhang, Y.-W. Yang, Chem. Eur. J. 2012, 18,
9212 – 9216.
[
[
[
7] E. Aznar, R. Casasffls, B. Garcꢁa-Acosta, M. D. Marcos, R.
Martꢁnez-MꢂÇez, F. Sancenꢃn, J. Soto, P. Amorꢃs, Adv. Mater.
2007, 19, 2228 – 2231.
8] a) R. Liu, Y. Zhang, P.-Y. Feng, J. Am. Chem. Soc. 2009, 131,
15128 – 15129; b) R. Liu, X. Zhao, T. Wu, P. Feng, J. Am. Chem.
Soc. 2008, 130, 14418 – 14419.
9] a) Y. Zhao, B. G. Trewyn, I. I. Slowing, V. S.-Y. Lin, J. Am. Chem.
Soc. 2009, 131, 8398 – 8400; b) Z. Luo, K. Cai, Y. Hu, L. Zhao, P.
Liu, L. Duan, W. Yang, Angew. Chem. 2011, 123, 666 – 669;
Angew. Chem. Int. Ed. 2011, 50, 640 – 643.
[10] a) E. Climent, R. Martꢁnez-MꢂÇez, F. Sancenꢃn, M. D. Marcos, J.
Soto, A. Maquieira, P. Amorꢃs, Angew. Chem. 2010, 122, 7439 –
7
441; Angew. Chem. Int. Ed. 2010, 49, 7281 – 7283; b) C. Chen, F.
Pu, Z. Huang, Z. Liu, J. Ren, X. Qu, Nucleic Acids Res. 2011, 39,
638 – 1644.
1
[
11] A. Popat, B. P. Ross, J. Liu, S. Jambhrunkar, F. Kleitz, S. Z. Qiao,
Angew. Chem. 2012, 124, 12654 – 12657; Angew. Chem. Int. Ed.
2012, 51, 12486 – 12489.
Received: February 3, 2013
Published online: && &&, &&&&
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Angewandte
Chemie
[
12] A. Schlossbauer, J. Kecht, T. Bein, Angew. Chem. 2009, 121,
138 – 3141; Angew. Chem. Int. Ed. 2009, 48, 3092 – 3095.
[18] a) E. Mahon, T. Aastrup, M. Barboiu, Chem. Commun. 2010, 46,
3
2441 – 2443; b) J.-F. Nierengarten, J. Iehl, V. Oerthel, M. Holler,
B. M. Illescas, A. MuÇoz, N. Martꢁn, J. Rojo, M. Sꢂnchez-
Navarro, S. Cecioni, S. Vidal, K. Buffet, M. Durka, S. P. Vincent,
Chem. Commun. 2010, 46, 3860 – 3862; c) X. Wang, O. Ram-
strçm, M. Yan, Anal. Chem. 2010, 82, 9082 – 9089; d) O. Norberg,
I. H. Lee, T. Aastrup, M. Yan, O. Ramstrçm, Biosens. Bioelec-
tron. 2012, 34, 51 – 56.
[
13] E. Climent, A. Bernardos, R. Martꢁnez-MꢂÇez, A. Maquieira,
M. D. Marcos, N. Pastor-Navarro, R. Puchades, F. Sancenꢃn, J.
Soto, P. Amorꢃs, J. Am. Chem. Soc. 2009, 131, 14075 – 14080.
14] M. Chen, C. Huang, C. He, W. Zhu, Y. Xu, Y. Lu, Chem.
Commun. 2012, 48, 9522 – 9524.
15] C. R. Bertozzi, L. L. Kiessling, Science 2001, 291, 2357 – 2364.
16] a) E. A. Smith, W. D. Thomas, L. L. Kiessling, R. M. Corn, J.
Am. Chem. Soc. 2003, 125, 6140 – 6148; b) P.-H. Liang, S.-K.
Wang, C.-H. Wong, J. Am. Chem. Soc. 2007, 129, 11177 – 11184;
c) H. Zheng, X. Du, J. Phys. Chem. B 2009, 113, 11330 – 11337;
d) H. Zheng, X. Du, Biochim. Biophys. Acta 2013, 1828, 792 –
[
[
[
[19] J. Zhu, L. Liao, X. Bian, J. Kong, P. Yang, B. Liu, Small 2012, 8,
2715 – 2720.
[20] a) M. Jia, A. Seifert, W. R. Thiel, Chem. Mater. 2003, 15, 2174 –
2180; b) M. Jia, A. Seifert, M. Berger, H. Giegengack, S. Schulze,
W. R. Thiel, Chem. Mater. 2004, 16, 877 – 882.
8
00.
17] a) K. D. Hardman, C. F. Ainsworth, Biochemistry 1972, 11,
910 – 4949; b) J. W. Becker, G. N. Reeke, Jr., B. A. Cunning-
[21] a) D. W. Sindorf, G. E. Maciel, J. Am. Chem. Soc. 1983, 105,
3767 – 3776; b) E. Lindner, T. Schneller, F. Auer, H. A. Mayer,
Angew. Chem. 1999, 111, 2288 – 2309; Angew. Chem. Int. Ed.
1999, 38, 2154 – 2174.
[22] C. T. Kresge, M. E. Leonowicz, W. J. Roth, J. C. Vartuli, J. S.
Beck, Nature 1992, 359, 710 – 712.
[
4
ham, G. M. Edelman, Nature 1976, 259, 406 – 409; c) G. M.
Edelman, B. A. Cunningham, G. N. Reeke, Jr., J. W. Becker,
M. J. Waxdal, J. L. Wang, Proc. Natl. Acad. Sci. USA 1972, 69,
2580 – 2584.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
Drug Delivery
S. Wu, X. Huang, X. Du*
&&&& — &&&&
Glucose- and pH-Responsive Controlled
Release of Cargo from Protein-Gated
Carbohydrate-Functionalized
Mesoporous Silica Nanocontainers
Learning to let go: Controlled release of
cargo (purple cubes) from lectin (blue
squares)-gated nanopores was achieved
using mannose (green loops)-functional-
ized mesoporous silica (see scheme).
The protein nanogates could be opened
either by decreasing the pH of the buffer
or by adding competing glucose (yellow
rings) to release the cargo from the pores.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!