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A Journal of
Accepted Article
Title: Mesoporous Silica Nanocarriers with Cyclic Peptide Gatekeeper:
Specific Targeting of Aminopeptidase N and Triggered Drug
Release by Stimuli-Responsive Conformational Transformation
Authors: Jeonghun Lee, Eun-Taex Oh, Yeji Han, Ha Gyeong Kim,
Heon Joo Park, and Chulhee Kim
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201704309
Link to VoR: http://dx.doi.org/10.1002/chem.201704309
Supported by
10.1002/chem.201704309
Chemistry - A European Journal
COMMUNICATION
Mesoporous Silica Nanocarriers with Cyclic Peptide Gatekeeper:
Specific Targeting of Aminopeptidase N and Triggered Drug
Release by Stimuli-Responsive Conformational Transformation
Abstract: Utilizing stimuli-responsive conformational transformation
of a cyclic peptide as a gatekeeper for mesoporous nanocarriers has
several advantages such as facile introduction of targeting
capabilities, low enzymatic degradation during blood circulation and
enhanced specific binding to selected cells. In this report, a NGRcontaining dual functional cyclic peptide gatekeeper on the surface
of mesoporous nanocarrier is prepared not only for active targeting
of the aminopeptidase N (APN) expressed on cancer cells but also
stimuli-responsive intracellular drug release triggered by a GSHinduced conformational transformation of the peptide gatekeeper.
The peptide gatekeeper on the surface of nanocarriers exhibits onoff gatekeeping via conformational transformation triggered by
intracellular glutathione of the cancer cells. H1299 cells (high APN
expression) showed greater uptake of the nanocarrier by
endocytosis and higher apoptosis than A549 cells (low APN
expression).
Reducing the side effects of anticancer chemotherapy can
increase its therapeutic efficacy.[1] Among many approaches in
such reduction, use of smart delivery carriers containing
anticancer drug is of great interest due to its fascinating
approach such as targeted delivery and on-site drug release.[1-3]
Many delivery carriers have been investigated, including
liposomes, polymer micelles, dendrimers, proteins, and
inorganic nanoparticles.[1, 4-7] In particular, mesoporous silica
nanocarriers (MSNs) have attracted considerable attention
because of their benefits, which include ease of surface
modification, chemical stability, adjustable size, low cytotoxicity
and high surface area and pore volume for drug loading.[8-14]
Moreover, MSNs with gatekeepers such as cyclodextrins,
cucurbiturils, polymers, dendrimers, inorganic nanoparticles and
peptides could achieve the zero release characteristics during
blood circulation, thereby reducing undesirable side effects at
off-target sites.[15-16] Furthermore, proper design of the
[a]
[b]
[c]
[+]
Dr. J. Lee, Y. Han, Prof. Dr. C. Kim
Department of Polymer Science and Engineering
Inha University
Yonghyun-dong, Nam-gu, Incheon 22212, Korea
E-mail: chk@inha.ac.kr
Dr. E.-T. Oh
Department of Biomedical Sciences, School of Medicine
Inha University
Yonghyun-dong, Nam-gu, Incheon 22212, Korea
H. G. Kim, Prof. Dr. H. J. Park
Department of Microbiology, Hypoxia-related Disease Research
Center, College of Medicine
Inha University
Yonghyun-dong, Nam-gu, Incheon 22212, Korea
E-mail: park001@inha.ac.kr
These Authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
gatekeeper structure enables the release of drugs entrapped in
the mesopores of MSNs in response to stimuli such as pH, light,
enzymes and redox potential.[11, 17-28] Notably, using peptides as
gatekeepers of MSNs has several advantages, including high
biocompatibility, specific active targeting of the desired cells,
enhanced endosomal escape and/or the use of enzymatic
degradation as a specific stimulus for the triggered release of
entrapped drugs. [11, 24-27, 29]
Recently, we developed a cyclic peptide gatekeeper with the
capability of triggered drug release by stimuli-responsive
conformational conversion.[26-27, 30] Based on the difference of the
gatekeeping capability of the peptide with a turn and a random
conformation on the surface of MSNs, we developed a stimuliresponsive peptide gatekeeper with an intramolecular disulfide
bond that caused the peptide with a random structure to take on
a turn structure.[26] MSNs with this peptide gatekeeper (FmocCGGC-SS-Si) retained drug molecules in their mesopores. Upon
addition of glutathione (GSH), a biological reductase
upregulated in various cancer cells,[31-33] the intramolecular
disulfide bond of the peptide gatekeeper was reduced, resulting
in the conformational conversion of the peptide from a turn to a
random structure and releasing the entrapped guests. Then, we
reported the MSN (PEG-WCGKC-SS-Si) with optimized
sequence of the peptide gatekeeper for enhanced
biocompatibility.[27] In response to intracellular GSH-induced
conformational transformation, PEG-WCGKC-SS-Si selectively
released entrapped drugs in A549 human lung cancer cells
(which express high GSH level) in a controlled manner but not in
CCD normal lung cells (which express low GSH level).
Utilizing stimuli-responsive conformational transformation of
a cyclic peptide as a gatekeeper for MSNs has several
advantages. First, targeting capabilities could be easily
introduced into an on-off cyclic gatekeeper by inserting
appropriate peptide sequences, such as RGD or NGR, between
the two cysteine units. These sequences can act as ligands that
selectively target certain cells that contain receptors that bind
these ligands maintaining the capability of stimuli-responsive
intracellular drug release. Second, because many enzymes
have a lower ability to degrade cyclic than linear peptides,
nanocarriers with cyclic peptide gatekeepers can circulate for
longer periods in the blood, while retaining their targeting
capability.[34-35] Third, in several cases such as RGD and NGR,
cyclic structure of the peptide targeting ligand enhances the
specific binding to selected cells via their specific receptors than
linear one.[34, 36-38]
Therefore, as a proof of concept, we here demonstrate the
dual function of MSN (PEG-WKCNGRC-SS-Si) with the NGR
between the two cysteine units of the cyclic peptide gatekeeper
not only for active targeting of the cancer cells but also stimuliresponsive intracellular drug release triggered by the GSH-
This article is protected by copyright. All rights reserved.
Accepted Manuscript
Jeonghun Lee+,[a] Eun-Taex Oh+,[b] Yeji Han,[a] Ha Gyeong Kim,[c] Heon Joo Park,*[c]
and Chulhee Kim*[a]
10.1002/chem.201704309
Chemistry - A European Journal
induced conformational transformation of the peptide gatekeeper,
as shown in Figure 1. The NGR peptide can specifically bind to
the aminopeptidase N (APN, also known as CD13), a receptor
overexpressed in tumour endothelial cells and in various tumour
cell lines.[37-40] Cyclic NGR has shown stronger affinity and
higher specificity towards APN receptors than linear NGR.[37-38]
Furthermore, cyclic peptides generally exhibit greater resistance
to enzymatic degradation than linear peptides,[34-35] Therefore,
the introduction of the cyclic CNGRC peptide as a gatekeeper
onto the surface of mesoporous nanocarriers would result in an
effective drug carrier with greater targeting capacity and
therapeutic efficacy via increased intratumoral uptake.[34-36, 41]
reaction, generating DOX-loaded MSNs with a peptide
gatekeeper (WKCNGRC-SS-Si). The peptide with azide
functionality (WKCNGRC-N3) was prepared by a solid-phase
peptide synthesis method using Fmoc-chemistry (see Figure S3
and the experimental section for details). The intramolecular
disulfide bond was introduced by oxygen bubbling into a solution
of WKCNGRC-N3 in acetonitrile/water (50:50 v/v), forming the
cyclic peptide (WKCNGRC-SS-N3). The presence of the peptide
gatekeeper on the surface of MSNs (WKCNGRC-SS-Si) was
confirmed by FT-IR (amide II near 1554 cm−1), as shown in
Figure S2. Based on the 5,5’-dithio-bis-(2-nitrobenzoic acid)
(DTNB) titration of thiol units after reduction of the disulfide bond
on the surface of WKCNGRC-SS-Si using GSH, the weight
percentage of the peptide units on the surface of MSN was 1.8
wt%.
Figure 2. Release profiles of DOX from WKCNGRC-SS-Si (a) and CNGRCSS-Si (b) in PBS buffer (pH = 7.4, 30 mM). The final concentration of GSH
was 0.1 mM and the concentration of the nanocarrier was 0.1 mg/mL.
Figure 1. Schematic representation of the MSNs with peptide gatekeepers for
targeting APN and drug release in response to GSH-induced conformational
transformation. Conditions: i) 3-aminopropyltriethoxysilane; ii) propargyl
bromide; iii) surfactant removal, DOX loading, WKCNGRC-SS-N3, sodium
ascorbate, copper (II) sulfate; iv) PEG-NCO.
To investigate the gatekeeping characteristics and targeting
capacity of the MSN (PEG-WKCNGRC-SS-Si) with this peptide
gatekeeper, we prepared MCM-41-type MSNs with a diameter of
80 nm and hexagonally ordered pores as described
previously.[26-27] The Barrett-Joyner-Halenda (BJH) pore size
distribution analysis (Figure S1) showed that the average
diameter of the mesopore was 2.5 nm. Next, we modified the
surface of MSNs with 3-aminopropyltriethoxysilane by a sol–gel
reaction to introduce amino groups (Si-NH2), which was
confirmed by Fourier transform infrared (FT-IR) spectroscopy
(N–H bend absorption at 1490 cm−1, as shown in Figure S2) and
a positive zeta potential (+11.54 mV). Then, alkyne groups were
introduced onto the surface of MSNs (Si-alkyne) by reacting the
Si-NH2 with propargyl bromide. The introduction of the alkyne
group was confirmed by FT-IR (alkyne stretching band at 2133
Figure
S2).
After
removing
the
surfactant,
cm−1,
cetyltrimethylammonium bromide, from the mesopores of Sialkyne using ammonium nitrate in ethanol, we loaded the guest
anticancer drug (doxorubicin, DOX) by immersing the
nanoparticles in a DMF solution of DOX. Finally, the cyclic
peptide with an azide group at its C-terminal (WKCNGRC-SSN3) was conjugated onto the surface of Si-alkyne by a click
The gatekeeping abilities of the peptide gatekeepers with
linear (WKCNGRC) and cyclic (WKCNGRC-SS) structures were
investigated by monitoring the change in the photoluminescence
(PL) intensity of DOX entrapped in the mesopores of MSNs in
phosphate-buffered saline (PBS, pH 7.4). In the absence of any
stimulus, DOX in WKCNGRC-SS-Si was retained within the
mesopores of MSNs for more than 700 min (Figure 2a). Upon
the addition of GSH, a reducing agent expressed at high levels
in various cancer cells, the DOX entrapped in WKCNGRC-SS-Si
was released over time. These results indicate that GSH
triggered the structural transformation of the peptide gatekeeper,
from a cyclic structure (WKCNGRC-SS) with gatekeeping ability
to a linear structure (WKCNGRC) lacking gatekeeping ability.
Therefore, the peptide gatekeeper (WKCNGRC-SS) could be
utilized as a stimuli-responsive gatekeeper on the surface of
MSNs. To investigate the effect of the tryptophan moiety at the
end of the peptide gatekeeper, the CNGRC-SS-N3 peptide was
synthesized and MSNs with the peptide (CNGRC-SS-Si) were
prepared as described in the experimental section of the
Supporting Information. The entrapped DOX in CNGRC-SS-Si
was released in the absence of any external stimulus (Figure 2b).
This result indicates that the cyclic CNGRC sequence itself does
not have gatekeeping ability, and that the tryptophan unit of
WKCNGRC-SS-Si is important, along with the conformational
transformation, for on-off gatekeeping. Because the terminal
tryptophan unit has a bulky indole ring, the steric hindrance
induced by tryptophan units would interfere the transport of the
drug molecules from the mesopore to the aqueous media.
This article is protected by copyright. All rights reserved.
Accepted Manuscript
COMMUNICATION
10.1002/chem.201704309
Chemistry - A European Journal
COMMUNICATION
results demonstrate that the NGR sequence on the surface of
MSNs increased the cellular uptake of MSNs by targeting high
levels of cell surface APN in cancer cells.
Figure 4. APN-mediated cellular uptake of silica nanoparticles (PEGWKCNGRC-SS-Si) and intracellular release of DOX from MSNs in APNexpressing cancer cells. CLSM images were taken showing the time course of
DOX fluorescence intensity in H1299 and A549 cells treated with PEGWKCNGRC-SS-Si for 12 hr.
Figure 3. a) TEM images of PEG-WKCNGRC-SS-Si. b) Release profile of
DOX from PEG-WKCNGRC-SS-Si in PBS buffer. The final concentration of
GSH was 0.1 mM and the concentration of the nanocarrier was 0.1 mg/mL.
H1299 and A549 cells have been shown to express high and
low levels of APN, respectively.[42] Similarly, we found that APN
was overexpressed in H1299, but not in A549 cells (Figure S6).
We therefore investigated APN-mediated cellular uptake by
PEG-WKCNGRC-SS-Si and intracellular GSH-induced release
of DOX from PEG-WKCNGRC-SS-Si in H1299 and A549 cells.
The nucleus is the primary site of cytotoxic action of DOX, where
it intercalates into DNA, forming DNA adducts and inhibiting
topoisomerase II.[43] Therefore, the release of DOX from PEGWKCNGRC-SS-Si in the cells was determined by confocal laser
scanning microscopy (CLSM). CLSM images showed that the
fluorescence intensity of DOX increased in H1299 and A549
cells incubated for 12 h with PEG-WKCNGRC-SS-Si loaded with
3 μM DOX (Figure 4). Marked accumulation of DOX was
observed in the nuclei of H1299, but not of A549 cells. To
confirm the intracellular release of DOX from PEG-WKCNGRCSS-Si and the accumulation of DOX in the nuclei, the nucleic
acids of these cells were stained with DAPI (4’,6’-diamidino-2phenyl-indole). DOX and DAPI fluorescence overlapped in
H1299 cells, but not in A549 cells (Figure 5). Collectively, these
Next, we investigated the ability of PEG-WKCNGRC-SS-Si
to kill target cancer cells expressing high levels of surface APN.
Treatment of both H1299 and A549 cells with free DOX for 4 hr
decreased their clonogenic survival (Figure 6). Incubation with
PEG-WKCNGRC-SS-Si loaded with 3 μM DOX for 4 hr reduced
the surviving fractions of H1299 and A549 cells to 1.9 × 10-4 and
4.7 × 10-3, respectively (Figure 6). To confirm these results, we
investigated the ability of PEG-WKCNGRC-SS-Si loaded with 3
μM DOX to induce apoptosis using TUNEL (terminal
deoxytransferase-mediated dUTP-biotin nick-end labeling)
assays. PEG-WKCNGRC-SS-Si loaded with 3 μM DOX induced
significant apoptosis in H1299 cells, whereas it induced
negligible apoptosis in A549 cells (Figures 7 and 8). In these
results, PEG-WKCNGRC-SS-Si loaded with 3 μM DOX showed
significant clonogenic cell death (Figure 6) and acute cell death
(Figure 7 and 8) in HT1299 cells expressing high APN. In A549
cells expressing low APN, it showed significant clonogenic cell
death compared to the control (Figure 6). However, it showed
negligible acute apoptosis in TUNEL assay. A previous report
demonstrated that clonogenic survival assay is a realistic model
to determine the effect of drugs on proliferating cancer cells.[44]
This assay is time-consuming to set up and analyse.[44] Another
report described that a high concentration (~μM) of doxorubicin
causes an apoptotic cancer cell death after 1 day of doxorubicin
This article is protected by copyright. All rights reserved.
Accepted Manuscript
To investigate the in vitro stimuli-responsive drug-release
and targeting properties of the nanocarrier, we enhanced its
biocompatibility and dispersion stability by modifying the amine
group of DOX-loaded WKCNGRC-SS-Si using monomethoxy
poly(ethylene glycol) isocyanate (PEG-NCO; MW 2000) (see
experimental section for details). After PEGylation, the zeta
potential value was changed from +17.05 to -22.54 mV, and the
hydrodynamic radius was changed from 235 nm to 107 nm as
shown in Figure S4. TEM images showed that the mesoporous
nature and diameter of PEG-WKCNGRC-SS-Si were preserved
during surface modification (Figure 3a and Figure S5). In
addition, gatekeeping ability was maintained after PEGylation
(Figure 3b). In the absence of an external stimulus, DOX in
PEG-WKCNGRC-SS-Si was not released over 700 min in PBS
buffer. Upon addition of GSH, DOX in the pores was released
due to structural transformation of the peptide from a cyclic to a
linear conformation. These results indicate that the stimuliresponsive gatekeeping capacity of WKCNGRC-SS was
maintained even after functionalization of the peptide
gatekeeper with PEG. Based on the total released amounts of
DOX for the MSN, the loading percent of DOX in PEGWKCNGRC-SS-Si was 2.5 wt%.
10.1002/chem.201704309
Chemistry - A European Journal
COMMUNICATION
Figure 6. Clonogenic survival of H1299 and A549 cells treated for 4 hr with 3
μM DOX or PEG-WKCNGRC-SS-Si alone or loaded with 3 μM DOX. The cells
were subsequently washed three times with PBS and cultured for an additional
14 days, and the proportions of surviving cells were calculated. *P < 0.05.
Figure 5. APN-mediated cellular uptake of PEG-WKCNGRC-SS-Si and
intracellular release of DOX from MSNs in APN-expressing cancer cells.
H1299 and A549 cells were treated with PEG-WKCNGRC-SS-Si for 4 hr, were
fixed with 4% PFA, washed three times with PBS, and stained with DAPI. The
fluorescence intensities of DOX and DAPI-stained nuclei were examined using
a TE2000E laser-scanning confocal microscope.
Figure 7. Representative photomicrographs of apoptotic cells (i.e., TUNELpositive cells). H1299 and A549 cells were treated with 3 μM DOX or PEGWKCNGRC-SS-Si, alone or loaded with 3 μM DOX, for 12 hr. TUNEL-positive
cells were detected by confocal microscopy.
This article is protected by copyright. All rights reserved.
Accepted Manuscript
treatment, while a low concentration (~nM) of doxorubicin
causes a senescence like cancer cell death after 6 days of
doxorubicin treatment.[45] Therefore, little intracellular uptake of
PEG-WKCNGRC-SS-Si loaded with 3 μM DOX by endocytosis
caused significant clonogenic cell death in A549 cells expressing
low APN in clonogenic survival assay (Figure 6), while it did not
cause acute DNA damage in TUNEL assay (Figure 7 and 8).
These results indicate that the APN-targeting ligand of the
peptide gatekeeper plays a central role in the cellular uptake of
MSNs in cancer cells expressing high surface levels of APN and
their resultant DOX-induced cell death.
10.1002/chem.201704309
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In conclusion, we prepared a dual functional MSN (PEGWKCNGRC-SS-Si) with a cyclic peptide gatekeeper containing
the NGR sequence not only for active targeting of the APN
expressed on cancer cells but also stimuli-responsive
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C. K. thanks the National Research Foundation of Korea (NRF)
(NRF-2015M2B2B1068625 and NRF-2016R1D1A1B03930953)
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Keywords: peptides • gatekeepers • conformational
transformation • stimuli-responsiveness • mesoporous silica
nanocarriers
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This article is protected by copyright. All rights reserved.
Accepted Manuscript
Figure 8. Ratio of TUNEL-positive to DAPI-stained H1299 and A549 cells
treated with 3 μM DOX or PEG-WKCNGRC-SS-Si, alone or loaded with 3 μM
DOX, for 12 hr. Data are expressed as the mean ± standard deviation of three
independent experiments. Columns represent the compiled data derived from
five independent experiments. ****P < 0.0001
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Chemistry - A European Journal
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Accepted Manuscript
[38]
R. Pasqualini, E. Koivunen, R. Kain, J. Lahdenranta, M. Sakamoto, A. Stryhn,
This article is protected by copyright. All rights reserved.
10.1002/chem.201704309
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
J. Lee, E.-T. Oh, Y. Han, H. G. Kim, H.
J. Park*, C. Kim*
Page No. – Page No.
Mesoporous Silica Nanocarriers with
Cyclic Peptide Gatekeeper: Specific
Targeting of Aminopeptidase N and
Triggered Drug Release by StimuliResponsive Conformational
Transformation
This article is protected by copyright. All rights reserved.
Accepted Manuscript
A NGR-containing dual functional
cyclic peptide gatekeeper on the
surface of mesoporous nanocarrier is
prepared not only for active targeting
of the aminopeptidase N expressed
on cancer cells but also stimuliresponsive intracellular drug release
triggered by a glutathione-induced
conformational transformation of the
peptide gatekeeper.
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